Proc. Natl. Acad. Sci. USA Vol. 85, pp. 5141-5145, July 1988 Evolution Comparative evolution: Latent potentials for anagenetic advance (adaptive shifts/constraints/anagenesis) G. LEDYARD STEBBINS* AND DANIEL L. HARTLtt *Department of Genetics, University of California, Davis, CA 95616; and tDepartment of Genetics, Washington University School of Medicine, Box 8031, 660 South Euclid Avenue, Saint Louis, MO 63110 Contributed by G. Ledyard Stebbins, April 4, 1988

ABSTRACT One of the principles that has emerged from genetic variation available for evolutionary changes (2), a experimental evolutionary studies of microorganisms is that major concern of modem evolutionists is explaining how the polymorphic alleles or new mutations can sometimes possess a vast amount of genetic variation that actually exists can be latent potential to respond to selection in different environ- maintained. Given the fact that in complex higher organisms ments, although the alleles may be functionally equivalent or most new mutations with visible effects on phenotype are disfavored under typical conditions. We suggest that such deleterious, many biologists, particularly Kimura (3), have responses to selection in microorganisms serve as experimental sought to solve the problem by proposing that much genetic models of evolutionary advances that occur over much longer variation is selectively neutral or nearly so, at least at the periods of time in higher organisms. We propose as a general molecular level. Amidst a background of what may be largely evolutionary principle that anagenic advances often come from neutral or nearly neutral genetic variation, adaptive evolution capitalizing on preexisting latent selection potentials in the nevertheless occurs. While much of natural selection at the presence of novel ecological opportunity. molecular level must involve minor improvements in fitness, major adaptive advances in the complexity oforganisms-for One of the research strategies that has been most useful in example, the origin of aerobic respiration; of the sexual generating progress in molecular biology is based on the cycle; of multicellularity; ofjaws, teeth, and limbs of verte- notion that simple model systems illustrate mechanisms and brates, etc.-must ultimately emanate from the molecular principles that are found to be generally applicable. This level through genes that provide new functions and that strategy has been particularly successful in the study of the regulate and integrate these functions. molecular genetics of bacteria and bacterial viruses. As the The challenge ofunderstanding morphological evolution at field of evolutionary genetics becomes increasingly molecu- the molecular level cannot be met straightaway with attempts lar, a similar strategy is also becoming productive in this area to analyze major shifts that occur in complex multicellular (1). Microbial organisms may prove to be useful as model organisms, because of the presently inadequate understand- systems in studies of population and evolutionary biology. ing of the relevant molecular principles of development. An In point of fact, a good deal of evolutionary work with alternative place to start is via analysis of adaptive reactions microbial organisms has already been carried out, and the in microorganisms, in which the relationship between mo- results are only just beginning to be integrated into evolu- lecular change and adaptation to the environment is often tionary thinking. The present paper attempts to add to this relatively direct. Microorganisms have additional practical synthesis by showing that certain evolutionary principles that advantages for this purpose. Populations of 1010 or greater have emerged from microbial experiments can be applied as can be studied in chemostats or Petri dishes in experiments paradigms to higher levels ofthe evolutionary hierarchy. The lasting only a few days or weeks, and progressive genetic following sections provide the background of the principles changes can be followed for hundreds of generations. The and examples of their application to complex evolving sys- success of such experiments in analyzing the genetic and tems, including both microevolution and macroevolution. molecular basis of adaptive shifts is well documented (4-7). Current evolutionary biology continues to debate whether Given the demonstration that adaptive shifts can be ana- major adaptive shifts and anagenetic advances in evolution lyzed in microorganisms, can the results be extrapolated to result from one or two macromutations that bring about the help explain the much more complex situation in multicellular changes relatively suddenly or from the slow accumulation of highly differentiated organisms? We believe that it can, for many small differences gradually acquired during millions of the following reasons: years. We believe that the classification of evolutionary (i) Chemostat experiments with unicellular lower