Copyrighted Material I.15 and Philip Hedrick

OUTLINE can be represented as a binomial of the al­ lele frequencies. 1. Introduction neutral . Genetic change is primarily the result of 2. and effective and genetic drift, and different molecular 3. Neutral theory are neutral with respect to each other. 4. flow and population population. A group of interbreeding individuals that 5. Selection exist together in and space. 6. Future directions . Favorable that re­ sults in a region of low closely About 40 years ago, first strongly advocated the linked to the selected region. integration of and into population (Singh and Uyenoyama, 2004). Even today these two disciplines are not really integrated, but 1. INTRODUCTION there is a general appreciation of population genetic con­ The primary goals of population genetics are to un­ cepts in population ecology and vice versa. For example, the derstand the factors determining evolutionary change new subdiscipline , and many articles and stasis and the amount and pattern of genetic var­ in the journal Molecular Ecology, use genetic markers and iation within and between (Hedrick, 2005; principles to examine both ecological and evolutionary Hartl and Clark, 2007). In the 1920s and 1930s, shortly questions. Although some aspects of population genet­ after widespread acceptance of Mendelian genetics, the ics have changed quickly in recent years, many of its fun­ theoretical basis of population genetics was developed damentals are still important for aspects of ecological by Ronald A. Fisher, J.B.S. Haldane, and . study. Population genetics may be unique among biological because it was first developed as a theoretical discipline by these men before experimental research GLOSSARY had a significant impact. coalescence. The point at which common ancestry for The advent of molecular genetic data of populations two at a gene occurs in the past. in the late 1960s and DNA sequence data in the 1980s effective population size. An population that in­ revolutionized population genetics and produced many corporates such factors as variation in the ratio new questions. Population genetics and its ­ of breeding individuals, the offspring number per ary interpretations provided a fundamental context in individual, and numbers of breeding individuals in which to interpret these new molecular genetic data. different . Further, population genetic approaches have made gene flow. Movement between groups that results in fundamental contributions to understanding the role genetic exchange. of molecular variation in adaptive differences in mor­ genetic bottleneck. A period during which only a few phology, behavior, and . A primary goal in individuals survive and become the only determining the extent and pattern of genetic variation of the future generations of the population. is to document the variation that results in selective genetic drift. Chance changes in frequencies that differences among individuals, the ‘‘stuff of evolution.’’ result from . The amount and kind of genetic variation in popu­ Hardy-Weinberg principle. After one of lations are potentially affected by a number of factors, random mating, single- frequencies but primarily by selection, , genetic drift, Copyrighted Material

