heredity Encyclopædia Britannica Article

sum of all biological processes by which particular characteristics are transmitted from parents to their offspring. Among organisms that reproduce sexually, progeny are not exact duplicates of their parents but usually vary in many traits. and variation, two sides of the same coin, are the subject matter of the science of . Genetics may be defined as the study of the way in which genes—the functional units of heritable material—operate and are transmitted from parents to offspring. Modern genetics also involves study of the mechanism of gene action; that is, the way in which the genetic material affects physiological reactions within the cell.

In many languages the same words are used for both the inheritance of biological traits and the inheritance of property. Biological and legal inheritances are, however, very different processes. Inherited objects are actually transferred from one owner to another. Inherited traits are not. Offspring inherit a genetic constitution from their parents. This hereditary endowment, the sum total of the genes that the individual has received from both parents, is called the genotype. The genotype must be contrasted to the phenotype, which is the organism's outward appearance: its bodily structures, physiological processes, behaviour, etc. Although the genotype determines the broad limits of the features an organism may develop, the features that actually develop—i.e., the phenotype—depend upon complex interactions between genes and their environment. Since the environment, both internal and external, of an individual changes continuously, so does the phenotype. Thus the same individual shows different phenotypes in childhood, in adulthood, and in old age. The genotype, on the other hand, does not change during an individual's lifetime. In conducting genetic studies it is crucial to discover the degree to which the observable trait (the phenotype) is attributable to the pattern of genes in the cells (the genotype) and to what extent it arises from environmental influence.

The essence of heredity is the of the carriers of genetic information, the genes. As a result, biological organisms, including human beings, reproduce organisms resembling themselves; human children are always recognizably human and have phenotypes similar to those of their parents. On the other hand, since the offspring of sexually reproducing organisms receive varying combinations of genetic material from both parents, no two offspring (except for identical twins) have exactly the same genotype. This genetic diversity is always modified by an equally diverse environment, so the resulting phenotype is never exactly the same, even among identical twins.

Genetics is often called the core science of biology. This does not necessarily mean that genetics is the most fundamental among the biological disciplines. It implies only that genetics impinges upon almost every kind of study of life. Anthropology, medicine, biochemistry, physiology, psychology, ecology, systematics, comparative morphology, and paleontology all have intersections with genetics. Like so many basic, or “theoretical,” sciences, genetics has many actual and potential practical applications. The understanding and control of hereditary disorders and the breeding of improved crops and livestock are just two such applications.

Knowledge of heredity dates to prehistoric times and has been applied to the breeding of plants and animals for centuries. Most of the mechanisms of heredity, however, remained a mystery until the 20th century. The pioneering work in elucidating the mechanisms of gene action took place even more recently, and the science of genetics is considered as yet in its infancy. This article examines the discoveries that led to an understanding of heredity and discusses in detail the structure and function of the gene and mutation and other processes by which genetic information is altered.

Basic features of heredity

Early conceptions of heredity

Heredity was for a long time one of the most puzzling and mysterious phenomena of nature. This was so because the sex cells, which form the bridge across which heredity must pass between the generations, are usually invisible to the naked eye. Only after the invention of microscopes early in the 17th century, and the discovery of the sex cells, could the essentials of heredity be grasped. Before that time, (4th century BC) speculated that the relative contributions of the female and the male parents were very unequal—the female was thought to supply what he called the “matter” and the male the “motion.” The Institutes of Manu, composed in India between AD 100 and 300, consider the role of the female like that of the field and of the male like that of the seed; new bodies are formed “by the united operation of the seed and the field.” In reality both parents transmit the heredity pattern equally, and, on the average, children resemble their mothers as much as they do their fathers. Nevertheless, the female and male sex cells may be very different in size and in structure; the mass of an is sometimes millions of times greater than that of a .

The ancient Babylonians knew that pollen from a male date palm tree must be applied to the pistils of a female tree to produce fruits. Rudolph Jacob Camerarius showed in 1694 that the same is true in corn (maize). Carolus Linnaeus in 1760 and Josef Gottlieb Kölreuter, in a series of works published from 1761 to 1798, described crosses of varieties and species of plants. They found that these hybrids were on the whole intermediate between the parents, although in some characteristics they may be closer to one and in others closer to the other parent. Kölreuter compared the offspring of reciprocal crosses—i.e., of crosses of variety A functioning as a female to variety B as a male and the reverse, variety B as a female to A as a male. The hybrid progenies of these reciprocal crosses were usually alike, indicating that, contrary to the belief of Aristotle, the hereditary endowment of the progeny was derived equally from the female and the male parents. Many experiments on plant hybrids were made in the 1800s. These investigations revealed that hybrids were usually intermediate between the parents. They more or less incidentally recorded most of the facts that later led (see below) to formulate his celebrated rules and to found the theory of the gene. Apparently, none of Mendel's predecessors saw the significance of the data that were being accumulated. The general intermediacy of hybrids seemed to agree best with the belief that heredity was transmitted from the parents to offspring by “blood,” and this belief was accepted by most 19th-century biologists, the evolutionist being included among these.

The blood theory of heredity, if this notion can be dignified with such a name, is really a part of the folklore antedating scientific biology. It is implicit in such popular phrases as “half blood,” “new blood,” “blue blood.” It does not mean that heredity is actually transmitted through the red liquid in blood vessels; the essential point is the belief that a parent transmits to each child all its characteristics and that the hereditary endowment of a child is an alloy, a blend of the endowments of its parents, grandparents, and more remote ancestors. This idea appeals to those who pride themselves on having a noble or remarkable “blood” line. It strikes a snag, however, when one observes that a child has some characteristics that are not present in either parent but are present in some other relatives or were present in more remote ancestors. Even more often one sees that brothers and sisters, though showing a family resemblance in some traits, are clearly different in others. How could the same parents transmit different “bloods” to each of their children? Mendel disproved the blood theory. He showed (1) that heredity is transmitted through factors (now called genes) that do not blend but segregate, (2) that parents transmit only one-half of the genes they have to each child, and they transmit different sets of genes to different children, and (3) that, although brothers and sisters receive their heredities from the same parents, they do not receive the same heredities (an exception is identical twins). Mendel thus showed that, even if the eminence of some ancestor were entirely the reflection of his genes, it is quite likely that some of his descendants, especially the more remote ones, would not inherit these “good” genes at all. In sexually reproducing organisms, humans included, every individual has a unique hereditary endowment.

Lamarckism—a school of thought named for the 19th-century pioneer French evolutionist Jean-Baptiste, chevalier de Lamarck—assumed that characters acquired during an individual's life are inherited by his progeny, or, to put it in modern terms, that the modifications wrought by the environment in the phenotype are reflected in similar changes in the genotype. If this were so, the results of physical exercise would make exercise much easier or even dispensable in a person's offspring. Not only Lamarck but also other 19th-century biologists, including Darwin, accepted the inheritance of acquired traits. It was questioned by , whose famous experiments in the late 1890s on amputation of tails in generations of mice showed that such modification resulted neither in disappearance nor even in shortening of the tails in the descendants. Weismann concluded that the hereditary endowment of the organism, which he called the germ plasm, is wholly separate and is protected against the influences emanating from the rest of the body, the somatoplasm or soma. The germ plasm–somatoplasm are related to the genotype–phenotype concepts, but they are not identical and should not be confused with them.

The noninheritance of acquired traits does not mean that the genes cannot be changed by environmental influences: X rays and other mutagens certainly do change them, and the genotype of a population can be altered by selection. It simply means that what is acquired by parents in their physique and their intellect is not inherited by their children. Related to these misconceptions are the beliefs in “prepotency”—that some individuals impress their heredities on their progenies more effectively than others—and in “prenatal influences” or “maternal impressions”—that the events experienced by a pregnant female are reflected in the constitution of the child to be born. How ancient these beliefs are is suggested in the Book of Genesis, in which Laban produced spotted or striped progeny in sheep by showing the pregnant ewes striped hazel rods. Another such belief is “telegony,” which goes back to Aristotle; it alleged that the heredity of an individual is influenced not only by his father but also by males with whom the female may have mated and who have caused previous pregnancies. Even Darwin, as late as 1868, seriously discussed an alleged case of telegony: that of a mare that was mated to a and subsequently to an Arabian stallion by whom the mare produced a foal with faint stripes on his legs. The simple explanation for this result is that such stripes occur naturally in some breeds of horses.

All these beliefs, from inheritance of acquired traits to telegony, must now be classed as superstitions. They do not stand up under experimental investigation and are incompatible with what is known about the mechanisms of heredity and about the remarkable and predictable properties of the genetic materials. Nevertheless, some people still cling to these beliefs. Some animal breeders take telegony seriously and do not regard as “pure bred” the individuals whose parents are admittedly “pure” but whose mothers had mated with males of other breeds. The agronomist Trofim Denisovich Lysenko was able for close to a quarter of a century, roughly between 1938 and 1963, to make his special brand of Lamarckism the official creed in the Soviet Union and to suppress most of the teaching and research in orthodox genetics. He and his partisans published hundreds of articles and books allegedly proving their contentions, which effectively deny the achievements of biology for at least a century. The Lysenkoists were officially discredited in 1964. Mendelian genetics

Discovery and rediscovery of Mendel's laws

Gregor Mendel published his work in the proceedings of the local society of naturalists in Brünn, Austria (now Brno, Czechoslovakia), in 1866, but none of his contemporaries appreciated its significance. It was not until 1900, 16 years after Mendel's death, that his work was rediscovered independently by Hugo de Vries in Holland, Carl Erich Correns in Germany, and Erich Tschermak von Seysenegg in Austria. Like several investigators before him, Mendel experimented on hybrids of different varieties of a plant. Mendel investigated the common pea plant (Pisum sativum). His methods differed in two essential respects from those of his predecessors. First, instead of trying to describe the appearance of whole plants with all their characteristics, Mendel followed the inheritance of single, easily visible and distinguishable traits, such as round versus wrinkled seed, yellow versus green seed, purple versus white flowers, etc. Second, he made exact counts of the numbers of plants bearing this or that trait; it was from such quantitative data that he deduced the rules governing inheritance.

Since pea plants reproduce usually by self-pollination of their flowers, the varieties Mendel obtained from seedsmen were “pure”—i.e., descended for several to many generations from plants with similar traits. Mendel crossed them by deliberately transferring the pollen of one variety to the pistils of another; the resulting first- generation hybrids, denoted by the symbol F1, usually showed the traits of only one parent. For example, the crossing of yellow-seeded plants with green-seeded ones gave yellow seeds; the crossing of purple-flowered plants with white-flowered ones gave purple-flowered plants, etc. Traits such as the yellow-seed colour and the purple-flower colour Mendel called dominant; the green-seed colour and the white- flower colour he called recessive. It looked as if the yellow and purple “bloods” overcame or consumed the green and white “bloods.”

That this was not so became evident when Mendel allowed the F1 hybrid plants to self-pollinate and produce the second hybrid generation, F2. Here both the dominant and the recessive traits reappeared, as pure and uncontaminated as they were in the original parents (generation P). Moreover, these traits now appeared in constant 3 proportions: about /4 of the plants in the second generation showed the dominant 1 trait and /4 showed the recessive, a 3 to 1 ratio. It can be seen in Table 1 that Mendel's actual counts were as close to the ideal ratio as one could expect allowing for the sampling deviations present in all statistical data.

Mendel concluded that the sex cells, the gametes, of the purple-flowered plants carried some factor that caused the progeny to develop purple flowers, and the gametes of the white-flowered variety had a variant factor that induced the development of white flowers. In 1909 the Danish biologist Wilhelm Ludvig Johannsen proposed to call these factors genes.

An example of one of Mendel's experiments will illustrate how the genes are transmitted and in what particular ratios. Let R stand for the gene for purple flowers and r for the gene for white flowers (dominant genes are conventionally symbolized by capital letters and recessive genes by small letters). Since each pea plant contains a gene endowment half of whose set is derived from the mother and half from the father, each plant has two genes for flower colour. If the two genes are alike, for Figure 1: Mendel's law of segregation. Cross of a instance, both having come from white-flowered parents (rr), purple-flowered and a the plant is termed a homozygote (Figure 1). The union of white-flowered … gametes with different genes give a hybrid plant termed a Encyclopædia Britannica, Inc. heterozygote (Rr). Since the gene R, for purple, is dominant over r, for white, the F1 generation hybrids will show purple flowers. They are phenotypically purple, but their genotype contains both R and r genes, and these alternative (allelic or allelomorphic) genes do not blend or contaminate each other. Mendel inferred that when a heterozygote forms its sex cells, the allelic genes segregate and pass to different gametes. This is expressed in the first law of Mendel, the law of segregation of unit genes. Equal numbers of gametes, ovules, or pollen grains are formed that contain the genes R and r. Now, if the gametes unite 1 3 at random, then the F2 generation should contain about /4 white-flowered and /4 purple-flowered plants. The white-flowered plants, which must be recessive 1 homozygotes, bear the genotype rr. About /3 of the plants exhibiting the 2 dominant trait of purple flowers must be homozygotes, RR, and /3 heterozygotes, Rr. The prediction is tested by obtaining a third generation, F3, from the purple- 2 flowered plants; though phenotypically all purple-flowered, /3 of this group of plants reveal the presence of the recessive gene allele, r, in their genotype by 1 producing about /4 white-flowered plants in the F3 generation.

Mendel also crossbred varieties of peas that differed in two or more easily distinguishable traits. When a variety with yellow round seed was crossed to a green wrinkled seed variety (Figure 2), the F1 generation hybrids produced yellow round seed. Evidently yellow (A) and round (B) are dominant traits, green (a) and wrinkled (b) are recessive. By allowing the F1 plants (genotype AaBb) to self-pollinate, Mendel obtained an F2 Figure 2: Mendel's law of independent assortment. generation of 315 yellow round, 101 yellow wrinkled, 108 green Cross of peas having round, and 32 green wrinkled seeds, a ratio approximately 9 : 3 yellow and smooth … : 3 : 1. The important point here is that the segregation of the colour (A–a) is independent of the segregation of the trait of seed surface (B–b). This is expected if the F1 generation produces equal numbers of four kinds of gametes, carrying the four possible combinations of the parental genes: AB, Ab, aB, and ab. Random union of these gametes gives, then, the four phenotypes in a ratio 9 dominant–dominant : 3 recessive–dominant : 3 dominant–recessive : 1 recessive–recessive. Among these four phenotypic classes there must be nine different genotypes, a supposition that can be tested experimentally by raising a third hybrid generation. The predicted genotypes are actually found. Another test is by means of a backcross (or testcross)—the F1 hybrid (phenotype yellow round seed; genotype AaBb) is crossed to a double recessive plant (phenotype green wrinkled seed; genotype aabb). If the hybrid gives four kinds of gametes in equal numbers and if all the gametes of the double recessive are alike (ab), the predicted progeny of the backcross are yellow round, yellow wrinkled, green round, and green wrinkled seed in a ratio 1 : 1 : 1 : 1. This prediction is realized in experiments. When the varieties crossed differ in three genes, the F1 hybrid forms 23 or eight kinds of gametes (2n = kinds of gametes, n being the number of genes). 3 The second generation of hybrids, the F2, has 27 (3 ) genotypically distinct kinds of individuals but only eight different phenotypes. From these results and others Mendel derived his second law, the law of recombination or independent assortment of genes.

Universality of Mendel's laws

Although Mendel experimented with varieties of peas, his laws have been shown to apply to the inheritance of many kinds of characters in almost all organisms. In 1902 was demonstrated in poultry and in mice. The following year, albinism became the first human trait shown to be a Mendelian recessive, with pigmented skin the corresponding dominant.

In 1902 and 1909 Sir Archibald Garrod initiated the analysis of inborn errors of metabolism in humans in terms of biochemical genetics. Alkaptonuria, inherited as a recessive, is characterized by excretion in the urine of large amounts of the substance called alkapton, or homogentisic acid, which renders the urine black on exposure to air. In normal (i.e., nonalkaptonuric) persons the homogentisic acid is changed to acetoacetic acid, the reaction being facilitated by an enzyme, homogentisic acid oxidase. Garrod advanced the hypothesis that this enzyme is absent or inactive in homozygous carriers of the defective recessive alkaptonuria gene; hence the homogentisic acid accumulates and is excreted in the urine. Mendelian inheritance of numerous traits in humans has been studied since then.

In analyzing Mendelian inheritance, it should be borne in mind that an organism is not an aggregate of independent traits, each determined by one gene. A “trait” is really an abstraction, a term of convenience in description. One gene may affect many traits (a condition termed pleiotropic). The gene white in Drosophila flies is pleiotropic; it affects the colour of the eyes and of the testicular envelope in the males, the fecundity and the shape of the spermatheca in the females, and the longevity of both sexes. In humans many diseases caused by a single defective gene will have a variety of symptoms, all pleitropic manifestations of the gene.

Allelic interactions

Dominance relationships

The operation of Mendelian inheritance is frequently more complex than in the case of the traits recorded by Mendel. In the first place, clear-cut and recessiveness are by no means always found. When red- and white-flowered varieties of four-o'clock plants or snapdragons are crossed, for example, the F1 hybrids have flowers of intermediate pink or rose colour, a situation that seems more explicable by the blending notion of inheritance than by Mendelian concepts. That the inheritance of flower colour is indeed due to Mendelian mechanisms becomes apparent when the F1 hybrids are allowed to cross, yielding an F2 generation of red-, pink-, and white-flowered plants in a ratio of 1 red : 2 pink : 1 white. Obviously the hereditary information for the production of red and white flowers had not been blended away in the first hybrid generation, as flowers of these colours were produced in the second generation of hybrids.

The apparent blending in the F1 generation is explained by the fact that the gene alleles that govern flower colour in four-o'clocks show an incomplete dominance relationship. Suppose, then, that a gene allele R1 is responsible for red and R2 for white flowers; the homozygotes R1R1 and R2R2 are red and white respectively, and the heterozygotes R1R2 have pink flowers. A similar pattern of lack of dominance is found in shorthorn cattle. In diverse organisms, dominance ranges from complete (a heterozygote indistinguishable from one of the homozygotes) through incomplete (heterozygotes exactly intermediate) to excessive or over-dominance (a heterozygote more extreme than either homozygote).

Another form of dominance is one in which the heterozygote displays the phenotypic characteristics of both alleles. This is called codominance; an example is seen in the MN blood group system of human beings. MN blood type is governed by two alleles, M and N. Individuals who are homozygous for the M allele have a surface molecule (called the M antigen) on their red blood cells. Similarly, those homozygous for the N allele have the N antigen on the red blood cells. Heterozygotes—those with both alleles—carry both antigens.

Multiple alleles

The traits discussed so far all have been governed by the interaction of two possible alleles. Many genes, however, are represented by multiple allelic forms within a population. (One individual, of course, can possess only two of these multiple alleles.) Human blood groups—in this case, the well-known ABO system— again provide an example. The gene that governs ABO blood types has three alleles: IA, IB, and IO. IA and IB are codominant, but IO is recessive. Because of the multiple alleles and their various dominance relationships, there are four phenotypic ABO blood types: type A (genotypes IAIA and IAIO), type B (genotypes IBIB and IBIO), type AB (genotype IAIB), and type O (genotype IOIO).

Gene interactions

Many individual traits are affected by more than one gene. For example, the coat colour in many mammals is determined by numerous genes interacting to produce the result. The great variety of colour patterns in cats, dogs, and other domesticated animals is the result of different combinations of complexly interacting genes. The gradual unravelling of their modes of inheritance was one of the active fields of research in the early years of genetics.

Two or more genes may produce similar and cumulative effects on the same trait. In humans, the skin colour difference between so-called blacks and so-called whites is due to several (probably four or more) interacting pairs of genes, each of which increases or decreases the skin pigmentation by a relatively small amount.