eukary- advance based on the number of favorable mutations is arbi- otes, such as yeast, suggest that adaptations to different trary and artificial. Rather, the arguments that follow lead us to environments involve molecular mechanisms and principles believe that evolutionary advances result from occasions in similar to those observed in prokaryotes (8-10). which populations fortuitously exposed to various selection (ii) Comparisons among unicellular lower eukaryotes that pressures are coincidentally able to respond to them-no matter differ greatly in size and in methods of nutrition reveal a whether the genetic basis ofthe response resides in one or a few wealth of intermediate situations in which the origin of such lucky mutations or a larger number gradually accumulated. major advances as ingestion of food particles, filter feeding, gametic conjugation, etc., may be analyzed at the molecular Background level (see reviews in ref. 11). (iii) Major adaptive shifts in higher organisms consist of a During the past 25 years, knowledge ofthe nature and extent complex sequence of genetic and morphological alterations, ofgenetic variation has increased dramatically. While in 1960 the individual elements of which may be analogous to many geneticists were concerned with the seeming paucity of metabolic shifts in simpler organisms. For instance, trophic shifts in a vertebrate animal, such as from filter or suspension feeding to the ingestion of larger organisms, entail several The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 5141 Downloaded by guest on September 26, 2021 5142 Evolution: Stebbins and HartPProc. Natl. Acad. Sci. USA 85 (1988) biochemical events of breakdown and digestion that may be enzyme kinetics (whence the term), in which many reactions comparable to metabolic shifts in bacteria, plus alterations in exhibit a hyperbolic relationship between the activity of a external morphology. Because understanding any series of particular enzyme in a metabolic pathway and metabolic flux biological processes, including evolution, requires that re- through the pathway. At low activities, the flux increases ductional analyses precede final syntheses, reductional anal- almost linearly with enzyme activity, but at higher activities ysis of adaptive shifts may be made more precise by analogy the system becomes saturated and the relationship between with results of experiments on simpler organisms. flux and activity becomes almost flat. (iv) In many instances, the evolutionary consequences of Organizational constraints result from physical structures adaptive shifts lie not in their degree of complexity, but in the or the manner in which they are organized. For example, one ecologic or phylogenetic context in which they occur. For of the cardinal discoveries of molecular evolution is that example, the evolutionary progression from a flying bird that different structural domains of the same protein molecule nests on solid ground on an island to a swimming penguin that often evolve at different rates. Domains requiring precise hatches its eggs and raises its young on glacial ice was fully physical interactions with other molecules, such as the active as profound and complex as the evolution of a primitive and binding sites of enzymes, or that associate with ligands labyrinthodont amphibian from a rhipidistian fish. Yet, the such as heme, are often constrained so that their rate of penguin has never been and probably will never be the evolution is slower than that of other domains with less ancestor of an evolutionary lineage, because the sparse stringent requirements for interaction. niches of its antarctic marine habitat are already filled, while the labyrinthodont was in the fortunate position of pioneering Types of Constraints in a terrestrial habitat that offered a wealth of vacant niches to receive its evolving descendants. Similarly, the shift in Saturational constraints resulting from diminishing-return modern genera of flowering plants from insect to bird effects have been observed at many levels of biological pollination may seem trivial to nonbotanists, because the organization. The following sections outline examples rang- effects are relatively slight with reference to most floras. Yet, ing from the molecular level to that of the whole organism. from the genetic and morphological point of view, the various As noted, many biochemical pathways exhibit some type changes that occur are comparable in complexity to the shift of saturation kinetics, usually indicated by a concave curve in the earliest flowering plants or their ancestors from wind that expresses asymptotic convergence of reaction velocity pollination to insect pollination, which ultimately gave rise to to a plateau as the activity of an enzyme in the pathway the wealth of floral beauty that surrounds us. increases. In the simplest types of linear metabolic pathways (v) As we will attempt to show in the remainder of this