110 Autecology gene flow, mutation, and recombination. These factors Weinberg equilibrium [HWE]). It states that after one may have general or particular effects; for example, generation of random mating, single-locus genotype genetic drift and inbreeding can be considered to al­ frequencies can be represented by a binomial (with two ways reduce the amount of variation, and mutation to alleles) or multinomial (with multiple alleles) function always increase the amount of variation. Other factors, of the allele frequencies. This principle allows great such as selection and gene flow, may either increase or simplification of the description of a population’s ge­ reduce genetic variation, depending on the particular netic content by reducing the number of parameters situation. Combinations of two or more of these fac­ that must be considered. Furthermore, in the absence tors can generate many different levels and patterns of of factors that change (selection, ge­ genetic variation. In 1968, introduced netic drift, gene flow, and mutation), and in the contin­ the important ‘‘neutral theory’’ of ued presence of random mating, the Hardy-Weinberg that assumes that genetic variation results from a com­ genotype proportions will not change over time. bination of mutation generating variation and genetic drift eliminating it (Kimura, 1983). This theory is 2. GENETIC DRIFT AND EFFECTIVE called neutral because allele and genotype differences POPULATION SIZE at a gene are selectively neutral with respect to each other. This theory is consistent with many observations Since the beginning of population genetics, there has of molecular genetic variation (see below). been controversy concerning the importance of chance To understand the influence of these evolutionary changes in allele frequencies because of small popula­ factors, one must first be able to describe and quantify tion size, termed genetic drift. Part of this controversy the amount of genetic variation in a population and the has resulted from the large numbers of individuals pattern of genetic variation among populations. In re­ observed in many natural populations, large enough to cent years, new laboratory techniques have made it think that chance effects would be small in comparison possible to obtain molecular genetic data in any spe­ to the effects of other factors, such as selection and cies, and a number of software packages have become gene flow. However, if the selective effects or amount available to estimate the important parameters in of gene flow are small relative to genetic drift, then population genetics and related topics. In addition, the long-term genetic change caused by genetic drift may online Evolution Directory (EvolDir) is a source of in­ be important. formation about different molecular techniques, esti­ Under certain conditions, a finite population may be mation procedures, and other current evolutionary so small that genetic drift is significant even for loci genetic . with sizable selective effects, or when there is gene Let us first define the evolutionary or genetic con­ flow. For example, some populations may be contin­ notation of the term population. As a simple ideal, uously small for relatively long periods of time because a population is group of interbreeding individuals that of limited resources in the populated area, low ten­ exist together in time and space. Often it is assumed dency or capacity to disperse between suitable , that a population is geographically well defined, al­ or territoriality among individuals. In addition, some though this may not always be true. Below we discuss populations may have intermittent small population the concept of effective population size, which provides sizes. Examples of such episodes are the overwintering a more explicit definition of population in evolutionary loss of population numbers in many and terms. epidemics that periodically decimate populations of Many of the theoretical developments in population both and . Such population fluctuations genetics assume a large, random-mating population generate genetic bottlenecks, or periods during which that forms the from which the and only a few individuals survive and become the only male are drawn. In some real- situations, ancestors of the future generations of the population. such as dense populations of or Small population size is also important when a pop­ plants, this ideal may be nearly correct, but in many ulation grows from a few founder individuals, a phe­ natural situations, it is not closely approximated. For nomenon termed founder effect. For example, many example, there may not be random mating, as in self- island populations appear to have started from a very fertilizing plants, or there may be small or isolated small number of individuals. If a single female who was populations as in rare or endangered . In these fertilized by a single male founds a population, then cases, modifications of the theoretical ideal must be only four (assuming a diploid ), two made. from the female and two from the male, may start a One of the basic concepts of population genetics new population. In plants, a whole population may is the Hardy-Weinberg principle (often called Hardy- be initiated from a single seed—only two genomes, if Copyrighted Material