Epistatic genes

Some genes mask the expression of other genes just as a fully dominant allele masks the expression of its recessive counterpart. The gene that masks the phenotypic effect of another gene is called the epistatic gene; the gene it subordinates is the hypostatic gene. The gene for albinism (lack of pigment) in humans is an epistatic gene. It is not part of the interacting skin-colour genes described above; rather, its dominant allele is necessary for the development of any skin pigment, and its recessive homozygous state results in the albino condition regardless of how many other pigment genes may be present. Albinism thus occurs in some individuals among people who belong to the dark- or intermediate- pigmented races, such as blacks and American Indians, as well as among whites.

The presence of epistatic genes explains much of the variability seen in the expression of such dominantly inherited human diseases as Marfan's syndrome and neurofibromatosis. Because of the effects of an epistatic gene, some individuals who inherit the dominant, disease-causing gene show only partial symptoms of the disease; some, in fact, may show no expression of the disease-causing gene, a condition referred to as nonpenetrance. The individual in whom such a nonpenetrant mutant gene exists will be phenotypically normal but still capable of passing the deleterious gene on to offspring, who may exhibit the full-blown disease.

Examples of epistasis abound in nonhuman organisms. In mice, as in humans, the gene for albinism has two variants: the allele for nonalbino and the allele for albino. The latter allele is unable to synthesize the pigment melanin. Mice, however, have another pair of alleles involved in melanin placement. These are the agouti allele, which produces dark melanization of the hair except for a yellow band at the tip, and the black allele, which produces melanization of the whole hair. If melanin cannot be formed (the situation in the mouse homozygous for the albino gene) neither agouti nor black can be expressed. Hence homozygosity for the albinism gene is epistatic to the agouti/black alleles and prevents their expression.

Complementation

The phenomenon of complementation is another form of interaction between nonallelic genes. For example, there are mutant genes that in the homozygous state produce profound deafness in humans. One would expect that the children of two persons suffering from such hereditary deafness would all be deaf. This is frequently not the case, because the parents' deafness is often caused by different genes. Since the mutant genes are not alleles, the child becomes heterozygous for the two genes and hears normally. In other words, the two mutant genes complement each other in the child. Complementation thus becomes a test for allelism. In the case of congenital deafness cited above, if all the children had been deaf, one could assume that the deafness in each of the parents was due to mutant genes that were alleles. This would be more likely to occur if the parents were genetically related (consanguineous).

Polygenic inheritance

The greatest difficulties of analysis and interpretation are presented by the inheritance of many quantitative or continuously varying traits. Inheritance of this kind produces variations in degree rather than in kind, in contrast to the inheritance of discontinuous traits resulting from single genes of major effect (see above). The yield of milk in different breeds of cattle, egg-laying capacity in poultry, and stature, shape of the head, blood pressure, and intelligence in humans range in continuous series from one extreme to the other and are significantly dependent on environmental conditions. Crosses of two varieties differing in such characters usually give F1 hybrids intermediate between the parents. At first sight, this situation suggests a blending inheritance through “blood” rather than Mendelian inheritance; in fact, it was probably observations of this kind of inheritance that suggested the folk idea of “blood theory.”

It has, however, been shown that these characters are polygenic—i.e., determined by several or many genes, each taken separately producing only a slight effect on the phenotype, as small as or smaller than that caused by environmental influences on the same characters. That Mendelian segregation does take place with polygenes, as with the genes having major effects (sometimes called oligogenes), is shown by the variation among F2 and further generation hybrids being usually much greater than that in the F1 generation. By selecting among the segregating progenies the desired variants, for example, individuals or families with the greatest yield, the best size, or a desirable behaviour, it is possible to produce new breeds or varieties sometimes exceeding the parental forms. Hybridization and selection are consequently potent methods that can be used for improvement of agricultural plants and animals.

Polygenic inheritance also applies to many of the birth defects (congenital malformations) seen in humans. Although expression of the defect itself may be discontinuous (as in clubfoot, for example), susceptibility to the trait is continuously variable and follows the rules of polygenic inheritance. When a developmental threshold produced by a polygenically inherited susceptibility and a variety of environmental factors is exceeded, the birth defect results.

Heredity and environment

Preformism and epigenesis

A notion that was widespread among pioneer biologists in the 18th century was that the fetus, and hence the adult organism that develops from it, is preformed in the sex cells. Some early microscopists even imagined that they saw a tiny “homunculus,” a diminutive human figure, encased in the human spermatozoon. The development of the individual from the sex cells appeared deceptively simple— it was merely increase in size and growth of what was already present in the sex cells. The antithesis of the early preformation theories were theories of epigenesis, which claimed that the sex cells were structureless jelly and contained nothing at all in the way of rudiments of future organisms. The naive early versions of preformation and epigenesis had to be given up when embryologists showed that the embryo develops by a series of complex but orderly and gradual transformations (see animal development). Darwin's “Provisional Hypothesis of Pangenesis” was distinctly preformistic; Weismann's theory of determinants in the germ plasm as well as the early ideas about the relations between genes and traits also tended toward preformism. Heredity has been defined as a process that results in the progeny's resembling their parents. A further qualification of this definition states that what is inherited is a potential that expresses itself only after interacting with and being modified by environmental factors. In short, all phenotypic expressions have both hereditary and environmental components, the amount of each varying for different traits. Thus, a trait that is primarily hereditary (e.g., skin colour in humans) may be modified by environmental influences (e.g., suntanning). And conversely, a trait sensitive to environmental modifications (e.g., weight in humans) is also genetically conditioned. Organic development is preformistic insofar as a fertilized egg cell contains a genotype that conditions the events that may occur and is epigenetic insofar as a given genotype allows a variety of possible outcomes. These considerations should dispel the reluctance felt by many people to accept the fact that mental as well as physiological and physical traits in humans are genetically conditioned. Genetic conditioning does not mean that heredity is the “dice of destiny.” At least in principle, but not invariably in practice, the development of a trait may be manipulated by changes in the environment.

Heritability

Although hereditary diseases and malformations are, unfortunately, by no means uncommon in the aggregate, no one of them occurs very frequently. The characteristics by which one person is distinguished from another, such as facial features, stature, shape of the head, skin, eye and hair colours, and voice, are not usually inherited in a clear-cut Mendelian manner, as are some hereditary malformations and diseases. This is not as strange as it may seem. The kinds of gene changes, or mutations, that produce morphological or physiological effects drastic enough to be clearly set apart from the more usual phenotypes are likely to cause diseases or malformations just because they are so drastic.

The variations that occur among healthy persons are, as a general rule, caused by polygenes with individually small effects. The same is true of individual differences among members of various animal and plant species. Even brown-blue eye colour in humans, which in many families behaves as if caused by two forms of a single gene (brown being dominant and blue recessive), is often blurred by minor gene modifiers of the pigmentation. Some apparently blue-eyed persons actually carry the gene for the brown eye colour, but several additional modifier genes decrease the amount of brown pigment in the iris. This type of genetic process can influence susceptibility to many diseases (e.g., diabetes) or birth defects (for example, cleft lip—with or without cleft palate).

The question geneticists must often attempt to answer is how much of the observed diversity between persons, or between individuals of any species, is due to hereditary, or genotypic, variations and how much of it is due to environmental influences. Applied to human beings, this is sometimes referred to as the nature–nurture problem. With animals or plants the problem is evidently more easily soluble than it is with people. Two complementary approaches are possible. First, individual organisms, or their progenies, are raised in environments as uniform as can be provided, with food, temperature, light, humidity, etc., carefully controlled. The differences that persist between such individuals or progenies probably reflect genotypic differences. Second, individuals with similar or identical genotypes are placed in different environments. The phenotypic differences then may be ascribed to environmental induction. Experiments combining both approaches have been carried out on several species of plants that grow naturally at different altitudes, from sea level to the alpine zone of the Sierra Nevada of California. Young yarrow plants (Achillea) were cut in three parts and the cuttings replanted in experimental gardens at sea level, at midaltitude (4,800 feet [1,460 metres]), and at a high altitude (10,000 feet [3,050 metres]). The plants native at sea level grow best in their native habitat, grow less well at midaltitudes, and die at high altitudes. On the other hand, the alpine race survives and develops better at the high-altitude transplant station than it does at lower altitudes. With organisms that cannot survive being cut in pieces and placed in controlled environments, a partitioning of the observed variability into genetic and environmental components may be attempted by other methods. Suppose that in a certain population individuals vary in stature, weight, or some other trait. These characters can be measured in many pairs of parents and in their progenies raised under different environmental conditions. If the variation is due entirely to environment and not at all to heredity, then the expression of the character in the parents and in the offspring will show no correlation at all (heritability = zero). On the other hand, if the environment is unimportant and the character is uncomplicated by dominance, then the means of this character in the progenies will be the same as the means of the parents; with differences in the expression in females and in males taken into account, the heritability will equal unity. In reality, most heritabilities are found to lie between zero and one. Some examples of heritabilities of traits in different animals are given in Table 2.

It is important to understand clearly the meaning of heritability estimates. They show that, given the range of the environments in which the experimental animals lived, one could predict the average body sizes in the progenies of pigs better than one could predict the average numbers of piglets in a litter. The heritability is, however, not an inherent or unchangeable property of each character. If one could make the environments more uniform, the heritabilities would rise, and with more diversified environments they would decrease. Similarly, in populations that are more variable genetically the heritabilities increase, and in genetically uniform ones they decrease. In humans the situation is even more complex because the environments of the parents and of their children are in many ways interdependent. Suppose, for example, that one wishes to study the heritability of stature, weight, or susceptibility to tuberculosis. The stature, weight, and liability to contract tuberculosis depend to some extent on the quality of nutrition and generally on the economic well-being of the family. If no allowance is made for this fact, the heritability estimates arrived at may be spurious; such heritabilities have indeed been claimed for such things as administrative, legal, or military talents and for social eminence in general. It is evident that having socially eminent parents makes it easier for the children to achieve such eminence also; biological heredity may have little or nothing to do with this.

A general conclusion from the evidence now available may be stated as follows: diversity in almost any trait, physical, physiological, or behavioral, is due in part to genetic and in part to environmental variables. In any array of environments, individuals with more nearly similar genetic endowments are likely to show a greater average resemblance than the carriers of more diverse genetic endowments. It is, however, also true that in different environments the carriers of similar genetic endowments may grow, develop, and behave in different ways.

The physical basis of heredity

When Mendel formulated his laws of heredity, he postulated a particulate nature for the units of inheritance. What exactly these particles were he did not know. Today scientists understand not only the physical location of hereditary units (i.e., the genes) but their molecular composition as well. The unravelling of the physical basis of heredity makes up one of the most fascinating chapters in the history of biology.

Chromosomes and genes

As has been discussed, each individual in a sexually reproducing species inherits two alleles for each gene, one from each parent. Furthermore, when such an individual forms sex cells, each of the resultant gametes receives one member of each allelic pair. The formation of gametes occurs through a process of cell division called meiosis; it is also known as reduction division, because the amount of hereditary material present in the gametes has been reduced by half. When gametes unite in fertilization, the double dose of hereditary material is restored, and a new individual is created. This individual, consisting at first of only one cell, grows via mitosis, a process of repeated cell divisions. Mitosis differs from meiosis in that each daughter cell receives a full copy of all the hereditary material found in the parent cell.

It is apparent that the genes must physically reside in cellular structures that meet two criteria. First, these structures must be replicated and passed on to each generation of daughter cells during mitosis. Second, they must be organized into homologous pairs, one member of which is parcelled out to each gamete formed during meiosis.

As early as 1848, biologists had observed that cell nuclei resolve themselves into small, rodlike bodies during mitosis; later these structures were found to absorb certain dyes and so came to be called (coloured bodies). During the early years of the 20th century, cellular studies using ordinary light microscopes clarified the behaviour of chromosomes during mitosis and meiosis, which led to the conclusion that chromosomes are the carriers of genes.

The behaviour of chromosomes during cell division

During mitosis

When the chromosomes condense during cell division, they have already undergone replication. Each thus consists of two identical replicas, called chromatids, joined at a point called the centromere. During mitosis the sister chromatids separate, one going to each daughter cell. Chromosomes thus meet the first criterion for being the repository of genes: they are replicated and a full copy is passed to each daughter cell during mitosis.

During meiosis

It was the behaviour of chromosomes during meiosis, however, that provided the strongest evidence for their being the carriers of genes. In 1902 the American Walter S. Sutton reported on his observations of the action of chromosomes during sperm formation in grasshoppers. Sutton had observed that during meiosis, each chromosome (consisting of two chromatids) becomes paired with another, physically similar chromosome. These homologous chromosomes separate during meiosis, with one member of each pair going to a different cell. Assuming that one member of each homologous pair was of maternal origin and the other was paternally derived, here was an event that fulfilled the behaviour of genes postulated in Mendel's first law.

It is now known that the number of chromosomes within the nucleus is usually constant in all individuals of a given species—for example, 46 in humans; 40 in the house mouse; 8 in the vinegar, or fruit, fly (Drosophila melanogaster); 20 in corn (maize); 24 in the tomato; 48 in the potato. In sexually reproducing organisms, this number is called the diploid number of chromosomes, as it represents the double dose of chromosomes received from two parents. The nucleus of a gamete, however, contains half this number of chromosomes, or the haploid number. Thus a human gamete contains 23 chromosomes, while a Drosophila gamete contains four. Meiosis produces the haploid gametes.

The essential features of meiosis are shown in Figure 3. For the sake of simplicity, the diploid parent cell is shown to contain a Figure 3: Behaviour of chromosomes at meiosis single pair of homologous chromosomes, one member of which (see text). is represented black (from the father) and the other white (from the mother). At the leptotene stage the chromosomes appear as long, thin threads. At pachytene they pair, the corresponding portions of the two chromosomes lying side-by- Figure 3: Behaviour of chromosomes at meiosis side. The chromosomes then duplicate and contract into paired chromosomes at meiosis (see text). chromatids. At this stage the pair of chromosomes is known as a tetrad, as it consists of four chromatids. Also at this stage an extremely important event occurs: portions of the maternal and paternal chromosomes are exchanged. This exchange process, called crossing over, results in chromatids that include both paternal and maternal genes and consequently introduces new genetic combinations. The first meiotic, or reduction, division separates the chromosomal tetrads, with the paternal chromosome (whose chromatids now contain some maternal genes) going to one cell, and the maternal chromosome (containing some paternal genes) going to another cell. During the second meiotic division the chromatids separate. The original diploid cell has thus given rise to four haploid gametes (only two of which are shown in Figure 3). Not only has a reduction in chromosome number occurred, but the resulting single member of each homologous chromosome pair may be a new combination (through crossing over) of genes present in the original diploid cell.

Suppose that the white chromosome shown in Figure 3 carries the gene for albinism, and the black chromosome carries the Figure 3: Behaviour of chromosomes at meiosis gene for dark pigmentation. It is evident that the two gene (see text). alleles will undergo segregation at meiosis, and that one-half of the gametes formed will contain the albino gene and the other half the pigmentation gene. Following the scheme in Figure 1, random combination of the gametes with the albino and the pigmentation gene will give two kinds of homozygotes and one kind of heterozygote in a ratio 1 : 1 : 2. Mendel's law of segregation is, thus, the outcome of chromosome behaviour at meiosis. The same is true of the second law, that of the independent assortment.

Figure 1: Mendel's law of segregation. Cross of a Consider the inheritance of two pairs of genes, such as Mendel's purple-flowered and a factors for seed coloration and seed surface in peas; these white-flowered … genes are located on different pairs of chromosomes. Since Encyclopædia Britannica, Inc. maternal and paternal members of different chromosome pairs are assorted independently, so are the genes they contain. This explains, in part, the genetic variety seen among the progeny of the same pair of parents. As stated above, humans have 46 chromosomes in the body cells and in the cells (oogonia and spermatogonia) from which the sex cells arise. At meiosis these 46 chromosomes form 23 pairs, one of the chromosomes of each pair being of maternal and the other of paternal origin. Independent assortment is, then, capable of producing 223, or 8,388,608, kinds of sex cells with different combinations of the grandmaternal and grandpaternal chromosomes. Since each parent has the potentiality of producing 223 kinds of sex cells, the total number of possible combinations of the grandparental chromosomes is 223 ´ 223 = 246. The population of the world is now more than 4,000,000,000 persons, or approximately 232 persons. It is, therefore, certain that only a tiny fraction of the potentially possible chromosome and gene combinations can ever be realized. Yet even 246 is an underestimate of the variety potentially possible. The grandmaternal and grandpaternal members of the chromosome pairs are not indivisible units. Each chromosome carries many genes, and the chromosome pairs exchange segments at meiosis through the process of crossing over. This is evidence that the genes rather than the chromosomes are the units of Mendelian segregation.

Linkage of traits

Simple linkage

As pointed out above, the random assortment of the maternal and paternal chromosomes at meiosis is the physical basis of the independent assortment of genes and of the traits they control. This is the basis of the second law of Mendel. The Figure 4: Linkage of genes as illustrated by body number of the genes in a sex cell is, however, much greater as illustrated by body colour and wing length in than that of the chromosomes. When two or more genes are Drosophila flies … borne on the same chromosome these genes may not be From T. Dobzhansky, Heredity and the Nature assorted independently; such genes are said to be linked. When of Man, (1964); Harcourt a Drosophila fly homozygous for a normal gray body and long Brace Jovanovich, Inc. wings is crossed with one having a black body and vestigial wings, the F1 consists of hybrid gray, long-winged flies (Figure 4). Gray body (B) is evidently dominant over black body (b), and long wing (V) is dominant over vestigial wing (v). Now consider a backcross of the heterozygous F1 males to double recessive black-vestigial females (bbvv). Independent assortment would be expected to give in the progeny of the backcross the following: 1 gray-long : 1 gray-vestigial : 1 black-long : 1 black-vestigial. In reality only gray-long and black- vestigial flies are produced, in approximately equal numbers; the genes remain linked in the same combinations in which they were found in the parents. The backcross of the heterozygous F1 females to double recessive males gives a somewhat different result: 42 percent each of gray-long and black-vestigial flies and about 8 percent each of black-long and gray-vestigial classes. In sum, 84 percent of the progeny have the parental combinations of traits, and 16 percent have the traits recombined. The interpretation of these results given in 1911 by the U.S. geneticist Thomas Hunt Morgan laid the foundations of the theory of linear arrangement of genes in the chromosomes.

Traits that exhibit linkage in experimental crosses (such as black body and vestigial wings) are determined by genes located in the same chromosome. As more and more genes became known in Drosophila melanogaster, they fell neatly into four linkage groups corresponding to the four pairs of the chromosomes this species possesses. One linkage group consists of sex-linked genes, located in the X chromosome (see below); of the three remaining linkage groups, two have many more genes than the remaining one; this corresponds to the presence of two pairs of large chromosomes and one pair of tiny dotlike chromosomes. The numbers of linkage groups in other organisms are equal to or smaller than the numbers of the chromosomes in the sex cells; e.g., 10 linkage groups and 10 chromosomes in corn, 19 linkage groups and 20 chromosomes in the house mouse, 23 linkage groups and 23 chromosomes in human beings.