involving enzymes that follow Michaelis-Menten kinetics, article, the organism-environment interactions that constrain the relationship between metabolite flux and enzyme activity evolutionary change, as well as those that promote it, are is a hyperbola (12). Even when not precisely hyperbolic, the similar at all levels of the evolutionary family. relationship between flux and enzyme activity must often be concave, simply as a result of saturation effects at high Some Principles of Macroevolution enzyme activity (13). Saturation kinetics justifies the assump- tion that fitness functions will generally be concave with In relation to evolutionary advance and the principles that respect to enzyme activity, with the fitness effects of incre- constrain it, the following generalizations are relevant: mental changes in enzyme activity diminishing as the plateau (i) Major anagenetic steps are so rare as to be exceptional, is reached (14-16). A hyperbolic relationship between en- and most of them are unique. The word major is necessarily zyme activity and fitness has been empirically determined for vague in this context; refers to such breakthroughs as the ,B-galactosidase in Escherichia coli cells competing for lac- evolution of the exoskeleton, lungs, or the placenta. tose in chemostats (17, 18). The relationship between fitness (ii) Rarity is often due to the necessity for the simulta- and activity of the 8-galactosidase and the j-galactoside neous presence of several independently occurring elements, permease is also hyperbolic in two dimensions (19). Addi- each of which is uncommon. For example, jaws provide an tional examples such as alcohol dehydrogenase activity in advantage over filter feeding only when smaller animals are Drosophila melanogaster and 6-phosphogluconate dehydro- abundant and the predator can catch them with relative ease. genase activity in E. coli suggest that functional constraints (iii) Lack of adaptive advantage of each separate element resulting from diminishing returns of enzyme activity are places strong constraints on evolution and promotes persis- widespread and perhaps nearly universal (20, 21). tence of less efficient organisms, even when favorable com- Constraints involving cellular processes can be inferred binations might enable a major evolutionary advance. from the research of Sonneborn (22) and Nanney (23) on (iv) Various kinds of constraints occur at all levels of ciliate Protozoa. Species of ciliates differ with respect to complexity and throughout the evolutionary history of life, geometric patterns of cilia on the cuticle affecting both but occasional combinations of circumstances have enabled motility and ingestion of food. During cycles of asexual constraints to be overcome. Among the multitude of types of fission, a specific pattern is maintained by the capacity of constraints that can be distinguished, we wish to highlight newly translated polypeptide chains to become attached to two that are neither mutually exclusive nor exhaustive, but preexisting structures at particular positions on the cuticle. illustrate the nature of constraints and mechanisms to over- Each morphological species includes a cluster of sibling come them. These are saturational and organizational. species or "syngens" that are identical with respect to the Saturational constraints are based on general principles of intimate structure of their cellular cortex. Nevertheless, the limiting factors and diminishing returns. For example, if a proteins that make up the cortex and its cilia can evolve particular process constitutes a limiting factor for the growth differences that correspond to differences between sibling and reproduction of an organism, then even small improve- species (22). The morphological species are probably tens or ments in the efficiency of the process may provide a signif- hundreds of millions of years old. icant adaptive value. However, as the efficiency of the Constraints can also operate at the level of development, process improves incrementally, the selective advantage of morphology, and even higher levels. An example of ecolog- each increment will diminish, until a point is reached at which ical constraints due to environmental saturation can be seen increments in functional efficiency result in negligible im- in comparisons of the beaks of birds belonging to various provements in fitness. A classical example of diminishing mainland families with those exhibited by the Drepanididae returns of this sort occurs with saturation phenomena in of the Hawaiian islands (24). On the mainland, birds having Downloaded by guest on September 26, 2021 Evolution: Stebbins and Hard Proc. Natl. Acad. Sci. USA 85 (1988) 5143