As seen above, the linkage of the genes black and vestigial in Drosophila is complete in heterozygous males, while in the Figure 3: Behaviour of chromosomes at meiosis progeny of females there appear about 17 percent of (see text). recombination classes. With very rare exceptions, the linkage of all genes belonging to the same linkage group is complete in Drosophila males, while in the females different pairs of genes exhibit all degrees of linkage from complete (no recombination) to 50 percent (random assortment). Morgan's inference was that the degree of linkage depends on physical distance between the genes in the chromosome: the closer the genes the tighter the linkage, and vice versa. Furthermore, Morgan perceived that the chiasmata, crosses that occur in meiotic chromosomes, indicate the mechanism underlying the phenomena of linkage and crossing over. As shown schematically in Figure 3, the maternal and paternal chromosomes (represented black and white) cross over and exchange segments, so that a chromosome emerging from the process of meiosis may consist of some maternal (grandmaternal) and some paternal (grandpaternal) sections. If the probability of crossing-over taking place is uniform along the length of a chromosome (which was later shown to be not quite true), then genes close together will be recombined less frequently than those far apart.

This realization opened an opportunity to map the arrangement of the genes and the estimated distances between them in the chromosome by studying the frequencies of recombination of various traits in the progenies of hybrids. In other words, the linkage maps of the chromosomes are really summaries of many statistical observations on the outcomes of hybridization experiments. In principle at least, such maps could be prepared even if the chromosomes, not to speak of the chiasmata at meiosis, were unknown. But an interesting and relevant fact is that in Drosophila males the linkage of the genes in the same chromosome is complete, and observations under the microscope show that no chiasmata are formed in the chromosomes at meiosis. In most organisms, including humans, chiasmata are seen in the meiotic chromosomes in both sexes, and observations on hybrid progenies show that recombination of linked genes occurs also in both sexes.

The most detailed chromosome maps have been constructed for Morgan's classical material—Drosophila melanogaster. Less detailed chromosome maps exist for some other species of Drosophila flies, for corn, the house mouse, the bread mold Neurospora crassa, and for some bacteria and bacteriophages (viruses that infect bacteria). Until quite late in the 20th century, the mapping of human chromosomes presented a particularly difficult problem: experimental crosses could not be arranged in humans and only a few linkages could be determined by analysis of unique family histories. However, the development of genetics (see below) provided new understanding of human genetic processes and new methods of research. Using the techniques of somatic cell genetics, hundreds of genes have been mapped to the human chromosomes and many linkages established.

Sex linkage

The male of many animals has one chromosome pair, the sex chromosomes, consisting of unequal members called X and Y. At meiosis the X and Y chromosomes first pair, then disjoin and pass to different cells. One-half of the gametes (spermatozoa) formed contain the X and the other half the Y chromosome. The female has two X chromosomes, and all egg cells normally carry a single X. The eggs fertilized by X-bearing spermatozoa give females (XX), and those fertilized by Y-bearing spermatozoa give males (XY).

The genes located in the X chromosomes exhibit what is known as sex-linkage or crisscross inheritance. This is due to a crucial difference between the paired sex chromosomes and the other pairs of chromosomes (called autosomes). The members of the autosome pairs are truly homologous; that is, each member of a pair contains a full complement of the same genes (albeit, perhaps, in different allelic forms). The sex chromosomes, on the other hand, do not constitute a homologous pair, as the X chromosome is much larger and carries far more genes than does the Y. Consequently, many recessive alleles carried on the X chromosome of a male will be expressed just as if they were dominant, for the Y chromosome carries no genes to counteract them. The classic case of sex-linked inheritance, described by Morgan in 1910, is that of the white eyes in Drosophila. White-eyed females crossed to males with the normal red eye colour produce red- eyed daughters and white-eyed sons in the F1 generation and equal numbers of white-eyed and red-eyed females and males in the F2 generation. The cross of red- eyed females to white-eyed males gives a different result: both sexes are red eyed in F1, the females in the F2 generation are red eyed, half of the males are red eyed, and the other half white eyed. As interpreted by Morgan, the gene that determines the red or white eyes is borne on the X chromosome, and the allele for red eye is dominant over that for white eye. Since a male receives its single X chromosome from his mother, all sons of white-eyed females also have white eyes. A female inherits one X chromosome from her mother and the other X from her father. Red-eyed females may have genes for red eyes in both of their X chromosomes (homozygotes) or may have one X with the gene for red and the other for white (heterozygotes). In the progeny of heterozygous females one half of the sons will receive the X chromosome with the gene for white and will have white eyes, and the other half will receive the X with the gene for red eyes. The daughters of the heterozygous females crossed with white-eyed males will have either two X chromosomes with the gene for white and hence white eyes or will have one X with white and the other X with the gene for red eyes and will be red- eyed heterozygotes.

In humans, the red-green colour blindness and hemophilia are among many traits showing sex-linked inheritance and consequently are due to genes borne in the X chromosome.

In some animals—birds, butterflies and moths, some fish, and at least some amphibians and reptiles—the chromosomal mechanism of sex determination is a mirror image of that described above. The male has two X chromosomes and the female an X and Y chromosome. Here the spermatozoa all have an X chromosome; the eggs are of two kinds, some with X and others with Y chromosomes, usually in equal numbers. The sex of the offspring is then determined by the egg rather than by the spermatozoon. Sex-linked inheritance is altered correspondingly. A male homozygous for a sex-linked recessive trait, crossed to a female with the dominant one, gives in the F1 generation daughters with the recessive trait and heterozygous sons with the corresponding dominant trait. The F2 generation has recessive and dominant females and males in equal numbers. A male with a dominant trait crossed to a female with a recessive trait gives uniformly dominant F1 and a segregation in a ratio of 2 dominant males : 1 dominant female : 1 recessive female.

Observations on pedigrees or experimental crosses show that certain traits exhibit sex-linked inheritance; the behaviour of the X chromosomes at meiosis is such that the genes they carry may be expected to exhibit sex-linkage. This evidence still failed to convince some skeptics that the genes for the sex-linked traits were in fact borne in certain chromosomes seen under the microscope. An elegant experimental proof was furnished in 1916 by the U.S. geneticist Calvin Blackman Bridges. As stated above, white-eyed Drosophila females crossed to red-eyed males usually produce red-eyed female and white-eyed male progeny. Among thousands of such “regular” offspring there are occasionally found exceptional white-eyed females and red-eyed males. Bridges constructed the following working hypothesis. Suppose that during meiosis in the female, gametogenesis occasionally goes wrong, and the two X chromosomes fail to disjoin. Exceptional eggs will then be produced carrying two X chromosomes and eggs carrying none. An egg with two X chromosomes coming from a white-eyed female fertilized by a spermatozoon with a Y chromosome will give an exceptional white-eyed female. An egg with no X chromosome fertilized by a spermatozoon with an X chromosome derived from a red-eyed father will yield an exceptional red-eyed male. This hypothesis can be rigorously tested. The exceptional white-eyed females should have not only the two X chromosomes but also a Y chromosome, which normal females do not have. The exceptional males should, on the other hand, lack a Y chromosome, which normal males do have. Both predictions were verified by examination under a microscope of the chromosomes of exceptional females and males. The hypothesis also predicts that exceptional eggs with two X chromosomes fertilized by X-bearing spermatozoa must give individuals with three X chromosomes; such individuals were later identified by Bridges as poorly viable “superfemales.” Exceptional eggs with no Xs, fertilized by Y-bearing spermatozoa, will give zygotes without X chromosomes; such zygotes die in early stages of development.

Chromosomal aberrations

Two general types of chromosomal abnormalities occur: numerical and structural. Numerical aberrations result from nondisjunction; that is, from the failure of a pair of homologous chromosomes or a pair of sister chromatids to separate during cell division. As described above, when nondisjunction occurs during meiosis two types of germ cells will be formed, those with an extra chromosome and those with a missing chromosome. If one of the former combines with a normal germ cell, the new fertilized egg and all the cells of the individual it produces will have an extra chromosome (trisomy); if one of the latter combines with a normal germ cell, the fertilized egg will lack a chromosome (monosomy). If nondisjunction occurs after fertilization, the resulting individual will be a mosaic and will have two or more populations of cells differing in chromosomal number.

Structural aberrations result from chromosome breakages. Chromosomes may break spontaneously, or they may be broken by such environmental agents as radiation, viruses, and toxic chemicals. If a chromosomal segment breaks off and is not rejoined, it may be lost entirely in the gametes or somatic cells that derive, respectively, from meiosis or mitosis. Such a loss is called a deletion. In other instances, the broken-off segment may rejoin its chromosome but with its position inverted 180°; such inversions can alter the sequence of genetic information along the chromosome. In other cases, the segment may become translocated; that is, it may become attached to a different chromosome. When such a rearrangement occurs between two nonhomologous chromosomes without net loss or gain of chromosomal material, it is called a balanced, or reciprocal, translocation, and the individual is not phenotypically affected. If, however, the translocation results in the deletion or duplication of chromosomal material in gametes or somatic cells, the effects may be severe. This is especially true in the event of gametes that carry autosomal translocations; such chromosomal aberrations often produce lethal phenotypic effects.

Theodosius Dobzhansky

Arthur Robinson

Molecular genetics

The data accumulated by the geneticists of the early 20th century provided compelling evidence that chromosomes are the carriers of the genes. But the nature of the genes themselves remained a mystery, as did the mechanism by which they exert their influence. Molecular genetics—the study of the molecular structure of the genes and the methods by which genes control the activities of the cell—provided the answers to these fundamental questions.

Much of the information in molecular genetics has come from the study of microorganisms, particularly the bacterium Escherichia coli (a common inhabitant of the human intestine) and its interactions with various bacteriophages. Bacteria have many features that make them especially useful in genetics research. For example, they have an extremely short life cycle, so that many generations can be raised in a brief period of time. Equally important, bacteria have only one basic function—to reproduce. Consequently, their genome is relatively limited. Furthermore, unlike most higher organisms, bacteria are not diploid, so their genome does not include two alleles of each gene. This makes it easy to identify a bacterium that carries a mutant gene, as the effects of the mutation cannot be masked by a normal allele. Although they are not diploid, bacteria can and do occasionally exchange genetic information through a variety of processes. This genetic exchange feature has been important in certain lines of molecular genetics research. Viruses also have advantages in genetics studies. Although they can reproduce only in a living cell, they have the simplest form of genetic material and evidence both genetically controlled properties and the ability to mutate.

Because of the relative simplicity of gene action in microorganisms, their study profoundly influenced early understanding of molecular genetics. Studies of the genetics of microorganisms involves the production of specific gene mutations and the examination of their biochemical effects. These studies have permitted the delineation of the metabolic pathways that produced the mutation in the experimental microorganism, as well as the isolation of the large molecules that contain the genetic information.

Although there are virtues to bacteria as experimental subjects in genetics research, it should be pointed out that bacteria differ from higher organisms in some rather fundamental ways. In fact, bacteria (along with the cyanophytes, or blue-green algae) are sufficiently distinct as to constitute their own kingdom, the Monera. Monerans, unlike protists, plants, and animals, are procaryotic. This means that their cells lack a true, membrane-enclosed nucleus, the cellular structure that contains the chromosomes in all other organisms (which are known as eucaryotes). Perhaps more important in a discussion of genetics, the bacterial chromosome differs in composition from the chromosomes of eucaryotes, so much so that some authorities prefer to avoid the term chromosome in describing the genetic material of bacteria. In eucaryotes, the chromosomes consist primarily of deoxyribonucleic acid (DNA) and a variety of proteins. Bacterial chromosomes have little protein, which proved to be an important clue in determining the chemical nature of the hereditary substance. Finally, all the progeny of a bacterium are identical, whereas the cell progeny of the fertilized egg of a complex, multicellular organism gives rise to many different tissues and organs whose component cells display specific patterns of different gene activities. This latter process is called differentiation.

Heredity and nucleic acids

One of the most impressive and spectacular advances of biology in the 20th century was the discovery of the nature of the genetic material. The way information is encoded in the genes has been clarified and much has been learned about the mechanisms that translate this information into the developmental processes of the organism.

In 1869 a substance containing nitrogen and phosphorus was extracted from cell nuclei. It was originally called nuclein, but is now known as DNA. DNA is the chemical component of the chromosomes that is chiefly responsible for their staining properties in microscopic preparations. As stated above, the chromosomes of eucaryotes contain a variety of proteins in addition to DNA. The question naturally arose whether the nucleic acids or the proteins, or both together, are the carriers of the genetic information, which makes the genes of the same organism and of different organisms specifically different. Until the early 1950s most biologists were inclined to believe that the proteins were the chief carriers of heredity. Nucleic acids contain only four different unitary building blocks, but proteins are made up of 20 different amino acids. Proteins therefore appeared to have a greater diversity of structure, and the diversity of the genes seemed at first likely to rest on the diversity of the proteins.

The evidence that DNA acts as the carrier of the genetic information was first firmly demonstrated by exquisitely simple microbiological studies. One of these seminal studies was performed by the U.S. geneticist Oswald T. Avery and his coworkers in 1944. The background of Avery's study goes back to 1928, to research conducted by Fred Griffith of England, a bacteriologist who was studying the virulence of pneumococci, the bacteria that cause bacterial pneumonia. Griffith knew that the virulence of pneumococci—that is, their ability to cause infection— depends on the presence of an envelope composed of polysaccharides (sugar subunits) surrounding the bacterial cells. When grown on laboratory culture mediums, virulent pneumococci produced large colonies with a smooth, glistening surface. Bacteria from such cultures caused infection in mice. After many transfers to fresh laboratory mediums, however, some of the bacteria lost their polysaccharide envelopes and their ability to infect mice; correlated with these changes was the change to small colonies with rough outlines. The smooth and the rough variants were designated S and R, respectively. Griffith found that mice inoculated with either the living R pneumococci or with heat-killed S pneumococci remained free of infection, but mice inoculated with a mixture of living R and heat-killed S bacteria became infected. He further discovered that living S pneumococcal cultures could be obtained from such animals, proof that the virulent S cells were reconstituted from the mixture inoculated. Some material derived from the dead S bacteria had induced the transformation of R into S strains. Avery and his coworkers showed that the “transforming factor” which conferred the characteristic of virulence upon nonvirulent pneumococci consisted of DNA, which had been transferred from dead virulent pneumococci into living nonvirulent pneumococci. That this newly acquired characteristic was due to a specific genetic activity was demonstrated by its persistence in all of the offspring of the transformed bacteria. The DNA of the dead cells evidently accomplishes the transformation of the living ones by penetrating the wall of the living cell. Once a section of the transforming DNA strand is inside the recipient cell, there apparently occurs a pairing between homologous regions of the bacterial chromosome and the transforming DNA. There must follow breakage and subsequent reunion of the bacterial chromosome and the transforming DNA. Thus a portion of the transforming DNA becomes integrated into the bacterial chromosome. If this model is valid, one would expect that genes located near each other on the transforming DNA would appear together more often in a transformed cell than will genes relatively far apart in the transforming DNA. This expectation has been fulfilled, and the principle has been utilized as a means of mapping the donor-cell chromosome. In further research the principles involved in transformation have been confirmed in a more efficient process involving mammalian cells in culture. By means of a process called transfection, defined pieces of DNA enter the cell nucleus and are incorporated into the DNA, thus replacing a particular genetic deficiency formerly exhibited by the cell.

In the early 1950s Alfred D. Hershey and Martha Chase obtained evidence confirming that DNA serves as the physical basis of heredity. In their experiment, Hershey and Chase used a bacteriophage that infects Escherichia coli, a colon bacteria. This bacteriophage (or simply phage) is an ultramicroscopic tadpole- shaped particle, with a hexagonal head, a cylindrical tail, and an end plate with six tail fibres (see virus). The entire outer surface consists of protein, but within the interior space of the head there is DNA. When a phage infects E. coli, it injects its own genetic material into the bacterial cell. The phage genes then subvert the metabolic machinery of the bacterium, causing the host cell to make phage DNA and phage protein. When a new generation of phage particle is ready inside the host, they destroy (lyse) the bacterium. This lysis releases the new phage particles into the medium, where they can attack other bacterial cells.

Hershey and Chase prepared two populations of phage particles. In one population the phage protein was labelled with a radioactive isotope; in the other the phage DNA was radioactively labelled. After allowing both populations to attack E. coli cells, the experimenters analyzed the exterior and the interior of the infected cells for the presence of radioactive material. They discovered that the phage protein had remained outside of the host cell, while the phage DNA had been injected into the bacterium. This ingenious research demonstrated that the genetic material of the phage consists of DNA rather than protein.

The evidence is now overwhelming that the basic material constituting the gene is fundamentally the same in all organisms: it consists of chainlike molecules of nucleic acids—DNA in most organisms and RNA (ribonucleic acid, a close chemical relative of DNA) in certain viruses. As will be discussed later, the gene no longer stands for a discrete unit of heredity of definite and invariable length but is thought of as an operational entity whose properties are more fluid and depend upon the mode of measurement.

Structure of nucleic acids

The remarkable properties of the nucleic acids, which qualify these substances to serve as the carriers of genetic information, have claimed the attention of many investigators. The groundwork was laid by pioneer biochemists who found that nucleic acids are long chainlike molecules, the backbones of which consist of repeated sequences of phosphate and sugar Animated structure of a linkages—ribose sugar in RNA and deoxyribose sugars in DNA. DNA molecule. Deoxyribose sugar Attached to the sugar links in the backbone are two kinds of molecules (green) and nitrogenous bases: purines and pyrimidines. The purines are phosphate … adenine (A) and guanine (G) in both DNA and RNA; the Encyclopædia Britannica, Inc. pyrimidines are cytosine (C) and thymine (T) in DNA and cytosine (C) and uracil (U) in RNA. A single purine or a pyrimidine is attached to each sugar, and the entire phosphate–sugar–base subunit is called a nucleotide. The nucleic acids extracted from different species of animals and plants have different proportions of the four nucleotides. Some are relatively richer in adenine and thymine, while others have more guanine and cytosine; however, the ratios of A to T, and also of G to C, are equal.

With the general acceptance of DNA as the chemical basis of heredity in the early 1950s, many microbiologists turned their attention to determining the molecular structure of this substance. In 1953 James Watson and Francis Crick proposed their now-famous model, which shows DNA as composed of two spirally wound (i.e., helical) chains, in which the A's of one chain are linked by hydrogen bonds to the T's of the other, and the G's in one chain are linked to the C's of the other. The model looks something like a twisted ladder: the sides of the ladder are composed of the sugar and phosphate groups, while the rungs are made up of the paired nitrogenous bases. Watson and Crick based their model largely on X-ray crystallographic studies of DNA, which had been performed by Maurice Wilkins and Rosalind Franklin. This model fulfills the basic requirements—it makes it possible to envisage how genes replicate their precise structures when their copies are synthesized. It also makes it possible to explain how a gene can carry genetic information written in some chemical code. And, finally, it helps to envisage how mutational changes in the genes are produced.

DNA replication

The Watson–Crick model of the genetic material permits an explanation of the mechanism of precise replication of genes (Figure 5). The paired complementary strands of the DNA molecule may separate as a result of a breakage of the hydrogen bonds between the paired nitrogenous bases. If free nucleotides (base + sugar + phosphate) are present in the medium surrounding the gene, they might pair with the Figure 5: A possible method for the replication complementary bases on the single strands of DNA. An enzyme, of DNA according to DNA polymerase, functions to form the phosphate bonds Watson and Crick. The between the sugars in the DNA backbone. It has been used in arrows … Encyclopædia Britannica, the synthesis of DNA in vitro, in cell-free systems. The enzyme Inc. is extracted from rapidly dividing cells of E. coli. A supply of the four nucleotides, A, T, G, and C, is provided, as well as a source of energy, adenosine triphosphate (ATP). To start DNA synthesis another key component is added—a trace of DNA to serve as a primer, or template. The kind of DNA that is synthesized depends on the primer. Even though the enzyme came from E. coli, if the primer is DNA of some quite different organism, such as cattle, the DNA that is synthesized is not E. coli but cattle DNA.