beaks as different as those of small-seed eaters such as exoskeleton greatly restricts maximum size, since its weight finches (Emberizidae), large-seed eaters such as grosbeaks increases in proportion to the surface area of the animal. The (Fringillidae) or parrots (Psittacidae), bark probers such as internal skeleton of vertebrates restricts rapidity of move- woodpeckers (Picidae), and nectar seekers such as humming- ment but permitted the evolution of gigantic size, as in birds (Trochilidae), belong to different families. In Hawaii, by dinosaurs, elephants, and whales. In the ancestors of multi- contrast, the single family Drepanididae has been able to cellular plants, the evolution of a stiff cell wall consisting evolve all of these different kinds of beak structure. largely of cellulose made possible early invasion of the land, These differences may be explained by assuming that the as in mosses, but consigned them to a sessile existence. mainland ancestors of the Drepanididae possessed within The extreme specialization of many animals and plants their gene pools genes or gene combinations capable of includes the evolution of several different kinds of organiza- evolving directly or with a small number of mutations into the tional constraints. Examples are the aardvark (Orycteropo- various kinds of beaks found in their Hawaiian descendants. didae); subterranean mammals such as gophers (Geomy- These were able to fill niches that were vacant because of an idae), moles (Talpidae), and mole rats (Spalacidae); and impoverished bird fauna. In contrast, the mainland biota was among extinct organisms, saber-toothed cats (Felidae). so strongly saturated with well-adapted birds having the Given the multiplicity of constraints that organisms con- various kinds of beaks that the intermediate steps between front, one might ask how constraints are ever overcome, or, finch-like beaks and the various efficient mainland adapta- by implication, why evolution did not stop as soon as tions could never become established. primitive organisms had become highly successful in a The majority of constraints on the evolution of form and variety of habitats, and in so doing blocked further evolution pattern in higher organisms have been grouped under the along many different pathways because of the constraints. broad category of developmental constraints (25). This term, however, is misleading. Many types of patterns, such as The first relevant point is that major evolutionary break- fancy breeds of pigeons that have large numbers of tail throughs ofthe epochal type mentioned previously have been feathers, already noted by Darwin, as well as homeotic so rare as to be exceptional, and often unique. To understand mutants of Drosophila, ears of corn having extra rows of anagenetic advance, therefore, one must depart from con- nondehiscent kernels, and ornamental flowers having extra sideration of ubiquitous evolutionary processes and look for petals, are developmentally possible, and give rise to at least rare combinations of favorable circumstances. With respect partially fertile adults that live well under human care, but to gene pools and genetic potentialities of populations, many never survive in nature. For the most part, the distinction evolutionists have called attention to special combinations of between forms that are developmentally possible but inferior traits that have sometimes been called "preadaptations." In with respect to organization and function is difficult or a similar context, particular combinations of environmental impossible to make. All of these patterns, however, owe their factors to which "preadapted" populations might become absence in nature to inferior organization either with respect adapted have been suggested. However, the concept of to developmental processes or interrelationships between preadaptation with its implied foresight is at odds with the parts of the adult organism. Consequently, the term organi- concept of evolution as being opportunistic. In an effort to zational constraints for them is easier to define operationally, solve this dilemma, one of us (G.L.S.) coined the term and, therefore, more appropriate when referring to the ab- evolutionary competence (26). However, the term latent sence in nature of certain types of form or pattern that are selection potential, coined by D.L.H. and already published able to persist under human care. (27), is more appropriate, as is used here. An important feature oforganizational constraints, as here defined, is that they can be recognized at every level of Latent Selection Potential and Ecological Opportunity biological organization, from interactions between macro- molecules, to interactions between different organs, such as Genes exhibiting latent potentials for selection were identi- limbs, of a higher animal. The best known examples at the fied in experiments in which coisogenic strains of E. coli molecular level are different rates of evolution with respect containing different naturally occurring alleles underwent to different sites or domains of the same protein. Many competition for a source of carbon and energy in chemostats analyses of protein phylogeny have shown that amino acid (reviewed in ref. 27). Alleles offive different "housekeeping" sequence active sites and binding sites, for which precise enzymes were tested for selective equivalence versus differ- relationships with other macromolecules are of prime impor- ential rate of growth when grown in medium containing tance, are either completely static or evolve very slowly, limiting quantities of gluconate (or other appropriate sub- while sequences located between these sites usually evolve strate) as compared to limiting quantities of glucose. For more rapidly. three of the enzymes, no significant functional differences Organizational constraints at the cellular level include cells were found among any of the alleles, but with respect to the whose specialized structure adapts them for functions that other two enzymes, 6-phosphogluconate dehydrogenase and are similar in a wide range of organisms. In vertebrate phosphogluconate dehydratase, functional differences animals, the rods and cones of the eye are good examples, among alleles were considerable in gluconate medium, but and in plants, one can cite the guard cells of stomata. not in glucose. Since a normal substrate for E. coli is glucose, Organizational constraints at the level oforgans include the while gluconate is rare, the finding of selective equivalence in various ways in which hard parts of the body evolve in glucose, when constrated with the ability of some alleles of concert. For example, one can contrast the shells of molluscs the two enzymes to perform better in gluconate, was char- with the exoskeleton of arthropods and the internal skeleton acterized as resulting from a latent selection potential, which of vertebrates. The shell of molluscs offers excellent protec- is revealed only by the environmental challenge of growth in tion for the animal, but does not provide any surface to which limiting amounts ofgluconate. The situation is reminiscent of muscles of appendages can be attached. Pelecypods and Mayr's (28) redefinition of the term preadaptation: "[An] gastropods are limbless. Cephalopods (squids) turned their organism is said to be preadapted ifit is able to shift into a new bodies inside out, making possible tentacles that could serve habitat; a structure is said to be preadapted if it can assume as limbs of a sort. The external skeleton of arthropods a new function without interference with the original func- provides broad attachments for muscles, so that these orga- tion." We suggest that anagenic advance often comes from nisms could evolve very rapid movements, such as the wing capitalizing on preexisting latent selection potentials in the beat of the more advanced insects. At the same time, the presence of novel ecological opportunity. Downloaded by guest on September 26, 2021 5144 Evolution: Stebbins and HartPProc. Natl. Acad. Sci. USA 85 (1988) Nevertheless, even accepting Mayr's shading of the mean- relatively flat and bordered by shallow epicontinental seas, ing, the term preadaptation is a misnomer. Similar reserva- while shallow freshwater lakes and streams covered much of tions have prompted Gould and Vrba (29) to suggest the the continental surface area. Vascular plants, which evolved substitution of two terms: exaptation for genetic conditions in the preceding Silurian, were well developed in the Devo- that exist in one environment but are equally well adapted to nian, and were beginning to be browsed by herbivorous a different one, and preaptation for genetic conditions that arthropods, which in turn formed food for arthropod preda- can confer adaptations to a new environment via a small tors. Three groups of fishes, the Coelacanths, Dipnoi, and number of mutations or new gene combinations. These ideas Rhipidistians, which inhabited the epicontinental waters, had are very useful in some contexts. already two potentials for land life: lungs and relatively large Exaptations and preaptations are not mutually exclusive, size, which might enable them to remain out of water for a and the distinction between them is not always clear cut. This relatively long time without becoming desiccated (32). How- is illustrated by the case of the evolved f3-galactosidase gene ever, the Rhipidistians possessed two traits with selection (ebg) in E. coli. Wild-type E. coli possess a second f- potential that the Coelacanths and Dipnoi lacked. First, their galactosidase in addition to the well-studied P-galactosidase lateral fins were more muscular and, at least in some species, encoded by the lacZ gene in the lactose operon. Strains in contained bony skeletons that could be converted into carpal which the lacZ gene is deleted are unable to grow on lactose, and tarsal skeletons with relatively little change. Lateral fins but mutations in the ebg gene occur that do allow growth of Coelacanths were more fish-like, while those of Dipnoi because they increase the ability of the ebg /8-galactosidase were long, slender, and