The Watson–Crick model of the structure of DNA suggested several different ways that DNA might self-replicate. The experiments of Matthew Meselson and Franklin Stahl on E. coli in 1958 suggested that DNA replicates semiconservatively to form two helices, each with one old and one new strand, the old strand acting as a template for the formation of a new strand. J. Herbert Taylor, using cells of higher organisms, Figure 5: A possible method for the replication confirmed the validity of this interpretation. Synthesis of new of DNA according to DNA occurs while the old chromosome is in the process of Watson and Crick. The uncoiling (see Figure 5). arrows … Encyclopædia Britannica, Inc. The DNA in one human cell is approximately two metres long when stretched out. It has been estimated that if all the DNA in a human were stretched out, it would extend from the Earth to the Sun and back again. For the large amount of DNA in one cell to fit, it obviously must be carefully and tightly packaged. About 140 base pairs of the DNA helix wind around a cluster of chromosome proteins (histones) to form a nucleosome, a structure similar to a bead on a string. Between the nucleosome beads is a string (linker region) of 20 to 100 DNA base pairs associated with another histone protein. This structure is flexible enough to permit the coiling and folding necessary to pack the DNA into the cell nucleus in a way that makes it readily available when it becomes genetically active.

DNA as an information carrier: transcription and translation of the genetic code

As has been stated, the Watson–Crick model provides an explanation of how a gene can carry hereditary information in the form of a chemical code. This section will describe the genetic code and explain how it governs the biochemical processes of the cell.

Before turning to the language of the code, it is necessary to explain what it is that the code specifies. It is now known that genes encode instructions for the production of proteins, which are largely responsible for the structure and function of the organism. Proteins are large, complex molecules consisting of one or more polypeptide chains that, in turn, are composed of amino acids linked together by peptide bonds. Proteins play many roles in organisms. Some proteins make up structural components of the organism; an example is the protein collagen in vertebrate animals. Others perform particular functions; for example, the protein hemoglobin transports oxygen in the blood of mammals, and the proteins of the immune system (immunoglobulins) protect against diseases in many members of the animal kingdom. Still other proteins regulate the rate of specific biochemical reactions in cells. This latter class of proteins, called enzymes, functions as biological catalysts. Enzymes permit chemical reactions to occur with extreme rapidity at temperatures normal to living cells. Without these proteins, the molecular interactions would require much longer periods of time and much higher temperatures, and they would lose their specificity. It is certainly no exaggeration to say that life depends on enzymes.

DNA and RNA: transcription

Among eucaryotes, DNA never leaves the cell nucleus, despite the fact that protein synthesis takes place on the ribosomes, structures that lie in the cytoplasm (i.e., in the portion of the cell outside of the nucleus). Even among procaryotes, which have no membrane-enclosed nucleus, the DNA does not directly carry its instructions to the ribosomes. In both kinds of organisms, this function is performed by a type of RNA that copies the DNA message and carries it to the site of protein synthesis. Aptly enough, this RNA is called messenger RNA, or mRNA for short. The copying of the DNA instructions into messenger RNA is called the transcription function of DNA, to distinguish it from the replication function discussed above.

The sequence of the genetic letters, A (adenine), T (thymine), C (cytosine), and G (guanine), in the DNA is first transcribed into the corresponding sequence of the letters A, U (uracil), C, and G in the messenger RNA. This occurs through the action of the enzyme RNA polymerase. This enzyme synthesizes RNA in a test tube from a mixture of the A, U, C, and G bases, but it does so only in the presence of a primer DNA. The sequence of the bases in the primer is copied in the RNA. The steps involved in this process are as follows: (1) the DNA double helix unwinds by breaking the hydrogen bonds between the corresponding bases in the paired strands; (2) the RNA polymerase forms the bonds between the RNA bases that are complementary to the bases in the DNA; and (3) the messenger RNA thus formed passes into the cytoplasm and becomes attached to a ribosome. Ribosomes consist of proteins and another type of RNA, ribosomal RNA (rRNA).

Protein synthesis: translation

The process of protein synthesis is represented diagrammatically in Figure 6. The information contained in the sequence of the bases (letters) in the messenger RNA is then translated into a sequence of amino acids in a protein. This requires the presence of still another molecule that is capable of recognizing the code for a specific amino acid and selectively making the amino acid available at the right point Figure 6: Synthesis of in the protein synthesis, a soluble RNA fraction within cells protein. Encyclopædia Britannica, that can bind amino acids. Soluble, or transfer, RNA (SRNA, or Inc. tRNA) is a single-stranded molecule that forms about 20 percent of the total cellular RNA. If amino acids and a source of energy (usually ATP) are added to a mixture of transfer RNA's, reversible binding of the amino acids to the RNA molecules occurs. Furthermore, each amino acid is bonded to a specific transfer RNA molecule by a specific activating enzyme. There are at least 20 different kinds of transfer RNA's and activating enzymes that correspond to the 20 amino acids commonly found in proteins. The amino acid-transfer RNA complex becomes attached to the ribosome with its messenger RNA molecule; the addition of the amino acid to the growing polypeptide chain then occurs. A sequence of three nitrogenous bases (anticodon) on the transfer RNA molecule pairs with a complementary sequence (codon) on the messenger RNA molecule, which is held in the correct position by the ribosome. Once the recognition has occurred, a peptide bond is formed between the amino acid bound to the transfer RNA and the growing polypeptide chain.

The accuracy of the model described in Figure 6 has been confirmed by the achievement of protein synthesis in the test tube. This synthesis requires a DNA template (primer DNA), precursor nucleotide molecules, ribosomes, transfer RNA's, amino acids, and a set of enzymes and certain other factors.

Figure 6: Synthesis of protein. Encyclopædia Britannica, Inc.

The central dogma

The processes of transcription and translation, as described above, can be represented thus: DNA ® RNA ® protein. Soon after its elucidation, this understanding of the genetic control of protein synthesis became known as “the central dogma” of molecular genetics. Included as part of the dogma was the belief that reverse transfer of information does not occur; in other words, there is no storage of information in the protein molecules and no transcription of protein back into nucleic acids or of RNA back into DNA.

The central dogma has since been modified to accommodate the discovery that reverse transcription of RNA to DNA does occur, as first demonstrated in some viruses. These viruses, called retroviruses, have a genome composed of RNA. When retroviruses enter a host cell, they produce an enzyme called reverse transcriptase. This enzyme permits the transcription of the viral RNA into DNA, which then may become incorporated into the genetic material of the host cell.

A second modification was necessitated by the discovery that not all DNA codes for protein synthesis. As discussed below, some of the noncoding DNA is involved in regulating the biochemical processes of the cell. The amount of noncoding DNA is small in procaryotes, but in eucaryotes it may be most of the cell's DNA.

Reading the code

It is necessary to understand how the four letters—A, T, C, and G—specify, or code, for 20 different amino acids. If a single letter coded for an amino acid, only four amino acids could be specified. If two bases were needed to specify an amino acid, then 16 different combinations could be constructed, again an insufficient number (20 amino acids must be accounted for). Combinations of three letters allow 64 different words to be constructed, more than the necessary minimal number. A three-letter, triplet, code could be constructed in at least three different ways: (1) with words overlapping; (2) with words not overlapping and punctuated; and (3) with words not overlapping and not punctuated. An overlapping code is composed of words that overlap each other—i.e., the letters of any given word may belong to one, two, or three words. The DNA might contain, for example, the sequence AGCGTTACG; the first word is AGC, the second CGT, and so on. This type of code is improbable, because of the restrictions it would place upon the possible sequence of amino acids in protein. As the example above shows, if the first word is AGC, the second word must begin with C, etc. Examination of amino-acid sequences in a protein such as hemoglobin indicates that any amino acid can follow any other—a possibility not allowed for by an overlapping code.

If the code is nonoverlapping, a problem of distinguishing words from each other arises. DNA contains no spaces separating the words as in written sentences; therefore, there must be other indications of specific starting points for messenger RNA synthesis. The base sequence AGC AGC AGC . . . could be punctuated by the presence of a fourth base, T, between each AGC triplet. This would reduce the number of possible triplets to 27. That a punctuated code of this type is not realized is seen from the evidence of the degeneracy in the code for some amino acids. The degeneracy means that some amino acids are coded for by more than one triplet, and a punctuated code does not allow enough words. A second objection to this type of code comes from a consideration of the effects of mutation on the coding sequence. If one of the punctuation marks mutates to another base, or a coding base mutates to a punctuation mark, the resulting sequence will be complete nonsense functionally.

The third possibility is a nonoverlapping, nonpunctuated code, in which the reading starts from a specific point. In all organisms studied in this respect this is the method of coding used. A knowledge of the base sequence in the messenger RNA and the resulting amino-acid sequence in protein reveals the code for each amino acid. The triplet UUU, for example, is the code for the amino acid phenylalanine, corresponding to the sequence AAA in the DNA. Poly-A (AAA) and poly-C (CCC) are messenger RNA's codes for lysine and proline, respectively.

Other triplets were tested for their coding abilities by synthesizing messenger RNA molecules with varying proportions of the two bases. If, for example, a mixture of the two bases U and C in a 5 : 1 proportion are synthesized into RNA, the possible triplets and their probable frequency in the synthetic messenger RNA can be easily determined. The triplet UUU will be most common and will appear with the frequency 5/6 ´ 5/6 ´ 5/6; the triplets UUC, UCU, and CUU will appear in the frequencies of 5/6 ´ 5/6 ´ 1/6; the triplets UCC, CUC, and CCU will be the next most frequent and will appear with a frequency of 5/6 ´ 1/6 ´ 1/6; while the triplet CCC should appear only 1/216 of the time. A messenger RNA of this composition should result in the incorporation into protein of eight different amino acids. In fact, only four amino acids were present in the protein produced; this means that several of these triplets encode for the same amino acid and therefore that the code is degenerate.

The RNA code triplets (or codons) and the amino acids for which they stand are shown in Table 3. Triplets have been discovered that encode for starting and for stopping the synthesis of protein chains in E. coli. Many proteins of E. coli begin with the amino acid methionine. Two different transfer RNA's for methionine are known to exist, only one of which functions to initiate protein synthesis. After synthesis of the protein, an enzyme may remove a portion of the beginning of the chain to eliminate the obligatory methionine molecule. The second transfer RNA for methionine allows this amino acid to be incorporated into the middle of a polypeptide. Encyclopædia Britannica, Inc. Termination of the synthesis of a polypeptide chain is signalled by three different RNA codons that do not specify an amino acid: UAA, UAG, and UGA. These triplets were discovered as nonsense mutations that produced premature cessation of protein synthesis in many different genes. Specific proteins called release factors can read these codons and release the polypeptide chain from the ribosome.

Mutations in the code

The DNA content of the cell must accurately replicate itself prior to mitosis or meiosis. Given the complexity of the DNA molecule and the vast number of cell divisions that take place within the lifetime of a multicellular organism, it is obvious that copying errors are likely to occur. If unrepaired, such errors change the linear order of the DNA bases and produce mutations in the genetic code. Many mutations arise from unknown causes. In addition to these so-called spontaneous mutations, researchers have demonstrated that a variety of environmental agents— including ionizing radiation, toxic chemicals, and certain viruses—can induce mutations.

Kinds of mutations

The addition or deletion of one or more bases results in a frame-shift mutation, so named because the reading frame of the gene, and thus its message, is altered from that point forward. Suppose that a DNA message read from left to right reveals the triplets GAC, TCA, and TTA (which are transcribed in the RNA code as CUG, AGU, and AAU). Deletion of the first T alters the reading frame so that triplets GAC, CAT, TA . . . will be read. The first triplet is unchanged, but all the remaining triplets may specify wrong amino acids. The chemical addition of a base to the sequence likewise shifts the reading frame; such a mutant will also specify wrong amino acids beyond the point of the base addition. If an original mutant resulted from the deletion of a base from the DNA, the addition of a base at a point beyond the first mutation would restore the reading frame of the DNA sequence and would result in nearly normal function. For example, assume that the original DNA sequence reads ACT GGC TAG CTG TCA TCG . . . . Deletion of the C in the second triplet results in the following triplets being read: ACT, GGT, AGC, TGT, CAT, CG . . . . The subsequent addition of a base (A) between the third and fourth mutant triplets results in the following sequence: ACT GGT AGC ATG TCA TCG . . . . Note that the first, fifth, and sixth triplets are identical to those in the original sequence. Only the second, third, and fourth triplets are altered, and the reading of the code from the fifth triplet on will be identical to that in the original message. Frequently, suppressor mutations occur in proximity to other mutations and restore the reading frame of the DNA sequence, thereby allowing a sequence of amino acids differing only slightly from the original one to be formed in the protein.

Mutations in which one base is exchanged for another are called base substitutions, or point mutations. A base substitution may result in the incorporation of one wrong amino acid into the polypeptide chain encoded by the gene. What effect this has on the functioning of the protein of which the chain is part depends on the type and position of the wrong amino acid. In many cases, the effects are minor, but there are exceptions. The human disease sickle-cell anemia, for example, is the product of a single base substitution inherited from both parents. Sometimes a base substitution results in a codon for an amino acid being changed to one of the termination triplets. This type of point mutation will cause premature termination of protein synthesis and, probably, complete loss of function in the finished protein.

Thus far distinctions have been made between mutations in terms of their effects on the nucleotide sequence of DNA. It is also useful to differentiate between mutations that affect germ cells (i.e., eggs and sperm) and those that affect somatic cells. When a mutation occurs in a germ cell, it can be passed on to offspring, where it will be carried in every cell of the new individual. Mutations in somatic cells, on the other hand, are not passed on to offspring, and they affect only a certain population of cells (the original mutant cell and its mitotic descendants) within the affected individual.

Rollin C. Richmond

Theodosius Dobzhansky

Arthur Robinson

Mutation rates

Detectable results of germinal mutation among people are only very rarely encountered. Thus, the actual rate of mutation in human chromosomes defies full measurement. A major reason for this is that most mutations seem to be recessive and thus tend to be masked for generations. Efforts to measure mutation rate therefore are most conveniently directed toward selected dominant or codominant mutations for which phenotypic recognition is easier. Indirect (inferential) methods of measurement are still required.

One dominant gene that is useful for studying human mutation rates produces the form of dwarfism called achondroplasia. When an affected child appears in a family in which both parents are normal, the properly diagnosed condition can be ascribed to the occurrence of one new mutation. The frequency of such an event is customarily calculated on the basis of the number of gametes (egg and sperm cells) produced by the parents in one generation; for human achondroplasia, the mutation rate has been inferred to be 4.2 per 100,000 gametes. Analyses of a number of different gene loci in humans and in such experimental organisms as corn and the Drosophila fly show that the average mutation rate among living beings is on the order of one in 100,000 gametes (10-5). Nevertheless, each gene studied shows its unique mutational probability; the neurological disorder called Huntington's chorea shows only about 0.5 mutation per 100,000 gametes, whereas the figure for neurofibromatosis (a disorder with soft tumours distributed over the whole body) has been stated to be somewhat higher. The general average in humans is considered to be about the same as for achondroplasia, roughly four per 100,000 gametes.

Hampton L. Carson

It may well be, however, that mutation rates are considerably higher than this figure for the following reasons: (1) there undoubtedly are “silent” mutations that do not change the biological function of the gene product (protein) in a way that will change the phenotype; (2) some mutations may be so harmful as to be lethal early in embryonic development; and (3) different mutations can produce the same abnormal phenotype, a situation known as genetic heterogeneity. It follows from the above that more accurate mutation rates in humans will result only from DNA analysis that reveals changes in the specific nucleotides of the DNA chain.

DNA repair

A variety of agents in the cell's environment, both chemical and physical, can damage DNA. Organisms have developed a variety of mechanisms for repairing copying errors produced by damaged DNA, usually by enzymatically excising them. The enzyme DNA polymerase then catalyzes the replacement of the excised segment with the correct nucleotides, using the undamaged DNA strand as a template. Eucaryotic cells have a greater variety of DNA repair mechanisms than do bacteria. Malfunctioning of the repair mechanisms can lead to genetic disease, abnormal function, or cancer. Xeroderma pigmentosum, a lethal human disease that is recessively inherited, involves several defective repair mechanisms. Regulation of genes

The evidence accumulated in genetics makes it virtually certain that not all the genes present in a cell are active in directing the specific processes of protein synthesis. Gene action can be switched on or off in response to the cell's stage of development and external environment. In multicellular organisms, moreover, each cell has a complete copy of the organism's genetic instructions, though different kinds of cells come to express different parts of the genome. That is to say that a skin cell, a nerve cell, and a bone marrow cell from the same person all contain the same genes; the differences in structure and function among these cells result from the selective expression and repression of certain genes.

In bacteria

In 1961 the French molecular biologists François Jacob and Jacques Monod proposed a model for genetic regulation in E. coli. When grown on a minimum culture of carbohydrates and sulfur, these bacteria can synthesize all of their necessary amino acids. To accomplish this amino-acid synthesis, the bacteria must produce various enzymes, the activities of which can be detected in a growing culture. If certain amino acids are added to the culture medium, the bacteria stop producing the enzymes required for the synthesis of these amino acids. This phenomenon is known as repression, and the enzymes affected are repressible enzymes. The pathway for the synthesis of the amino acid arginine in E. coli is a good example of how these repressible enzymes work. This synthesis involves three steps and three separate enzymes:

When arginine is present in the medium, none of the three enzymes involved in this process is detected, but if arginine is removed, all three enzymes rapidly appear. The end product of this pathway, arginine, controls the production of the intermediate enzymes, since the addition of either ornithine or citrulline to the medium has no effect. A related process involves the production of enzymes whose substrates are not always present in cells. The presence of lactose in the medium, for example, induces the synthesis of three enzymes that proceed to degrade lactose; this phenomenon is termed induction.

The classes of genes involved in regulating the expression of a bacterial gene—repressing its action or inducing it—are shown in Figure 7. The part of the chromosome containing the genes concerned is divided into two regions, one of which includes Figure 7: Model of the operon and its relation to the structural genes (i.e., those genes that code for protein the regulator gene. synthesis) and the operator gene. This region is termed an Encyclopædia Britannica, operon. The other part contains only the regulator gene. The Inc. regulator gene need not be located close to the operon. The regulator gene produces some substance, a repressor, which affects a second gene, an operator. There are several lines of evidence that suggest that the repressor substance is a protein molecule. It would be necessary for such a molecule to have at least two areas or sites that interact with the operator gene or a metabolite or both in order to influence structural genes (repress or induce their action, depending on given conditions).

In higher organisms

Although the operon model has proved a useful description of gene regulation in bacteria, evidence indicates that different regulatory mechanisms are employed in eucaryotes. The series of events associated with gene expression in higher organisms is much more complex than in procaryotes, requiring multiple levels of regulation. This is particularly true in multicellular organisms, in which cell differentiation takes place.

The regulation of gene expression in eucaryotes is not fully understood, but research in the fields of somatic cell genetics and recombinant DNA have yielded at least partial explanations as to how this process occurs. (The techniques involved in such research are discussed below.) What this research has indicated may be the mechanisms of gene regulation in higher organisms.

Eucaryotic DNA comprises three different classes: (1) unique, or single copy, DNA, which contains the structural genes (protein coding sequences); (2) moderately repetitive DNA, some forms (families) of which are dispersed throughout the chromosomes in small clusters and which may contain some functional genes, such as those that code for certain forms of RNA; and (3) the highly repetitive DNA, which contains nucleotide sequences repeated up to 1,000,000 times. This last class of DNA is usually clustered near the centromeres and is often known as satellite DNA. The function of the families of satellite DNA is unknown. There is no indication that their remarkably constant sequences are ever transcribed.