relatively weak. Second, the Rhipi- to cleave lactose (30). While the P-galactosidase activity of distian teeth were well fitted to grinding up soft-shelled the ebg enzyme is clearly an exaptation, the lactase activity arthropods and, similar to those of their putative descen- of the enzyme is clearly a preaptation. Similar ambiguities dants, the labyrinthodont amphibians. The teeth of Coela- occur in the interpretation ofexperiments on the evolution of canths were longer and more pointed, adapted to grasping substrate specificity of amidase enzymes in Pseudomonas smaller fishes, upon which they may have preyed. Those of aeruginosa (31). Dipnoi were massive and best fitted to a diet of shelled In considering evolutionary constraints, we believe that molluscs, upon which some of the sluggish modern lung the central focus should be on the genotype-environment fishes feed. While all three groups possessed traits that were interactions that help overcome constraints and lead to new more or less equivalent in terms of adaptation to aquatic life, evolutionary advances and diversification. The concept of the successful evolution of Rhipidistians into labyrinthodont latent potential for selection provides this focus. Potential for amphibians was made possible by their greater overall selection is based on genetic variation that allows progress potential to respond to selection for terrestrial life. under natural selection. The genetic variation may occur The second example, from angiospermous plants, is based within populations and be functionally equivalent, or nearly largely on the experience of one of us (G.L.S.) with the flora equivalent, in the prevailing mosaic of environments, or it of California. Among its various genera are included more may occur among species and influence their relative ability than 40 examples of independent evolution from pollination to respond to directional selection. When the latent selection of flowers by bees and/or wasps to pollination by humming- potential of a trait is expressed, it may result in exaptations birds (Trochilidae) (33). Two genetically different adaptive or preaptations. shifts are necessary. Since insects are most strongly percep- The concept of latent selection potential is, in principle, tive to violet or ultraviolet light, while to birds the brightest amenable to being quantified, although the appropriate man- color is red, a shift from purple, lavender, or pink to red is one ner of doing so may differ according to context. Ideally, almost essential step. Also, flowers adapted to bees and quantifying the potential for selection would be done pro- wasps are most successful if they include a landing platform, spectively rather than retrospectively, such as by predicting while narrowly tubular flowers best fit the long beak of the ability ofan enzyme to accept a novel substrate or evolve hovering nectar-seeking hummingbirds. a novel function, solely from examination of its three-dimen- Consequently, white or yellow bowl-shaped or dish- sional structure, but structural analysis has not yet reached shaped flowers completely lack latent selection potential for this state of sophistication, and the potentials must be adaptation to hummingbird pollination. Genera such as determined empirically by directed evolution using the novel Ranunculus, Anemone, Stellaria, Potentilla, and all Apia- substrates (30, 31). In some cases, quantification may prove ceae (Umbelliferae) have such flowers, and in none of them difficult in practice, but one might quantify the latent selec- has hummingbird pollination evolved. On the other hand, in tion potential of a fish population to evolve into a terrestrial genera such as Delphinium, Penstemon, and Mimulus in amphibian on the basis of the number of traits that the which blue, purple, or pink vase-shaped flowers are frequent, organism possesses in different organs such as lungs, limbs, hummingbird pollination has evolved more than once in each and teeth, as well as overall body size, that could respond to genus. selection for terrestrial life. Successful response to an envi- Moreover, the hummingbird pollination has evolved in ronmental challenge will occur in populations having the each genus in such a way that the least modification of the greatest latent selection potential, meaning not only the type flower is involved. In Delphinium, both the spur of one petal of traits themselves but the existence of the requisite genetic and the shape of the others combine to make the narrow tube variation. At the level of single genes, populations might be (34); in Aquilegia, only a spurred petal is involved; in ranked according to their total selection potential based on Astragalus, both a tubular calyx and converging petals are the number of polymorphic alleles or genes that exhibit a involved; in Epilobium sect. Zauschneria, it is only the calyx; latent selection potential individually. and in most sympetalous