Since a very small percent of the DNA in higher organisms codes for proteins, the assumption is that the majority of DNA is involved in the control of gene action. If all the human structural genes functioned simultaneously, for example, metabolic chaos would ensue. Mechanisms exist for switching gene activity on and off at the appropriate time in development and in appropriate tissues, thus permitting the differentiation of the organs at various stages of development. Much of this regulation in higher organisms occurs during the processing of the RNA copies transcribed from DNA. Following the transcription of the DNA into this nuclear, or heterogenous, RNA, a process of editing and splicing takes place. The nuclear RNA contains long and often multiple noncoding intervening sequences of nucleotides. These sequences, called introns, are cut out, and the remaining coding regions, called exons, are spliced together to form the functional messenger RNA that can leave the nucleus to direct protein synthesis in the cytoplasm. Because the nuclear RNA, including its introns, is a mirror image of its DNA template, it follows that many genes of eucaryotes are discontinuous and may be characterized as mosaics of coding and noncoding regions. The role of the introns is not firmly established, but some evidence points to their possible involvement in regulating gene action. For example, researchers have shown that several forms of thalassemia (a common disease of hemoglobin) stem from intron mutations that interfere with the splicing action.

With the discovery of introns, molecular geneticists realized that it is impossible to determine the nucleotide sequence of a eucaryotic structural gene simply by analyzing the amino-acid sequence of its polypeptide product. This is so because the amino-acid sequence will not reflect the introns present in the native DNA. What is possible is to reconstruct the complementary DNA (cDNA), the DNA sequences consisting only of exons. As will be seen later, this has become an important part of recombinant DNA technology.

The analysis of nucleotide sequences has revealed a number of other mechanisms that help in the regulation of gene expression. Molecular geneticists have discovered small DNA sequences, about 100 base pairs in length, that interact with other constituents of the cell to produce specific regulatory effects on adjacent genes. These regulatory sites—called promoters, enhancers, or modulators—have been sequenced, and their effects studied on the quantitative expression of the products of a “standard” gene cloned by recombinant DNA techniques. Of particular interest is the enhancer site which may be involved in turning on specific genes in specific tissues at specific stages in development. In addition to illuminating the mysterious problems associated with normal development, chromosomal translocations may move these sites to abnormal positions where they can disturb cell multiplication and produce malignancy.

Cytoplasmic, or extranuclear, DNA

Some characteristics of organisms do not show Mendelian segregation and, among higher organisms, are inherited through the maternal line only. For example, the cells of green plants contain cytoplasmic bodies called chloroplasts, which carry the green pigment chlorophyll. In corn, variants are known whose leaves are striped green and yellow because of the absence of chlorophyll in the chloroplasts of some cells. Since no chloroplasts are present in pollen grains, the conclusion is that chloroplasts are self-replicating bodies in egg cells and in part control their own characteristics.

In the 1960s the existence of DNA within chloroplasts (in plants) and mitochondria (in complex animal cells) was demonstrated. The subsequent discoveries of ribosomes, transfer RNA's, and enzymes within mitochondria and chloroplasts have demonstrated that these cytoplasmic bodies synthesize part, but not all, of their own proteins.

The usual procedure for testing for extranuclear inheritance is to look at the progeny of reciprocal crosses of two different strains. Chromosomal (nuclear) inheritance predicts that offspring of the cross male A ´ female B should not differ phenotypically from those of the cross male B ´ female A. Cytoplasmic inheritance, on the other hand, is entirely maternal, as only the female gamete contributes chloroplasts or mitochondria to the zygote. Hence the offspring of male B ´ female A differ from those of male A ´ female B for traits controlled by extranuclear DNA. There is little evidence of cytoplasmic inheritance in humans. A large pedigree, however, has been reported of a family with a disease characterized by abnormal muscle fibres and abnormal mitochondria. In every case the disease was inherited from an affected mother, suggesting the presence of mutant mitochondrial DNA and cytoplasmic inheritance.

The biochemical products of gene expression

As stated above, the central function of genes (and hence of DNA) is to direct the production of proteins. The conceptual union of biochemistry and genetics, now called biochemical genetics, was first envisaged by Garrod, an English physician who has been called “the father of chemical genetics.” In lectures delivered in 1908, Garrod described four hereditary diseases (alkaptonuria, cystinuria, albinism, and pentosuria) that involve an enzyme deficiency. He dubbed these diseases “inborn errors of metabolism,” a name that persists to this day. Garrod stressed the unusual frequency of consanguineous matings in the parents of these patients. At a time when Mendel's laws were just being rediscovered, Garrod gave the first detailed description of recessive inheritance in humans, a point quickly appreciated by a pioneer in genetics, William Bateson.

Although the relationship between gene and enzyme was implicit in Garrod's work, it was more than 30 years before George W. Beadle and Edward L. Tatum of the United States made it explicit by their classical studies on genetic control of biochemical reactions in the bread mold Neurospora crassa. This work, for which Beadle and Tatum received the Nobel Prize for Physiology or Medicine for 1958, resulted in the formulation of the “one gene–one enzyme” hypothesis.

Most strains of N. crassa produce enzymes that enable the mold to grow on a minimal medium of sugar, inorganic salts, and the vitamin biotin. From these sources, N. crassa can synthesize all the amino acids, vitamins, and other substances necessary for its survival and reproduction. If, however, a genetic mutation results in the production of a chemically defective enzyme, the affected strain will not grow on the minimal medium unless the product of the now- defective enzymatic reaction is added. Let a metabolic pathway consist of a chain of reactions A ®(1) B ®(2) C ®(3) D, in which each reaction is mediated by a specific enzyme (1, 2, and 3, respectively). If the gene for enzyme 2 is mutated, C cannot be synthesized and the reaction stops. If, however, C is added to the medium, the reaction proceeds and D is formed. Meanwhile, however, B will accumulate in large amounts, which may be toxic.

The existence of metabolic pathways composed of successive steps, each of which is controlled by a single gene, appears to be a general phenomenon in the living world. One of the experimental techniques of somatic cell genetics (see below) has been to produce single-gene mutations that cause a nutritional defect in the experimental cell line. Through these abnormalities geneticists can elucidate the normal metabolic pathways of the cell and can map the gene to a specific chromosomal site. A similar phenomenon, of course, operates in the inborn errors of metabolism. Well over 100 different inborn errors of human metabolism are understood as defects in specific enzymes, secondary to specific gene mutations.

It was not, however, until the work of the U.S. biochemist Linus Pauling and his associates (1949) that the molecular basis for the relationship between a mutant gene and its protein product began to be understood. This was accomplished by the use of electrophoresis, a technique that separates different proteins by their movement through a liquid under the influence of an electric field. Pauling's electrophoretic separation of normal hemoglobin (hemoglobin A) from the hemoglobin of sickle-cell anemia (hemoglobin S) made it apparent for the first time that genetic disease could be understood in molecular terms. The hemoglobin molecule consists of two pairs of polypeptide chains, an alpha chain and a beta chain. Of fundamental importance was the determination by Vernon M. Ingram that the electrophoretic difference between hemoglobins A and S is due to the change of a single amino acid—glutamic acid being replaced by valine in position six of the beta chain. This results from a single base change in the DNA triplet responsible for the amino acid in position six: GAA is changed to GUA. The beta chain has 146 amino acids, but this one change disturbs the structure of the hemoglobin sufficiently to produce a most serious disease, sickle-cell anemia, in the homozygote.

Information resulting from this and other hemoglobin diseases demands that the “one gene–one enzyme” hypothesis be modified to the “one gene–one polypeptide” hypothesis or even more accurately to the “one structural gene–one polypeptide” principle. This has the advantage also of broadening the concept of inborn errors of metabolism to include any inherited deficiency of a protein, whether the protein is involved in enzymatic activity, transport, or structure.

Rollin C. Richmond

Theodosius Dobzhansky

Arthur Robinson

Somatic cell genetics

The development of molecular biology represented a fusion of biochemistry and genetics. As has been discussed, most of the pioneer research in this field utilized microorganisms. The great strides made in genetic-biochemical analysis resulted basically from the ability to place an experimental organism on a culture dish containing agar (a jellylike substance) and a nutrient medium supporting cell multiplication. The cells multiplied to produce discrete colonies. All the cells in a particular colony formed a clone; that is, they all had the same genetic constitution as the founding cell. By selecting a founding cell with a phenotypically observable mutation, researchers could easily establish clones with the mutant genotype. The biochemical products of these mutant cells could then be studied and compared to those of normal colonies. By contrast, the study of genetics in higher organisms was, for many years, limited to the analysis of the genetic effects of experimental matings. In human genetics, even this technique was not available, as the experimental mating of human beings is not only morally unjustifiable but also unworkable due to the long generation time (about 30 years) of the species. These obstacles precluded the observation of the segregation of human genes over multiple generations except by the classical methods of retrospective analysis of large family pedigrees.

During the late 1950s, molecular biologists learned to grow single mammalian somatic cells in culture, a feat hitherto thought impossible. This ability to treat “the mammalian cell as a microorganism” (a phrase coined by the U.S. molecular biologist Theodore T. Puck) has made it possible to study the genetics of higher organisms with techniques similar to those used in E. coli. Somatic cell genetics has permitted researchers to analyze mammalian cells in terms of their growth requirements and their responses to a variety of environmental agents and especially to study, at the molecular and cellular level, the processes of heredity in these cells. Because of such research, the characteristics of mammalian cells in culture can be analyzed in simple, quantifiable terms. In the study of human genetics, somatic cell techniques have revolutionized the diagnosis of genetic disease (including prenatal diagnosis), have made possible the analysis of the human chromosomes, and have elucidated some of the processes of normal and abnormal differentiation, including those involved in producing cancer.

Mammalian cells can be cultured from many different tissues (e.g., white cells from the blood, fibroblasts from the skin, marrow cells from the bone) for a variety of purposes. These include (1) studies of the chromosomes (cytogenetics), (2) biochemical assays to look for enzymatic defects associated with human diseases, (3) examination of DNA and the processes of replication, (4) interspecific and intraspecific somatic cell hybridization to gain information about the position of genes on the human chromosomes, and (5) the study of the structure and function of the cells and their organelles (constituent parts). These cells, with the exception of lymphocytes (white blood cells), can be kept in culture for long periods or stored in a frozen state to be thawed out and recultured later. The human lymphocyte, readily available from a peripheral blood sample, can be kept in culture for only several days. It can, however, be transformed into a permanent culture that can be frozen and reactivated at a later time by infecting it with certain viruses, particularly the Epstein–Barr virus.

The ability to fuse two cells, either of the same or of different mammalian species, has proved to be one of the most powerful tools of somatic cell genetics. Researchers accomplish such fusion by treating the cultured cells with an irradiated, killed virus (the sendai virus) or with particular chemical agents; in response the cytoplasm and nuclei of the cells merge to form a hybrid cell with a single, large nucleus that contains the genome of both “parent” cells.

The hybridization of two cells from the same species—each cell having been exposed to radiation or chemical agents to produce a desired phenotypic mutation —is useful in complementation analysis. Consider, for example, the fusion of two mutant cells (A and B) whose DNA has been damaged by a point mutation so that neither cell can grow in a medium lacking glycine. If the hybrid cell can grow in the absence of glycine, the two mutant genomes have complemented each other. In short, the defect in the DNA present in cell A involves a different gene at a different location than that in cell B, and the combined genome is able to compensate for each mutation. If, however, A and B have mutations at the same DNA locus, they cannot produce a glycine-independent hybrid. When complementation occurs, researchers can analyze the biochemical products of the “parent” cells to elucidate the nature of the mutation that exists in each cell.

The fusion of cells of two different species (e.g., of a human cell and a Chinese hamster cell) produces a hybrid cell that, when cultured, undergoes extensive chromosome loss, primarily of the species whose cultured cells have the longer generation time. In the case of the human–Chinese hamster hybrid, human chromosomes are lost. If a mutant hamster cell with a nutritional deficiency (e.g., one that cannot grow in the absence of glycine) is hybridized with a human cell without the deficiency, the hybrid cell will not show the deficiency (in this instance the hybrid will be able to grow in a medium without glycine). The hybrid cells will then produce clones showing extensive loss of the human chromosomes. The one human chromosome the hybrid cannot lose is the one that carries the human gene that compensates for the hamster cell mutation, for without that gene the cell would die. By employing this technique, researchers can identify the human chromosome on which a particular gene is located. In fact, by using a series of X rays or other manipulations to break the human chromosome, geneticists can locate the segment of the chromosome possessing the gene. Hundreds of human genes have been mapped to a specific chromosome, in many cases to a specific chromosomal region, by this method. Using increasingly small chromosome deletions, researchers have succeeded in locating the genes in their proper order on the chromosomes. By studying the recombination frequency between these genes (a task made simpler by the methods of recombinant DNA discussed below), the distances between them on the chromosome have been mapped. The ability to locate the human genes on the 23 pairs of chromosomes is of tremendous practical importance for understanding human genetics. When large numbers of genes are mapped, investigators can identify which are absent or supernumerary in the many diseases involving the human chromosomes. Mapping also helps geneticists elucidate the nature of gene control in mammals, which, as has been discussed, is significantly more complex than the relatively simple operon system in bacteria. Insights into gene regulation in mammals can increasingly be applied to understanding of cellular biochemical control in normal development and in human disease.

Genetic engineering: recombinant DNA

Since the 1970s, biologists have made major advances in understanding the molecular nature of genes and their functioning through the use of the powerful experimental techniques of recombinant DNA. The term recombinant DNA literally means the joining or recombining of two pieces of DNA from two different species. Recombinant DNA techniques allow an investigator to biologically purify (clone) a gene from one species by inserting it into the DNA of another species, where it is replicated along with the host DNA. Actually, the term includes a variety of molecular manoeuvres, including cleaving DNA by microbial enzymes called endonucleases, splicing or recombining fragments of DNA, inserting eucaryotic DNA into bacteria so that large quantities of the foreign genetic material can be produced, determining the nucleotide sequence of a segment of DNA, and even chemically synthesizing DNA.

Gene cloning ranks as one of the most significant accomplishments involving recombinant DNA. This procedure has enabled researchers to use E. coli to produce virtually limitless copies of donor genes from other organisms, including human beings. To perform gene cloning, researchers first use a class of bacterial enzymes called restriction endonucleases to remove from the donor cell a fragment of double-stranded DNA that contains the genes of interest. Restriction endonucleases can be thought of as “biological scissors”; each of these enzymes cleaves DNA at a specific site defined by a sequence of four or more nucleotides.

Once the desired DNA fragment has been removed from the donor cell, it must somehow be inserted into the bacterial cell. This is usually done by first inserting the donor DNA into a plasmid, one of the small, circular pieces of DNA that are found in E. coli and many other bacteria. Plasmids generally remain separate from the bacterial chromosome (although some plasmids do occasionally become incorporated into the chromosome), but they carry genes that can be expressed in the bacterium. Furthermore, plasmids generally replicate and are passed on to daughter cells along with the chromosome. By treating a plasmid with the same restriction endonuclease that was used to cleave the donor DNA, it is possible to incorporate the foreign DNA fragment into the plasmid ring. This can occur because the restriction enzyme cleaves double-stranded DNA in such a way as to leave chemically “sticky” end pieces. It is thus possible for the sticky-ended fragment of foreign DNA to attach to the complementary sticky ends of the cut-open plasmid ring. This laboratory procedure, called “gene splicing,” is the major operation of recombinant DNA technology.

The molecular biologist then uses the plasmids as vectors to carry the foreign gene into bacteria. This is accomplished by exposing bacteria to the plasmids. Plasmids are highly infective, and so many of the bacteria will take up the particles; to insure maximum uptake the bacteria are often treated with calcium salts, which makes their membranes more permeable. The incorporation of the plasmids into the bacterial cells marks the transfer of the genes of one species into the genome of another. Alternatively, bacteriophages are sometimes used as vectors to carry the foreign DNA into the bacteria. As a result of the high infectivity of plasmids and the rapid growth of E. coli, investigators can quickly culture large numbers of bacteria, many of which will have incorporated the foreign (often human) DNA. (As many as 1 ´ 109 bacteria can grow in one millilitre of medium overnight.) Researchers can select the bacteria that contain the foreign DNA by attaching to the fragment of DNA a gene that confers resistance to an antibiotic such as tetracycline. By treating the culture with tetracycline, all bacteria that have not incorporated the gene for resistance will be killed. The remaining cells can be grown in enormous numbers, most of which will contain the cloned fragment of foreign DNA.

The cloned DNA can be removed from the bacterial culture as follows. First, the bacteria are broken apart and the DNA content is separated by centrifugation. The DNA fraction is then heated, which causes the double-stranded molecules to separate into single strands. Upon cooling, each single strand will reanneal, or hybridize, to another single strand to which it is complementary (adenine opposite thymine, cytosine opposite guanine). This form of molecular hybridization has made possible the use of the complementary DNA (cDNA) as a probe for picking out the desired gene.

Investigators also use DNA to pick out a specific gene from a large piece of genomic DNA. In some cases where a cell makes large amounts of specific mRNA (such as globin mRNA in human red cells), the extracted mRNA can be treated with reverse transcriptase to produce cDNA. When labelled with a radioisotope, this then becomes a cDNA probe for the human globin gene. The technique for isolating and hybridizing the fragment of interest is called “southern blot” analysis.

The huge number of copies attained by gene cloning enables researchers to analyze the cloned DNA exhaustively, down to its nucleotide sequence. Nucleotide sequencing is accomplished by performing a series of biochemical manoeuvres on small, endonuclease-produced fragments (oligonucleotides) and then placing them in the correct order. Remarkably, molecular biologists have automated the entire procedure so that a “gene machine” can determine the nucleotide sequence of a gene in a relatively short time. In fact, if the amino-acid sequence of a protein is known, researchers can formulate the nucleotide sequence that produced it and then synthesize the gene. This has been done for insulin.

As has been discussed, a given restriction endonuclease can produce a very large number of discrete DNA fragments, which can be inserted into vector DNA incised by the same endonuclease. Researchers can clone the fragments as described above to produce a so-called library of genomic DNA. This library can be used to study the natural gene whenever a new probe is obtained. A given restriction enzyme generally will produce fragments that are the same for all individuals. However, different people occasionally vary in the size of specific fragments. This is due to the fact that in any string of several hundred bases in human DNA there occur single base changes, usually harmless substitutions that either change or remove the enzyme site. These fragment variations, known as restriction-fragment-length polymorphisms, are inherited and hence form genetic markers that can be used to trace mutant genes to which they are linked. If the fragments are separated by agarose gel electrophoresis and overlaid with a radioactively labelled cDNA probe, only the fragment whose DNA is complementary to that of the probe will hybridize with it. This hybridization can be detected by exposing the DNA fragments to photographic film; the resultant image is called an autoradiograph. When restriction-fragment-length polymorphisms are present, different-sized fragments will hybridize with the same probe. Linkage studies between a disease-producing mutant gene and a polymorphism will locate the gene to either the polymorphic or “wild-type” (i.e., normal) fragment. If large family studies show that the gene is linked closely enough to the fragment so that recombination is rare, this technique can be used for diagnosing the presence of a genetic disease for which the biochemical defect is unknown (see below).

One further result of the ability to analyze gene structure at the molecular level has been the discovery of its remarkable plasticity. Investigators have found sequences of nucleotides that have the capacity to move from one position on the chromosome to another, often carrying neighbouring sequences with them and thus rearranging the DNA. These “jumping genes”—known as transposable elements, or transposons—have been found in both procaryotes and eucaryotes. In the higher mammals, including humans, they are the source of the tremendous diversity necessary for antibody production by the immune system. It is also possible that some forms of cancer may develop as a result of these rearrangements.

In addition to producing copies of genes for molecular analysis and for use in medical diagnosis, recombinant DNA procedures have been used to convert bacteria into “factories” for the synthesis of foreign proteins. This is a tricky operation, for not only must the foreign DNA be inserted into the host bacterium, but it also must be incorporated into an operon so that its product will be expressed. Despite the technical difficulties, investigators have achieved the expression of foreign genes within E. coli. This fact has tremendous potential in medicine, as the “engineered” bacteria can be used to produce therapeutically valuable human proteins. Insulin, growth hormone, and antihemophilic globulin (the clotting factor missing in persons with hemophilia) are three such proteins that have been commercially “manufactured” via recombinant DNA in E. coli. As a result of this “engineering,” the host bacterium has been provided with new genetic properties. Both the scientific and lay communities have expressed concern over the creation of microorganisms with new genetic properties. Perhaps this genetic tailoring of infectious agents like E. coli could visit new and devastating epidemics on the population or could introduce cancer-causing genes into infected people. In the United States, federal agencies, with the assistance of molecular biologists, have laid down stringent guidelines to ensure the control of microorganisms containing the recombinant plasmids. The most effective measure has been the requirement to use strains of E. coli that have been modified so that they can survive in the laboratory but not in nature (and hence are not infectious). In addition, the guidelines require a physical containment system that securely seals off the laboratory, thereby preventing the escape of the bacteria from the facility. Molecular biologists have also called attention to the fact that recombinant processes are constantly occurring in nature, albeit at a slower rate.

Other forms of genetic engineering

The techniques discussed so far, all of which are outgrowths of somatic cell genetics, have made it possible to manipulate the genetic systems of a variety of organisms. The popular press has dubbed this research “genetic engineering” and has implied that it is somehow dangerous, unnatural, and immoral, especially when human chromosomes are manipulated. In one sense, of course, the selective breeding of desirable traits in both plants and animals has been practiced since ancient times and is a form of genetic manipulation. For this discussion, however, genetic engineering will be limited to the deliberate laboratory manipulation of the cellular or nucleic acid constitution of an organism so as to produce a specific genetic change that will persist as the cell, or cells, multiply.

The genetic engineering made possible by these techniques has caused people to consider social, ethical, and philosophical issues raised by the production of new forms of life. The U.S. Supreme Court has stated that the production of a new bacterium (E. coli) “with markedly different characteristics from any found in nature” may be patented by the scientist who makes it. Many have found this an objectionable form of “playing God,” which diminishes the mystery of life. Others claim that this new biotechnology developed out of human efforts to understand life and does not in the slightest affect its mystery. The nightmare of “mad geneticists” using these techniques to permanently alter the phenotype of the human species or to “clone” humans to genetic specifications may be possible in the distant future. To guard against such abuses requires careful regulation of various types of research on human embryos.

In addition to recombinant DNA, other forms of genetic manipulation that will increase knowledge of developmental processes and eventually may be of assistance in the replacement of mutant genes by normal genes include gene transfer, embryo transfer, and nuclear transplantation.

Gene transfer ranks as one of the most promising methods for increasing understanding of developmental genetics. In gene transfer, molecular biologists isolate segments of DNA containing a gene or genes of interest and then incorporate them into the DNA of somatic cells in culture. Investigators transfer the genes with the assistance of calcium ion by a process called transfection; alternatively, they can insert the genes by the delicate procedure of microinjection. These genes replicate with the cells and on occasion will produce their specific protein products. One mammal to which gene transfer has been successfully applied is the mouse. Researchers have microinjected foreign genes into fertilized mouse eggs and then transferred the surviving embryos into the uterus of an appropriately prepared (pseudopregnant) female mouse, where implantation and gestation occur. The mice born from these experiments have produced the foreign gene product and have passed the new gene on to their offspring. It should be emphasized that this procedure has the capability not only of counteracting the effects of a defective gene in the mouse but also of passing on the new gene to future generations, thus effecting a true genetic cure. Similar gene-transfer procedures might possibly be effective in treating genetic diseases in humans.

Embryo transfer refers to the process of transferring a pre-implantation embryo from the reproductive tract of one female to that of another, where it often implants and goes through a normal gestation. In an elaboration of this method in the 1960s, Beatrice Mintz and her coworkers disaggregated the cells from early embryos of two genetically different pure lines of mice, mixed them together, and then reimplanted the newly formed embryos into the uterus of a foster mother. The embryos developed and were born as tetraparental (allophenic) mice.

In nuclear transplantation, molecular biologists transfer the entire nucleus of one cell into a second, enucleated cell (i.e., a cell that has had its nucleus removed). This work has had its broadest application in the study of cell differentiation in higher animals. By transplanting the nucleus from a differentiated cell into a less specialized one, investigators have sought to answer some of the riddles of differentiation. One of the landmark experiments in nuclear transplantation was performed by the British molecular biologist John B. Gurdon. Gurdon transplanted a mature nucleus from an intestinal cell of a tadpole into an enucleated frog's egg which subsequently developed into a normal, adult frog. Gurdon thus demonstrated that a highly differentiated intestinal cell nucleus, with only intestinal cell genes functioning, could undifferentiate in the environment of the enucleated egg cell and could reactivate those genes necessary to create an entire frog. The frog that was produced was a “clone” in the sense that the entire genome of the donor tadpole was present in all the cells of the newly formed frog. Even such a frog, however, is not an exact replica of the donor because of the multiple levels at which gene expression is affected by changing environments. Cells from an adult frog, rather than a tadpole, were not successful in this experiment. Although it is not impossible that humans could be cloned in this way in the future, such cloning would be extremely difficult and of questionable use, certainly for large numbers. The moral dilemmas raised by this type of genetic engineering would be most serious.

Arthur Robinson

Heredity and evolution

The gene in populations

In the study of heredity the first question that arises is how the genotype of an individual is formed from the constituents of the genotypes of his parents. This is the genetics of individuals or basic genetics. One may also inquire how the genotype in a fertilized egg cell influences the developmental pattern of the organism and thus realizes its potentialities. This is developmental genetics. An individual, at least an individual of a sexually reproducing species, is not, however, biologically complete in itself. Its biological role is actualized through its membership in a reproductive community, a Mendelian population. A Mendelian population consists of individuals among whom matings may or do occur. An individual is mortal and temporary; a Mendelian population has a continuity through time. The genetic processes in Mendelian populations are the subject matter of population genetics.

The gene pool

A Mendelian population is said to have a gene pool. The gene pool is the sum total of the genes carried by the individual members of the population. The gene pool also continues through time. The genes of the individuals of the generation now living come from a sample of the genes of the previous generation; if these individuals reproduce, their genes will pass into the gene pool of the following generations. The Mendelian population and its gene pool in humans have a very complex structure. Individuals born and living close together are more likely to meet and to mate than those living far apart. In a widely distributed species such as Homo sapiens, the likelihood of mating of individuals born on different continents was, until the development of modern means of travel, very small. The gene pool of the human species is, accordingly, divided into the smaller gene pools of races and populations living in different regions. Aside from the geographic divisions, there are also linguistic, religious, social, economic, and educational barriers that break the gene pools into further, often overlapping, subdivisions. The smallest subdivision is referred to as an isolate or panmictic unit; it consists of a relatively limited number of persons (or animals or plants) that may be regarded as potential mates. Few of these divisions may be sharp enough to decide where one gene pool subdivision ends and the other begins, and yet these subdivisions are biologically meaningful.

A biological species, in sexually reproducing organisms, is defined as the most inclusive Mendelian population. The gene pool of Homo sapiens is an entity the limits of which are not in doubt, since no gene exchange between the human and any other related species takes place. Nor does the intraspecific differentiation impair the unity. There may never have been a marriage of, for example, an Eskimo and a Melanesian, but genetic communications between the Eskimo gene pool and the Melanesian gene pool occur through the chains of geographically intermediate populations. A genetic change arising anywhere in the world, if favourable, may spread throughout humanity. This is how genetic changes may have transformed the ancestral prehuman species into the present one. This genetic unity makes any genetic damage (e.g., that caused by exposure to high-energy radiation) a concern of all people, regardless of whether the damage is inflicted more heavily on one portion of the human population than on another.

The Hardy–Weinberg principle

In 1908, Godfrey Harold Hardy and Wilhelm Weinberg independently formulated a theorem that became the foundation of population genetics. According to the Hardy–Weinberg principle, two or more gene alleles will have the same frequency in the gene pool generation after generation, until some agent acts to change that frequency. Consider a population that is, as most human populations actually are, a mixture of individuals with M, N, and MN blood types. An individual with M blood is a homozygote with two M alleles (MM), an N individual has two N alleles (NN), and an MN individual is a heterozygote (MN). Suppose that a population consists of 49 percent of individuals with M, 42 percent with MN, and 9 percent with N bloods. The frequencies of the blood types in the next and the following generations can be calculated. Assume for simplicity that (1) marriages are at random with respect to the blood groups, (2) people with different blood groups have neither advantages nor disadvantages in survival or in reproduction, (3) the alleles M and N do not change frequently by mutation, (4) there is no migration into or out of the population, and (5) the population is large enough so that chance fluctuations may be ignored. Also assume that all individuals produce equal numbers of sex cells with each of the pair of alleles they carry and that the sex cells of the parents combine at random in fertilization.

Persons with M blood produce sex cells with the allele M, and these sex cells will amount to 49 percent of the total. Persons with MN blood produce equal numbers of M- and of N-bearing sex cells—i.e., 21 percent of each. Finally, persons with N blood will give N-bearing sex cells, 9 percent of the total. The gene pool will, therefore, contain 49 + 21 = 70 percent of M- and 21 + 9 = 30 percent of N-type sex cells, or, using decimals, 0.7 M and 0.3 N, respectively. These sex cells will combine to produce the following blood types in individuals: 0.7 ´ 0.7 = 0.49, or 49 percent of M; 0.3 ´ 0.3, or 9 percent of N; and 2 ´ 0.7 ´ 0.3, or 42 percent of MN. Generalizing, if the proportions of M and N genes in the gene pool are p and q, respectively, the frequencies of the blood groups will be, generation after generation:

(In this expression p2 represents the genotype MM, q2 the genotype NN, and pq the genotype MN.) This expression is the Hardy–Weinberg formula, which describes the genetic equilibrium status in populations. The genetic composition of a population can meaningfully be described in terms of the frequencies of various alleles of the genes in the gene pool. Different populations of the same species are likely to differ in the frequencies of some, probably of many, genes. If the gene frequencies are different, the populations are racially distinct; if the differences are large, one may decide to give these populations different racial (or subspecific) names.

Changes in gene frequencies

The Hardy–Weinberg principle predicts that gene frequencies will remain constant from generation to generation within a population that meets certain assumptions. It further predicts that if mating is random in regard to genetic traits, then the frequencies of genotypes will also remain constant in succeeding generations. Yet if all gene frequencies remained constant in populations indefinitely, evolution could not take place. Evolution is, in the last analysis, change of gene frequencies.

The assumptions that underlie the Hardy–Weinberg principle are, in fact, theoretical considerations that are never met in natural populations. Mutations and migrations can affect gene frequencies. Many natural populations are small enough that chance fluctuations can significantly alter gene frequencies. Moreover, in many cases matings may be selective rather than random in regard to certain genetic traits; this will alter the frequencies of genotypes in succeeding generations. The effects of these phenomena are described in this section.

Finally, and most importantly in considering the genetics of evolution, a certain genotype may offer an advantage in terms of reproduction or survival over its counterparts. Such advantageous genotypes, and their constituent alleles, will increase in frequency in succeeding generations. This phenomenon, called selection, is dealt with at length below (see Selection as an agent of change).

Mutations

As has been discussed, under most circumstances newly formed chromosomes and their genes are perfect of the originals. This remarkably stable copying process is the basis of the continuity of living species, generation after generation, for each specific characteristic encoded by the genes.

It also has been shown, however, that mutations—in the form of chromosomal aberrations and miscopying of DNA—do occur. Mutations produce the potential for new traits. Even when only a single gene in one cell is mutated, the copying process tends faithfully to reproduce the changed DNA in all the descendants of that particular cell. Indeed, mutation appears to be a basic cellular mechanism underlying evolution.

That mutations can arise in response to environmental agents was first demonstrated by Hermann J. Muller, who in 1926 demonstrated that Drosophila flies exposed to X rays suffer high rates of mutation. It is now known that other forms of radiation, as well as a variety of chemicals, can serve as potent mutagenic agents, producing both chromosomal aberrations and changes in the DNA of individual genes. The implications of these findings are discussed in the article human genetics.

In discussing mutation in the context of gene frequencies and evolution, it is imperative to recall the difference between germinal mutations and somatic mutations. Only the former are passed on to offspring, who will then “breed true” for the altered or defective trait. It is germinal mutations, then, that can produce the greatest effect in altering gene frequencies in succeeding generations of a population.

Gene flow

Migrations of individuals into a population can introduce new alleles or can increase the frequencies of those already present; similarly, migration out of a population can remove alleles or decrease their frequencies. This gene flow may be negligible in a highly isolated population, such as one on a remote island, but it operates freely among adjacent populations of species that occupy large ranges. Gene flow is most readily appreciated in human and other animal populations made up of mobile individuals; it occurs in plants as well, however, as pollen may be carried by wind or by animals from one population to another.

Genetic drift

This term refers to the effects of chance fluctuations on gene frequencies in small populations. Consider a small population in which there are two alleles—a and A— for a particular gene. If the frequency of one of these alleles, say a, is low to begin with, a chance event that has nothing to do with the selective value of that allele could result in its complete elimination from the population. The population would then consist entirely of AA individuals. Such an event is referred to as a fixation for gene A. Conversely, a chance event could result in the loss of several AA individuals from the population; in this case, the frequency of a would increase.

Genetic, or random, drift is most obviously manifested in what is known as the “founder effect.” This occurs when a small group of individuals—or even just one pregnant female—migrates into a new region, or when a small group becomes reproductively isolated from its parent population without migration. The genes carried by the founders of the new population will often be small, atypical, and unbalanced samples of the gene pool of the population whence they came. In the case of a new, small population established by migration, the subsequent frequencies of alleles will depend not only on the chance distributions carried by the founders but also on the environmental influences (i.e., the selection pressures) of the new location. In the case of reproductive isolation without migration, the situation depends more on the chance distribution of alleles in the small group at the time of isolation and the relative degree of consanguinity among those mating. These factors might explain the increased frequency of a relatively rare autosomal recessively inherited disease, Tay-Sachs, among Jews of eastern European origin. For many years these people were forced to live in small isolates and were socially ostracized by the population around them. As a result, a mutant gene present in the original small group had the opportunity to express itself as a lethal disease among homozygotes.

Selective mating

Mating may be selective rather than random with respect to a given gene. Suppose that persons with M, MN, and N bloods prefer to marry individuals with a blood group the same as themselves. Selective mating will not, by itself, change the gene frequencies, but it will disturb the Hardy–Weinberg equilibrium in another way. The relative frequencies of the homozygotes (MM and NN) will increase from generation to generation, while those of the heterozygotes (MN) will decrease. Eventually the population will consist of homozygotes only. Preferential mating of unlike genotypes will, on the contrary, increase the incidence of the heterozygotes, but it will not, no matter how long continued, eliminate the homozygotes.

Selection as an agent of change

Natural selection and Darwinian fitness

Sexual reproduction under simple (Mendelian) inheritance is a conservative force that tends to maintain the genetic status quo in a population. If a gene frequency is 1 percent in a population, it tends to remain at 1 percent indefinitely unless some force acts to change it. Outside of the laboratory, the most powerful force for changing gene frequencies is natural selection.

The carriers of some genes may survive more often or be more fecund than the carriers of other genes. When the carriers of different genes are not equally efficient in transmitting these genes to the succeeding generations, the result is natural selection. When the inequality of the transmission rates of the genes is imposed by human will, the result is artificial selection. In general, the genes that confer on their possessors a superior reproductive efficiency will increase in frequencies from generation to generation, and the reproductively inferior genes will become less frequent.

Imagine a population that carries two alleles—A1 and A2—for a particular gene. Suppose that the relative numbers of the surviving progeny left by the carriers of the genotypes A1A1 and A2A2 are in the ratio 1 : 1 - s (the value s is called the selection coefficient). If for every 100 offspring of A1A1 parents only 90 surviving offspring are left by A2A2 parents, then s = 1/10 or 0.1. The heterozygotes, A1A2, may leave as many progeny as A1A1 (if A1 is dominant) or as many as A2A2 (if A2 is dominant) or an intermediate number (if neither is dominant). Alternatively, the heterozygotes may exhibit the quality of hybrid vigour (heterosis); that is, they may be reproductively superior to both homozygotes A1A1 and A2A2. And finally (though this is rare except in species hybrids) the heterozygotes may be at a disadvantage compared to both homozygotes. The situation is simplest if the heterozygotes (A1A2) are equal in reproductive efficiency to one of the homozygotes or intermediate between the two.

Whichever gene, A1 or A2, confers a superior reproductive efficiency on its possessors will increase in frequency in the population. The increase will continue generation after generation; given enough time (i.e., enough generations) the more efficient gene will eliminate and supplant the less efficient one entirely. How rapid or slow the gene frequency changes will be depends on the magnitude of the selection coefficients. Table 4 gives several examples for a dominant allele, for a recessive allele, and for no dominance—i.e., for the case in which the fitness of the heterozygote is intermediate between the two homozygotes. The two alleles in the population with which the selection starts are assumed to be equally frequent, p = q = 0.5. The selection coefficients of one (lethal), 0.5, 0.1, and 0.01 are considered, and the gene frequencies after one, two, five, 10, 20, 50, and 100 generations of such selection are given.

The homozygotes for a recessive gene allele may not reproduce at all. With natural selection this may happen because they are inviable (lethal) or sterile; with artificial selection the same result is accomplished if the breeder kills them or does not use them as parents. The recessive allele is then opposed by a selection s = 1. Table 4 shows that a gene with an initial frequency of 0.5 will decrease to 0.33 after one generation, to 0.25 after two, and to 0.01 after 100 generations. With weaker selection (s smaller than unity) the decrease of the recessive allele will, of course, be slower. Note, however, that in all cases the frequency change is more rapid when the gene is common than when it is rare. A dominant allele opposed by a selection s = 1 (a dominant lethal) disappears in a single generation, and even weaker selections against dominants are more efficient than similar selections against recessives. A selection in favour of a recessive is, of course, just the reverse of that against a dominant, and vice versa. The frequencies can be read from Table 4 by subtracting the frequencies given from unity. When the dominance is absent, the efficiency of selection is, as shown in Table 4, intermediate between those for recessives and for dominants.

A most interesting, and at first sight paradoxical, outcome of selection arises if the heterozygote is superior to both homozygotes. Neither the gene A1 nor A2 is allowed to crowd the other out or to disappear entirely. Instead, a genetic equilibrium is reached, and the population attains the state of the so-called balanced polymorphism. All three genotypes continue to occur in the population, with frequencies dependent on the relative magnitudes of the selection coefficients s1 and s2. This will be true even if one of the homozygotes is seriously incapacitated, inviable, or sterile. The possible importance of this in human populations is considered below.

Darwin's description of the process of natural selection as the survival of the fittest in the struggle for life is a metaphor. “Struggle” does not necessarily mean contention, strife, or combat; “survival” does not mean that ravages of death are needed to make the selection effective; and “fittest” is virtually never a single optimal genotype but rather an array of genotypes that collectively enhance population survival rather than extinction. All these considerations are most apposite to consideration of natural selection in humans. Decreasing infant and childhood mortality rates do not necessarily mean that natural selection in the human species no longer operates. Theoretically, natural selection could be very effective if all the children born reached maturity. Two conditions are needed to make this theoretical possibility realized: first, variation in the number of children per family and, second, variation correlated with the genetic properties of the parents. Neither of these conditions is farfetched.