groups such as Penstemon, Castil- leja, and Mimulus, only the corolla is involved. These diverse Potential for Selection in Macroevolution adaptations illustrate a corollary to the principle of latent selection potential, that the manner in which an adaptive shift To illustrate the role of latent selection potential of traits in takes place depends on both the presence and the nature of organismic evolution, two examples may be taken as repre- latent selection potential. The economy of evolution usually sentative-the origin of terrestrial tetrapods among animals, follows a principle suggested long ago, that adaptive modi- and of bird-pollinated flowers among plants. fications are canalized along the pathway of least genetic The Devonian period offered particularly good opportuni- resistance, using the most readily available and smallest ties for vertebrates to invade the land. Many continents were amount of change needed to form the adaptation that meets Downloaded by guest on September 26, 2021 Evolution: Stebbins and Hartl Proc. Natl. Acad. Sci. USA 85 (1988) 5145 the immediate evolutionary challenge (35). This principle has sands of generations, these processes channel evolutionary been termed "tinkering" (36). lineages along a series of pathways toward local adaptive In our view, major evolutionary advances are the outcome peaks, each peak superseded in turn by yet a different, of interaction between special environmental conditions that although not necessarily higher, peak along the way. present a particular challenge, and a response to that chal- lenge on the part of populations that have become prepared We wish to dedicate this paper to the memory of Sewall Wright, to respond by virtue of a suitable latent selection potential. whose keen insight into the broader aspects of evolutionary theory Hence, posing a stark dichotomy between macromutations have inspired many of the ideas included in it. We are grateful to and micromutations is altogether misleading. James Ajioka, Glenn Bryan, Robert DuBose, Jeffrey Lawrence, and One reason for confusion is ambiguity in the term macro- Howard Ochman for suggesting many improvements in the manu- mutation. In using this term, many authors refer to the script. We are particularly grateful to Allan Campbell for a careful review of the entire manuscript and for his most helpful suggestions, hypothesis of Richard Goldschmidt. He, himself, however, on the basis of which the preferred the term systemic mutation. He believed that original manuscript was revised. systemic mutations reorganized the genome so as to produce 1. Mortlock, R. P., ed. (1984) Microorganisms as Model Systems for simultaneously both a novel phenotype, position effect, and Studying Evolution (Plenum, New York). a barrier of reproductive isolation separating the newly 2. Muller, H. J. (1964) Mutat. Res. 1, 2-9. formed from its via 3. Kimura, M. (1983) The Neutral Theory of Molecular Evolution (Cam- species progenitor chromosomal repat- bridge Univ. Press, Cambridge, U.K.). terning (pages 206-210 of ref. 37). During the last few years 4. Hartley, B. S. (1979) Proc. R. Soc. London Ser. B 205, 443-450. of his career, he attempted to find such effects through 5. Hartley, B. S., Altosser, I., Duthie, J. M. & Neugerger, M. S. (1976) in intensive investigations of homeotic mutations in D. mela- Proceedings of the Third John Innes Symposium, eds. Markham, R. & nogaster. Discoveries made since his death have the Horne, R. W. (North Holland, Amsterdam), pp. 191-200. proved 6. Mortlock, R. P. (1982) Evol. Biol. 14, 205-268. futility of his efforts and the absence of anything resembling 7. Rigby, P. W., Burleigh, R. D. & Hartley, B. S. (1974) Nature (London) "systemic mutations" in the material that he regarded as 251, 200-204. most favorable for them. The more than 500 species of 8. Adams, J., Paquin, C., Oeller, P. W. & Lee, C. W. 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Nat. 125, 118-143. 17. Dean, A. M., Dykhuizen, D. E. & Hartl, D. L. (1986) Genet. Res. 48, 1- genetic analysis of one of the most striking species differ- 8. ences within the group, that between Drosophila sylvestris 18. Dean, A. M., Dykhuizen, D. E. & Hartl, D. L. (1988) Mol. Biol. Evol., and Drosophila heteroneura, demonstrates that this differ- in press. ence is controlled by several genes, perhaps 10-20, of which 19. Dykhuizen, D. E., Dean, A. M. & Hartl, D. L. (1987) Genetics 115, 25- only 1 has a conspicuous effect on 31. morphological phenotype 20. Hartl, D. L., Dykhuizen, D. E. & Dean, A. M. (1985) Genetics 111, 655- in altering the shape of the head. The genetic basis of 674. homeotic mutations in D. melanogaster is becoming increas- 21. Hartl, D. L., Dean, A. M. & Dykhuizen, D. E. (1986) Genetics 114, ingly understood (39). Homeotic mutations do not involve 1037-1039. chromosomal but often shifts in 22. Sonneborn, T. M. (1975) Trans. Am. Microsc. 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