Darwinian fitness is sometimes referred to also as the adaptive value or the selective value; these terms are best treated as synonyms, although they may have somewhat different connotations. The Darwinian fitness of a genotype, or of a group of genotypes, is measured as the contribution of their carriers to the gene pool of the succeeding generation, relative to the contributions of other genotypes present in the same population. In the example given above, the Darwinian fitness of the genotype A1A1 was taken to be unity and the fitness of A2A2 as 1 - s or less than unity. The fitness is, of course, subject to change in different environments; the carriers of a genotype A1A1 may leave more surviving progeny than A2A2 in a certain environment, but the reverse may be the case in another environment. Darwinian fitness is reproductive fitness; bodily or mental vigour, health, and energy obviously contribute to this fitness but only insofar as they result in a superior reproductive capacity. Mules, no matter how strong and resistant, must be ranked zero in Darwinian fitness because they are sterile. The emphasis on reproductive success rather than on survival is characteristic of the modern concept of natural selection, as distinguished from the classical one. The difference is not, however, so great as it may seem at first glance; the carriers of a genotype evidently must survive in order to reproduce, and they must reproduce in order to survive in the next generation.

Varieties of natural selection

There are several kinds of natural selection, rather different in their biological consequences and in their importance to humans. The simplest of them is the normalizing selection, which was already known before Darwin but, of course, not under this name. Normalizing selection counteracts the accumulation in populations of hereditary diseases, malformations, and weaknesses. Suppose that a gene allele A1, the carriers of which have a high Darwinian fitness, mutates to a state A2, which lowers the fitness. If A2 is a dominant lethal or a gene that renders its carriers sterile, then (as shown in Table 4, column s = 1.0) all the A2 mutants will be eliminated in the same generation in which they arise. A new crop of mutants will, of course, appear in the next generation. If, however, the selection is not so completely efficient, some mutant genes will escape its dragnet and will be transmitted to the next generation. That generation will contain all the newly arisen mutants, a part of the mutants that arose in the preceding generation, a smaller part of those having arisen two generations ago, etc. How great a “genetic load” of uneliminated mutants a population can accumulate will depend principally on two factors—how often the mutation arises and how much it lowers the Darwinian fitness.

Simple formulas have been worked out to describe the situations that arise. Suppose that a deleterious mutation from A1 ® A2 occurs at a rate u per generation. Suppose further that the mutant is discriminated against by a selection coefficient s. If, then, the mutant A2 is dominant to the original state, A1, the frequency of A2 in the gene pool will be u/s. If A2 is recessive to A1, its accumulated frequency will be much higher, namely Öu/s. The reason deleterious recessive mutants are allowed to attain higher frequencies than equally deleterious dominants is simple: a recessive mutant may be carried in many heterozygotes, in which it does not express itself, and is consequently protected, or sheltered, from the weeding-out action of natural selection. With mutants that are neither dominant nor recessive, the accumulation will be intermediate between u/s and Öu/s.

All human populations doubtless carry genetic loads consisting of harmful mutant genes. This cannot be blamed entirely on culture, civilization, or on any other specifically human attributes. Populations of Drosophila flies and of other sexually reproducing organisms also carry genetic loads. The accumulation of the genetic loads is a necessary consequence of the occurrence of mutations, most of which are harmful but not always harmful enough to be eliminated immediately after they are produced. Harmful mutations are accumulated until the numbers of the respective mutant genes become equal to the numbers eliminated by natural selection in the same population. The population is then said to be in the state of “genetic equilibrium.” Muller has termed the elimination of harmful mutants “genetic death.” Genetic “death” is sometimes cruel, sometimes rather benign. The death of a child from a severe hereditary disease and the genetically conditioned failure to have one more child are both genetic deaths. The higher the mutation rates, the more harmful are the mutants produced and the more frequent are the genetic deaths. In populations that have reached genetic equilibrium, the total number of genetic deaths will be equal to the total number of the mutations subject to normalizing natural selection.

A very different form of natural selection is heterotic balancing selection. It occurs when the Darwinian fitness of a heterozygote exceeds the fitness of both homozygotes, a situation mentioned above. Heterotic balancing selection also leads to genetic equilibrium but not to an equilibrium between mutation and the normalizing selection. The balanced polymorphism that is established is due to the selection favouring the heterozygotes against the homozygotes. In a sexually reproducing population the heterozygotes tend, however, to produce a fresh crop of homozygotes in every generation. The maintenance in human populations of the grave hereditary disease sickle-cell anemia is apparently due to this form of selection. The sickling gene (HbS) produces a specific type of hemoglobin, while normal hemoglobin is related to another allele (HbA). Accordingly, the possible genotypes are HbAHbA, HbAHbS, and HbSHbS. The latter individuals are homozygous for the sickle-cell gene and will develop severe anemia. While the condition is not lethal before birth, such individuals rarely survive long enough to exhibit more than minimal fitness in the Darwinian sense of capacity to reproduce. On these grounds it might be concluded that natural selection eventually should drive the frequency of the HbS gene to complete elimination or at least down to the one in 100,000 level of the mutation rate. One would theorize a transient polymorphism; that is, one on the way out, toward fixation of the favoured allele.

Evidence, however, seems to contradict theory since, in a number of African tribes living in their ancestral tropical lowlands where the falciparum form of malaria is widespread, the HbS (sickling) gene is very common indeed. On the other hand, the same gene is rare in genetically related but isolated tribes living in highlands that are free of mosquitoes that transmit this type of malaria. This discrepancy between lowland and highland people has led to the hypothesis that the HbAHbS heterozygote is fitter and capable of leaving more offspring than is the homozygous normal HbAHbA in a highly malarious environment. This extra measure of protection is evidently provided by the sickle-cell hemoglobin (HbS), which is detrimental to the malaria parasite. In malarial environments, populations that contain the sickle- cell gene, therefore, have advantages over populations free of this gene. The former populations are in less danger from the ravages of malaria, although they “pay” for this advantage by sacrificing in every generation some individuals who die of anemia. The lethal disease caused by homozygosity for the sickle-cell gene certainly brings about some genetic deaths; it is a part of the genetic load of the populations. But this genetic load, due to a disadvantage of being homozygous for certain genes, is very different from the mutational load controlled by the normalizing selection. The former is maintained by the heterotic balancing selection, while the latter is maintained by recurrent mutation.

Another form of natural selection is diversifying, or disruptive, selection. In many discussions and mathematical analyses of selection this simplifying assumption is adopted: that the environment in which a population lives is uniform and that the selection advantages and disadvantages of different genotypes are independent of their frequencies in the population. This simplification, however, flies in the face of reality. Many animals can subsist on a variety of foods; many plants grow on different soils; humans have to fill many different employments, functions, professions, and social roles. It is most likely that some genotypes will be fitter in some environments than they are in other environments. Diversifying selection will then favour different genotypes in different subenvironments, or ecological niches, that occur in the population.

A special form of selection occurs in mammals due to the incompatibility of certain maternal genotypes with those of their unborn children. The best studied case in humans is that of a Rhesus-positive fetus in a Rhesus-negative mother. This selection should, theoretically, make the entire population either Rhesus positive or Rhesus negative. For reasons that have not been clarified, it does not appear to be doing this. Another special kind of selection is that due to so-called meiotic drives, disturbances of the Mendelian segregation mechanisms, which result in sex cells carrying certain gene alleles being more or less frequent than expected on a random basis.

The last to be mentioned, but in the long run possibly the most important form of selection, is directional selection. Suppose that the climate becomes warmer or cooler, that there appears a new source of food or a new predator or disease, or that there occur some other prominent environmental changes. Some genotypes will, then, become more favourable and others less favourable. Directional natural selection will operate to reconstruct the gene pool of the population in accord with the demands of the new environment.

Natural selection in operation

When the antibiotic streptomycin is added in a sufficient concentration to a culture of colon bacteria, only the streptomycin-resistant mutants are able to reproduce, while the streptomycin-sensitive cells are eliminated. If experimenters add the streptomycin to a culture in order to obtain resistant strains of the bacteria, they are effecting artificial selection. Natural selection acts, however, very much in the same fashion. Widespread and often rather indiscriminate utilization of antibiotics against various infectious microorganisms led to quite unintended consequences— the appearance of numerous “drug-fast” infections. In some instances (as with gonorrhea in some countries) the treatment with penicillin, originally very effectual, became less reliable or even useless as selection brought about a drug- resistant strain of gonococci.

Essentially the same process took place with more complex organisms, various insect pests, in response to the introduction of certain potent insecticides. The first such insecticide, DDT, was used on a large scale during and after World War II. The discovery of DDT, followed by invention of many other insecticides of similar or even greater potency, led to hope of eradication of all insect pests. This enthusiasm was short lived, since by 1947 DDT-resistant populations of the housefly were recorded in Italy and soon thereafter in other countries. It apparently takes the fly only two to three years to evolve a genetically conditioned resistance to DDT, and similar resistances arise against other insecticides as well. During the Korean War DDT-resistant lice emerged. Attempts to eradicate malaria-bearing mosquitoes by DDT sprays resulted in DDT-resistant mosquito populations. Laboratory experiments with Drosophila and with houseflies have shown that one can artificially select for insecticide resistance. Moreover, there are apparently genetically different resistant strains, some differing from the sensitive ones by a single gene with a strong effect and others by accumulation of several genetic changes, each increasing the resistance only slightly but giving strong resistance in the aggregate.

Colour changes in moth populations provide another example of natural selection. A black mutant of the peppered moth (Biston betularia) was found at Manchester, England, in 1848. Until that time the prevalent form of this species was light gray with dark speckles. The frequency of the black variant rapidly increased in the immediate area and reached about 99 percent by 1898. Dark coloration, melanism, has arisen and spread in many species of British moths belonging to different genera and families. The spread of the melanic forms was most rapid in and near industrial areas, where the foliage and the tree trunks are blackened with soot and other atmospheric pollutants. The spread of the dark forms is consequently known as industrial melanism. The light form of Biston betularia is protectively coloured when resting on tree trunks covered with lichens but conspicuous on blackened trunks on which the lichens have been largely destroyed by pollution. The selective agents are the insectivorous birds that feed on the moths; they find the light moths easily on dark tree bark and the black moths easily on light tree trunks. H.B.D. Kettlewell has verified the hypothesis by exposing known numbers of light and of melanic moths in localities with blackened and with unpolluted vegetation. A greater proportion of the blacks than of the whites remained alive and were recaptured on dark vegetation, and the opposite was observed on the unpolluted vegetation. Genetically, the difference between the light and the melanic forms has been shown to be due to a single gene, the allele for melanism being dominant to that for the light coloration.

Plants that grow in habitats created or modified by human activities are often different from their wild relatives and different in ways that adapt them to survive and reproduce in their respective habitats. Camelina sativa, a plant of the mustard family, is a common weed in fields of cultivated flax in Europe. The Camelina that contaminates the flax fields is, however, genetically different in several ways from that growing outside the fields. Camelina outside flax fields is a low-growing, branched plant with small seeds; that growing in flax fields is much taller, unbranched, and with larger seeds that resemble those of the flax in size and in specific gravity. The characteristics of Camelina growing in flax fields are such that it is harvested together with the flax, and its seeds remain with those of flax during the winnowing process. The variety in the flax fields is doubtless derived from the original form now found growing freely; the remarkable adaptations that are found in the former have, then, developed since farmers started to plant flax on fairly large scales. Genetically, the varieties of Camelina differ from each other in several, probably in many, genes. The process of natural selection—incidentally abetted by the human activity of flax cultivation—has, thus, created a new adaptive genetic system.

The examples of drug resistance in bacteria, pesticide resistance in insects, and industrial melanism in moths all involve directional natural selection, which, if continued long enough, leads to replacement of old gene alleles by new ones. Balancing natural selection has a different biological function—it maintains genetic diversity, or polymorphism, in populations. Selection pressures involved in balancing selection in nature are sometimes quite high. This is very useful to those engaged in research on selection, since it is evidently easier to detect strong selection than weak selection.

Striking examples of heterotic balancing selection have been found in nature in populations of some Drosophila. Many species of Drosophila are polymorphic for gene arrangements in their chromosomes; two or more kinds of chromosomes differing in inversions of blocks of genes occur in the same population. The carriers of the different chromosomes interbreed freely, and both homokaryotypes (two chromosomes of a pair with the same gene arrangement) and heterokaryotypes (the chromosomes of a pair with different arrangements) occur in different individuals. Some populations of Drosophila pseudoobscura in the western United States undergo cyclic seasonal changes in the frequencies of the chromosomal variants. The kinds of chromosomes denoted ST are relatively common in spring and autumn and rare in June; the chromosomes with the gene arrangement CH are, on the contrary, common in midsummer and relatively rare in spring and in autumn. The changes observed in nature can be reproduced in laboratory experiments. Experimental populations can be created with any desired frequencies of the chromosomal variants and can be left breeding freely for many generations. Samples are taken from time to time to determine the frequencies of the different kinds of chromosomes by microscopic examination, and the selection coefficients and the Darwinian fitnesses of the karyotypes can be calculated. As a rule, the heterokaryotypes show heterosis, fitness greater than in the homokaryotypes; selection coefficients of the order of 0.5 and even higher are often encountered.

Genetics of race and species differences

The nature and origin of races and species are dealt with in the article evolution, particularly in the section Species and speciation. Here it is necessary to consider only the genetic composition of the race and species differences in sexually reproducing and outbreeding organisms. In general, species are considered to be populations of organisms between which breeding is impossible or significantly limited under natural conditions. (This limitation does not hold for the mating [hybridization] of cells of different species by the methods of somatic cell genetics [see above]. Subgroups of an individual species with distinctive phenotypes form races, members of which can interbreed with members of other races of that species. The geneticist Curt Stern defined a race as a group more or less isolated geographically or culturally who share a common gene pool and who, statistically, are somewhat different at some loci from other populations.

In naturally occurring populations a species may split into races because of a gradual geographical separation and eventual rift between formerly interbreeding groups. Such races, which inhabit different territories, are called allopatric. If these races are brought together, they assume a sympatric status, interbreed, exchange genes, and fuse into a single genetically variable population. Races of human beings and of certain parasites are exceptional because they can coexist, at least for a time, sympatrically. In humans, social rather than geographical or biological factors slow down interbreeding and race fusion. Distinct species may, on the other hand, be either allopatric or sympatric. The exchange of genes between species populations is prevented not only by geographic distance (as with races) but also by genetically based reproductive isolating mechanisms. Reproductive isolation is achieved by a variety of means: differences in preferred habitats, in breeding seasons, in sexual attraction and courtship rites, in sexual structures (flowers in plants and genitalia in animals); incompatibility of sex cells; inviability of the hybrid progenies; sterility of the hybrids; and weakness of the gene recombination products of the gene complements of the species.

Race differences are more often quantitative than qualitative; racially distinct populations of a species differ usually in the frequency of certain genes rather than the presence or absence of certain genes. Studies on human blood groups have revealed some instructive situations. As discussed earlier, the four “classical” blood groups O, A, B, and AB are due to three alleles of a gene. Most human populations have individuals of all four types, and even parents and children, as well as brothers and sisters, may belong to different blood groups. However, some blood groups, and hence the gene alleles that produce them, are more frequent in some countries than in others. The gene for A blood, for example, increases in frequency from east to west in Europe; B blood is most frequent in some populations of India, Tibet, Mongolia, and Siberia. A majority of American Indians apparently had, before the arrival of Europeans and Africans, the O blood group only; however, the tribes of the Blackfoot and Bloods had the highest known frequencies of A blood, which is also very frequent among the Sami in northern Europe (see also blood group).

Human races differ certainly in many genetic traits, not in blood groups alone. Some theorists, imagining the human population as it might have been about 4000 BC, have speculated that there were perhaps five major races, one for each inhabited major landmass. The major human races are separated by their most readily recognized characteristics, such as skin colour, body size, and facial morphology. In modern times many of the barriers, both geographic and cultural, between the races have weakened. Since most of the external differences between races are polygenically and environmentally determined, interracial matings produce offspring that, in general, have a phenotype intermediate between those of the parents. Of the total number of loci existing in the human species, numbering at least 100,000, the majority of their alleles probably are present among the members of each race. Although one population of alleles—for example, those for dark skin colour—may be common in one race and rare in another, each particular skin-colour allele occurs in both races. In fact, studies involving many polymorphic loci (loci with two or more alleles occurring with a frequency of at least 1 percent) have revealed that the allelic diversity among individuals within a single race is greater than that between races.

Intelligence is a highly variable characteristic that some have claimed varies among different human races. This characteristic is difficult to define and even more difficult to measure. In addition, it is significantly influenced by environmental factors. Finally, the trait certainly varies more within members of a race than between races.

Races are genetically open systems, and gene exchange between races does take place. Species, by contrast, are genetically closed systems in which gene exchange is rare or absent. Race differentiation is reversible; hybridization or intermarriage may cause races to merge into a single population. It is an error to think that in a population resulting from race hybridization all individuals will be alike; in point of fact, such hybrid populations show a remarkable diversity of individuals. Species differentiation is irreversible. Races are populations, and an individual may have a genetic endowment that can occur in two or more different races or that is not common in any race. An individual belongs, however, to only one species, unless that individual is a species hybrid. Mules, hybrids between the horse and donkey, are sterile because of abnormalities in the processes of sex-cell formation in their gonads. Sterility of hybrids between species, if viable hybrids between them can be obtained at all, is observed very frequently, though some experimentally obtained species hybrids have proved to be fertile.

Scientists have asked what causes the development of the gene-frequency differences between populations that live in different territories, or, in other words, what makes these populations racially distinct. The probable explanation is that genetic differences between populations arise in most cases through natural selection in response to the local environments that prevail in the territories they inhabit. It is, however, very difficult to verify this explanation in many concrete instances of race differentiation. For example, it is probable that the dark skin pigmentation of many human populations that live, or have until recently lived, in tropical and subtropical countries protects them from sunburns. It is probable also that the light skin colours of the natives of Europe facilitate the acquisition of vitamin D in regions with deficient sunshine. The evidence for even these hypotheses is not as conclusive as might be desired. But when it comes to such racial traits as hair form and shapes of the nose, of the lips, and of the cheekbones, no acceptable evidence of adaptive significance is available. The situation is no better with races of animals and plants: for most racial differences the adaptive significance is unknown.

Attempts have been made to envisage factors other than natural selection that could be responsible for genetic differentiation of populations. Appeals are frequently made to pleiotropism of the gene action; a visible race difference may in itself be neither adaptive nor unadaptive, yet it may be only an outward sign of an underlying physiological difference that is adaptively important. An elegant example is the coloration of onions—red and purple bulbs are resistant to the attacks of a smudge fungus, while white bulbs are highly susceptible. A race trait may also be important as a sexual recognition mark, or it may play a role in the courtship ritual.

A most interesting possibility that should be seriously considered is that some differences between populations may be due to random genetic drift. As was discussed above, genetic drift acts on small populations. Suppose that a species lives in many isolated colonies, some of them consisting of only tens or perhaps hundreds of individuals. Chance events may cause the gene frequencies in the different colonies to drift apart. How important this random genetic drift may be in race differentiation is controversial. That genetic drift does occur is certain; a simple example is that in small villages a sizable fraction of the inhabitants sometimes have the same surname, and different surnames are frequent in different villages. Increasing or decreasing frequencies of the surnames evidently go together with increases or decreases of the frequencies of certain genes that the ancestors of the people with these surnames carried. As discussed, genetic drift can also arise from the founder effect. When the populations of new colonies founded by a small number of individuals expand, they will be found to differ genetically from each other and from the ancestral population. Natural selection will then come into operation, giving rise to new balanced gene pools. The founder effect was probably important in the development of some human populations. Many tribes and local races may be the descendants of small numbers of original migrants and settlers. Whether the random genetic drift alone can explain the origin of the gene complexes that differentiate races or species is very doubtful. The point is, however, that genetic drift and natural selection are not mutually exclusive alternatives; it is not one or the other but the interaction of both that brings about race differentiation. The founder effect is a special case of random genetic drift. The gene pool of a colony derived from a single immigrant or several pairs of immigrants may need a restructuring by natural selection to become properly adapted to the new environment.

Outbreeding and inbreeding

Human beings make up an outbreeding species. Marriage between close relatives is forbidden by custom and by law in most human societies. Whether the proscription initially was based on biological or social considerations is a matter of question. The prohibition may seem reasonable, however, in view of the evidence accumulated by practical breeders and geneticists. In normally outbreeding species, the progenies of matings in which the parents are close relatives tend to be less vigorous than the offspring of unrelated parents. This is a consequence of the genetic loads of deleterious recessive genes carried in populations. A recessive gene is more or less innocuous in the heterozygous condition, but its chances of becoming homozygous are greater in the offspring of parents who are close relatives (and therefore have more similar genotypes) than in families where the parents are not closely related.

It is worthwhile to stress at this point that the effects of outbreeding and inbreeding on the vigour, viability, and fertility of the offspring depend upon the reproductive biology of the species or the population in which they occur. Outbreeding is not invariably or necessarily invigorating, nor is inbreeding invariably or necessarily debilitating. Wheat is an example of a plant that is predominantly self-pollinating. Self-pollination is, of course, the closest possible form of inbreeding, but this inbreeding does not progressively weaken the vigour of a wheat strain. The converse, however, is observed with corn. Inbreeding decreases the yield, and the intercrossing of inbred lines restores hybrid vigour in the progeny. One may say that hybrid vigour (heterosis) is the normal state of a corn population, while inbreeding and a prevalence of homozygosis is the normal state in wheat. In species and populations in which the reproductive biology is adjusted to outbreeding, consanguinity leads to a decline in the average vigour and to the appearance of relatively many individuals with hereditary diseases and malformations. Just what kind of a malformation or ill health, if any, will appear in a given progeny depends on what deleterious recessive genes were carried by the common ancestor of the relatives who mate. This will certainly be different in different families. The histories of the reigning houses of Egypt and the Peruvian Incas, where the monarchs allegedly married their sisters, are not sufficiently well documented to conclude that in these instances the incestuous marriages resulted in no weakening of the progeny. High childhood mortality may have gone unrecorded; furthermore, “sister” may have been, in some instances, a title bestowed upon a person rather than indicative of an actual relationship.

It is important to study how much inbreeding depression will occur in a given species or population, and a great deal of information in this direction is being accumulated. With rare exceptions, the highest degree of consanguinity that occurs in human populations with appreciable frequency is marriage of first cousins, resulting in homozygosis of 6.25 percent of the genes in the progeny. A genetic counsellor would hardly be justified in discouraging all marriages of people known to be relatives, and yet he may point out that the chance of genetic weaknesses in the progeny of such marriages is measurably greater than when unrelated persons marry.

Genetic load and hybrid vigour

How hereditary variability is maintained in populations of sexually reproducing species is an unsettled and controversial question. The classical theory assumes that the pressure of mutation generating detrimental genetic variants is the main factor. The balance theory, while not denying that some variability is maintained by recurrent mutation, considers that a far from negligible portion of the variability is preserved by natural selection. These two theories, though they are not incompatible alternatives, have interestingly different theoretical and even philosophical implications.

According to the classical theory, a majority of the genes a species has are fixed, uniform, and homozygous in most, or even in all, individuals. The minority of the genes that are not fixed are represented by two or more variant alleles. One allele of each gene is “normal,” and it confers a high fitness on its possessors; the others are mutant, abnormal, and more or less deleterious. This view is logically connected with the conception of the “optimal” genotype. The optimal genotype is the one that contains only normal genes. Any deviation from the optimum genotype will be detrimental. Nevertheless, the process of mutation unrelentingly generates detrimental mutant genes, lowers fitness, and creates a genetic load. A genetic load can, in this view, be defined as the deviation of the observed fitness from that produced by the optimum genotype. The weakness of this definition is obvious: the optimum genotype is operationally elusive; it cannot be located and its fitness cannot be measured.

The balance theory of population structure takes a somewhat more optimistic view. Not all genetic variability present in populations is a regrettable departure from the optimal genotype. Some of this variability is, on the contrary, an adaptive device that permits the population to secure a firmer hold on its environment. The environment is never uniform; it has a greater or lesser variety of ecological niches, opportunities for living that members of the population can exploit. A living species or population faces many diverse environments, not a single environment. Two genetic strategies are possible to cope with environmental complexity. First, there may be genotypes that react favourably in several environments. Second, there may be a variety of more or less specialized genotypes to match the variety of environments.

Nature has used both strategies in the evolutionary process. A sexually reproducing population contains a variety of hereditary endowments. Most, and perhaps all, individuals may be heterozygous for many genes; it is now known, for example, that humans are heterozygous at a minimum of 30 percent of the genetic loci responsible for the serum proteins. Any gene that is rare will be carried in heterozygotes much more frequently than in homozygotes (except in highly inbred or self-fertilizing species). Natural selection operates in sexual populations chiefly with heterozygotes. It will tend to make the heterozygotes highly fit, even if the corresponding homozygotes are low in fitness. In other words, natural selection promotes hybrid vigour or heterosis and maintains the variant genes in a state of balanced polymorphism. It takes a variety of genetic endowments to make a world worth living in. Natural selection cannot prevent the appearance of some individuals of inferior fitness. In a population in which no two individuals carry the same genes, it is not possible to describe the genetic load as the deviation from the optimal genotype. This latter will be represented by a single individual or not at all. An operationally meaningful measure of fitness is that of the average or norm for a given population. The pronounced negative deviants from this average may be considered as constituents of the genetic load and the positive deviants as the genetic elite. Between the genetic load and the genetic elite there is the adaptive norm comprising a majority of the genotypes that are formed. The division lines between the load, the adaptive norm, and the elite can only be established by a convention. For most purposes, the load and the elite should probably refer to fairly extreme negative or positive deviations from the population mean. One may, however, foresee that some genetic processes will cause these deviations to become more or less frequent. For example, a genetic radiation damage or a greater incidence of marriages between relatives would increase the expressed genetic load compared to what it is at present.

The most impressive success scored to date, in attempts to utilize the genetic elite of an agricultural plant for increasing yields of a useful product, is represented by hybrid corn. Hybrid corn is obtained by artificially crossing inbred corn strains in order to exploit the phenomenon of hybrid vigour or heterosis.

Artificial selection

Hybrid corn is the most impressive but not the only achievement of genetics in agriculture. General accounts of animal and plant breeding can be found in the articles plant breeding and animal breeding. This section is concerned only with the genetic basis of the methods used in breeding programs. It should be kept in mind that the inbreeding-heterosis technique is most likely to succeed with species that are normally cross-fertilizing and outbred and less so in habitually inbreeding or self-pollinating forms (like wheat and barley).

In practicing artificial selection, the breeder seeks to identify and propagate those genotypes that, when placed in suitable and economically feasible environments, induce in their carriers the desired qualities. The improvement methods used in the breeding work must evidently be appropriate to the reproductive biology, the genetic population structure, and the economic value of the form to be improved. It is evidently impossible, for example, with large domestic animals such as cattle or horses to raise numbers of individuals from which selection is made comparable to that practicable with field crops. Collections of pedigrees, published in stud books for horses and in herd books for some breeds of cattle, are still regarded by commercial breeders as important in the choice of most prized animals. Progeny and sib testing are often used as aids for evaluation of the breeding worth of individual animals. A quite different situation is encountered with some useful plants in which cross-pollination happens only rarely, and the normal method of propagation is self-pollination (as in most cereals, peas, beans, and tomatoes) or parthenogenesis or asexual reproduction (sugarcane, bluegrass, bananas, and many citrus fruits). Here the problem is to identify the individual, or a small group of individuals, with a desired combination of traits and to propagate them to form pure lines (progenies obtained by self-pollination) or clones (progenies obtained asexually). Some of the most valuable varieties of wheats are descended from a single seed progenitor.

Selection, artificial as well as natural, can operate only if genetic diversity exists among the materials available. In a genetically uniform pure line or a clone, selection is without effect. Provision of genetic variability is the prime concern for a breeder. A powerful means of inducing genetic variability is hybridization and Mendelian segregation in the hybrid progenies. Two lines, neither of which is particularly good, may produce valuable genotypes in segregating hybrid progenies. This is the reason that modern breeders frequently endeavour to collect primitive varieties from far-off lands and use them as materials for hybridization followed by selection. Many, if not most, breeds and varieties, from thoroughbred horses to cultivated strawberries, are descended from hybrids of two or more ancient breeds or even of distinct species. The cultivated roses have genes from at least four wild ancestral species in their gene pool.

A technique to speed up the improvement of useful plants and animals is induction of mutations that increase the amount of genetic variability available for selection. Although a decided majority of mutants are harmful, some exceptional ones may be useful.

Theodosius Dobzhansky

Arthur Robinson

Eugenics

Breeders have been quite successful in improving, for human benefit, the genetic endowments of domesticated animals, cultivated plants, and even microorganisms. The question inevitably presents itself whether humans can succeed equally well in directing the evolution of their own species toward goals regarded as good and desirable. The term eugenics has been applied to theories and practices ostensibly designed to improve the human condition from the genetic point of view. The intention of so-called negative eugenics is to improve the human species by identifying individuals and couples at risk of perpetuating “inferior” genes and to prevent such persons from reproducing. On the other hand, positive eugenics attempts to identify “good” genes and thereby improve the species by encouraging the reproduction of those persons who are thought to carry them. All too often, however, the identification of desirable or undesirable hereditary human traits is a subjective and controversial matter, in which the opinions of one, often self- serving, group become the basis of reproductive decisions imposed upon another group. Furthermore, the concept of eugenics tends to ignore the sizable role that environment plays in the establishment of human characteristics.

The idea of applying knowledge of heredity to the improvement of the human race goes back to earliest times. References to eugenic ideals appear in the Old Testament, and Plato's Republic idealizes a society in which there is constant selection for the improvement of the human stock. A British economist, Thomas Robert Malthus, noted the struggle for existence; Darwin saw in it the means of evolution. It remained for Francis Galton, a scientist of many talents and a cousin of Darwin, to see that the theory of evolution implied that humans might in part direct their own evolutionary future. Galton's first important work, Hereditary Genius (1869), contained the results of his studies of the families of eminent men as evidence for his belief that “it would be quite practical to produce a highly gifted race of men by judicious marriages during several consecutive generations.” In 1883 he published Inquiries into Human Faculty, in which he coined the term eugenics. In Natural Inheritance (1889), Galton pioneered the development and application of advanced statistical methods to the study of man.

While Galton's thinking was much ahead of his time, he retained some of the prejudices of an English gentleman in regard to social class and race. In his studies of the families of eminent men Galton underestimated the effects of a favourable environment. But his faults in this respect were far less than those of many of his followers. He developed and used many of the statistical methods for the study of populations and was the first to recognize the value of the study of twins for research in heredity. He repudiated the Lamarckian view, then widely held, that acquired characteristics were inherited. Although Galton attached religious significance to the eugenic movement, he did not think of it in revolutionary terms but rather as “ . . . the new duty which is supposed to be exercised concurrently with and not in opposition to, the old ones upon which the social fabric depends.” For all his ability, Galton was not able to gain wide acceptance for eugenics, largely because much of the scientific and technical foundation was lacking.

Galton had endowed a research fellowship in eugenics in 1904 and, in his will, provided funds for a chair of eugenics at University College, London University. The fellowship and later the chair at University College were both occupied by , a brilliant mathematician who helped to create the science of biometry, the statistical aspects of biology. Pearson was a controversial figure who believed that environment had little to do with the development of mental or emotional qualities. He felt that the high birth rate of the poor was a threat to civilization and that the “higher” races must supplant the “lower.” His views gave countenance to those who believed in racial and class superiorities. Thus, Pearson shares the blame for the discredit later brought on eugenics in the United States and for making possible the dreadful misuse of the word eugenics in Adolf Hitler's propaganda. The English Eugenics Society, founded by Galton in 1907 as the Eugenics Education Society, opposed Pearson's views but was itself slow in throwing off the prevalent biases of that time.

In the United States the American Eugenics Society was founded in 1926 by men who believed that the white race was superior to other races and, further, that the “Nordic” white was superior to other whites. They thought of races as “pure” groups, quite separate from each other. They did not know that all races are mixtures of many types, the distribution of genes among the races varying in proportions rather than in kind, as evidenced by the distribution of the various blood groups among all of the races. They did not realize that environments are so uncontrollable that scientists cannot reasonably put forward views on the genetic differences in the performance of different races. Furthermore, they believed that the upper classes had superior hereditary qualities that justified their being the ruling class.

The science of that day supported extreme views on “feeblemindedness” and “criminal types.” Intelligence tests, introduced in the early 1900s by the French psychologist Alfred Binet, were thought, contrary to Binet's views, to be measures of innate, genetic intelligence. People whose test performance (e.g., intelligence quotient, or IQ) gave them a mental age of 12 or less could be classified as feebleminded or morons, even though the term would then include most of those brought up in deprived environments, such as the southern Appalachian highlands or the blighted rural and urban slums occupied by the descendants of slaves. Criminality was generally considered a concomitant of feeblemindedness. Studies on degenerate family stocks were taken to prove that hundreds of persons in each of these families were feebleminded or criminal types because of the inheritance they received from a single ancestor five or six generations back. Claims were made that immigrants from southern and eastern Europe, besides being socially inferior, included criminal and defective stocks. There was much in the intellectual atmosphere of the United States that fostered an extreme hereditarian racist view.

Even before 1905 eugenists had been active in the effort to restrict immigration. Their arguments, along with those of others who advocated restrictions for different reasons, culminated with the passage of the Immigration Act of 1924, which limited quota immigrants to about 150,000 annually, with no more than 2 percent of each nationality according to the number of persons of their national origin in the United States as of 1890, and providing that, beginning July 1, 1929, the quota of any country should have the same ratio to 150,000 as the number of persons of that national origin living in the United States had to the total U.S. population in the 1920 census. In later years it became clear that the material the eugenists had presented to congressional hearings had little scientific foundation.

Eugenists at this time laid great stress on the importance of sterilizing defective persons. By 1931 sterilization laws had been enacted by 27 states in the United States, and by 1935 sterilization laws had been passed in Denmark, Switzerland, Germany, Norway, and Sweden. Most of these laws provided for the voluntary or compulsory sterilization of certain classes of people thought to be insane, mentally retarded, or epileptic; some applied equally to habitual criminals and sexual deviants. In most cases the purpose was clearly eugenic, though some laws tacitly permitted sterilization for social rather than genetic reasons. In the United States most states did not generally enforce these rather extreme measures, and the number of sterilizations was seldom more than 100 per year. Exceptions were California, where sterilizations averaged more than 350 cases per year, with a total of 9,931 by 1935, and some of the southern states, with fairly high sterilization rates relative to their populations.

Unquestionably the greatest abuse of the concept of eugenics took place in Hitler's Germany, when as a rationale for producing a “master race” the Nazis murdered millions of people considered to have inferior genes.

As a result of these misuses, modern society has been disinclined to admit any validity to eugenic concepts. However, the practice of modern genetic counselling (see below) is in a special sense a eugenic activity, in that it attempts to prevent the conception or birth of individuals with most serious forms of maldevelopment who would be tragic burdens to themselves and to their families. This form of negative eugenics identifies individuals and couples at risk of perpetuating genes that lead to heritable diseases and disorders that contribute to a significant amount of human tragedy. Of importance is the fact that information on these risks is given to couples so that they can make informed and personal decisions about reproduction without societal pressure.

Frederick Henry Osborn

Arthur Robinson

Additional Reading

Classical genetics

THEODOSIUS DOBZHANSKY, Heredity and the Nature of Men (1964); THEODOSIUS DOBZHANSKY et al., Evolution (1977); and I. MICHAEL LERNER and WILLIAM J. LIBBY, Heredity, Evolution, and Society, 2nd ed. (1976), are excellent discussions of classical genetics and its social and cultural implications. CURT STERN, Genetic Mosaic, and Other Essays (1968), is a group of historical essays by a leading authority who discusses the development of knowledge on hermaphrodites and the relation of general to human genetics. JAMES A. PETERS (ed.), Classic Papers in Genetics (1959), is a collection of papers extending from 1865 (Mendel) to 1966 (Benzer) that form the cornerstone of classical Mendelian genetics. ARCHIBALD E. GARROD , Inborn Errors of Metabolism, ed. by HARRY HARRIS (1963), is a newer edition of this classic work.

Genetic texts

GEORGE P. RÉDEI, Genetics (1982); and LAURA LIVINGSTON MAYS, Genetics: A Molecular Approach (1981), provide good, up-to-date overview treatments for students. THEODORE T. PUCK, The Mammalian Cell as a Microorganism: Genetic and Biochemical Studies in Vitro (1982), presents a lucid introduction to the field of somatic cell genetics. JAMES D. WATSON, Molecular Biology of the Gene, 3rd ed. (1976), gives a thorough introduction to molecular biology. RICHARD L. DAVIDSON and FELIX F. DE LA CRUZ (eds.), Somatic Cell Hybridization (1974), is a collection of papers presented at a symposium on somatic cell genetics, interspecies hybrids, and gene localization; see also RICHARD L. DAVIDSON (ed.), Somatic Cell Genetics (1984); ROBERT T. SCHIMKE (ed.), Gene Amplification (1982); and THOMAS J. SILHAVY, MICHAEL L. BERMAN , and LYNN W. ENQUIST, Experiments with Gene Fusions (1984). H. HUGH FUDENBERG et al., Basic Immunogenetics, 3rd ed. (1984), is a comprehensive technical discussion.

The following articles in the monthly Scientific American are readable and well illustrated: F.H.C. CRICK, “The Genetic Code,” 207(4):66–74 (October 1962), and “The Genetic Code III,” 215(4):55–62 (October 1966); PIERRE CHAMBON, “Split Genes,” 244(5):60–71 (May 1981); W. FRENCH ANDERSON and ELAINE G. DIACUMAKOS, “Genetic Engineering in Mammalian Cells,” 245(1):106–121 (July 1981); PHILIP LEDER, “The Genetics of Antibody Diversity,” 246(5):102–115 (May 1982); J. MICHAEL BISHOP, “Oncogenes,” 246(3):80–92 (March 1982); ARTHUR C. UPTON, “The Biological Effects of Low-Level Ionizing Radiation,” 246(2):41–49 (February 1982); RICHARD E. DICKERSON, “The DNA Helix and How It Is Read,” 249(6):94–111 (December 1983); JAMES E. DARNELL, JR., “The Processing of RNA,” 249(4):90–100 (October 1983); TONY HUNTER, “The Proteins of Oncogenes,” 251(2):70–79 (August 1984); COREY GOODMAN and MICHAEL J. BASTIANI, “How Embryonic Nerve Cells Recognize One Another,” 251(6):58–66 (December 1984); MICHAEL S. BROWN and JOSEPH L. GOLDSTEIN, “How LDL Receptors Influence Cholesterol and Atherosclerosis,” 251(5):58–66 (November 1984); NINA V. FEDOROFF, “Transposable Genetic Elements in Maize,” 250(6):84–98 (June 1984); and RICHARD H. SCHELLER and RICHARD AXEL, “How Genes Control an Innate Behavior,” 250(3):54–62 (March 1984).

Arthur Robinson

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