Population Genetics and Ecology 111 self-fertilization occurs. As a result, populations des­ the parents of any progeny individual. In other words, cended from a small founder group may have low ge­ the gametes are drawn randomly from all breeding netic variation or by chance have a high or low fre­ individuals, and the probability of each adult pro­ quency of particular alleles. ducing a particular equals 1/N, where N is the Another situation in which small population size is number of breeding individuals. A straightforward of great significance occurs when the population (or approach that is often used to tell the impact of various species) in question is one of the many threatened or factors on the effective population size is the ratio of endangered species (Allendorf and Luikart, 2007). the effective population size to breeding (or sometimes For example, all approximately 500 whooping cranes census) population size, that is, Ne/N. Sometimes, this alive today descend from only 20 whooping cranes that ratio is only around 0.1 to 0.25, indicating that the were alive in 1920 because they were hunted and their effective population size may be much less than the destroyed. All 200,000 northern elephant seals number of breeding individuals. In general, the effect alive today descend from as few as 20 that survived of genetic drift is a function of the reciprocal of the nineteenth-century hunting on Isla Guadalupe, Mex­ number of gametes in a population, 1/(2Ne), for a ico. Further, all the living individuals of some species diploid population. If Ne is large, then this value is are descended from a few founders that were brought small, and there is little genetic drift influence. Or, if Ne into captivity to establish a protected population, such is small, then this value is relatively large, and genetic as Przewalski’s (13 founders), California con­ drift may be important. dors (13 founders), black-footed ferrets (6 founders), Gala´pagos tortoises from Espan˜ ola Island (15 found­ 3. NEUTRAL THEORY ers), and Mexican wolves (7 founders). The population size that is relevant for evolutionary Neutral theory assumes that selection plays a minor matters, the number of breeding individuals, may be role in determining the maintenance of molecular much less than the total number of individuals in an variants and proposes that different molecular geno­ area, the census population size, and is the appro­ types have almost identical relative fitnesses; that is, priate measure for many population ecology studies. they are neutral with respect to each other. The actual The size of the breeding population may sometimes be definition of selective neutrality depends on whether estimated with reasonable accuracy by counting indi­ changes in allele frequency are primarily determined cators of breeding activity such as nests, masses, by genetic drift. In a simple example, if s is the selec­ and colonies in animals or counting the number of tive difference between two alleles at a locus, and if flowering individuals in plants. But even the ­ s < 1/(2Ne), the alleles are said to be neutral with re­ ing population number may not be indicative of the spect to each other because the impact of genetic drift population size that is appropriate for evolutionary is larger than selection. This definition implies that considerations. alleles may be effectively neutral in a small population For example, factors such as variation in the sex but not in a large population. Neutral theory does not ratio of breeding individuals, the offspring number per claim that the relatively few allele substitutions re­ individual, and numbers of breeding individuals in sponsible for evolutionarily adaptive traits are neutral, different generations may be evolutionarily important. but it does suggest that the majority of allele substitu­ All these factors can influence the genetic contribution tions have no selective advantage over those that they to the next generation, and a general estimate of the replace. breeding population size does not necessarily take them Kimura also showed that the neutral theory was into account. As a result, the effective population size, consistent with a ; that is, there is a or Ne, a theoretical concept that incorporates varia­ constant rate of substitution over time for molecular tion in these factors and allows general predictions or variants. To illustrate the mathematical basis of the statements irrespective of the particular forces respon­ molecular clock, let us assume that mutation and ge­ sible, is quite useful. In other words, the concept of an netic drift are the determinants of changes in frequen­ ideal population with a given effective size enables us cies of molecular variants. Let the to a to draw inferences concerning the evolutionary effects new allele be u so that in a population of size 2N there of finite population size by providing a for are 2Nu new per generation. It can be shown incorporating factors that result in deviations from the that the probability of chance fixation of a new neutral ideal. is 1/(2N) (the initial frequency of the new The concept of the effective population size makes it mutant). Therefore, the rate of allele substitution k is possible to consider an ideal population of size N in the product of the number of new mutants per gener­ which all parents have an equal expectation of being ation and their probability of fixation, or Copyrighted Material

112 Autecology

cestry for two alleles occurs is called coalescence. If 1 k ¼ 2Nu ¼ u: one goes back far enough in time in the popula­ 2N tion, then all alleles in the sample will coalesce into a single common ancestral allele. Research using the In other words, this elegant prediction from the coalescent approach is the most dynamic area of the­ neutral theory is that the rate of substitution is equal to oretical population genetics because it is widely used the mutation rate at the locus and is constant over time. to analyze DNA sequence data in populations and Note that substitution rate is independent of the ef­ species. fective population size, a that may initially be counterintuitive. This independence occurs because in a 4. AND POPULATION STRUCTURE smaller population there are fewer mutants; that is, 2Nu is smaller, but the initial frequency of these mu­ In most species, populations are often subdivided into tants is higher, which increases the probability of fix­ smaller units because of geographic, ecological, or be­ ation, 1/2N, by the same magnitude by which the havioral factors. For example, the populations of fish number of mutants is reduced. This simple, elegant in pools, on mountains, and insects on plants mathematical prediction and others from the neutral are subdivided because suitable habitat for these spe­ theory provide the basis for the most important de­ cies is not continuous. Population subdivision can also velopments in in the past half- result from behavioral factors, such as troop formation century. in , territoriality in , and forma­ One of the appealing aspects of the neutral theory is tion in social insects. that, if it is used as a null hypothesis, then predictions When a population is subdivided, the amounts of about the magnitude and pattern of genetic variation genetic connectedness among the parts of the popula­ are possible. Initially, molecular genetic variation was tion can differ. Genetic connection depends primarily found to be consistent with that predicted from neu­ on the amount of gene flow, movement between groups trality theory. In recent years, examination of neutral that results in genetic exchange that takes place among theory predictions in DNA sequences has allowed tests the subpopulations or subgroups. When the amount of the cumulative effect of many generations of selec­ of gene flow between groups is high, gene flow has tion, and a number of examples of selection on mo­ the effect of homogenizing genetic variation over the lecular variants have been documented (see below). groups. When gene flow is low, genetic drift, selection, Traditionally, population genetics examines the im­ and even mutation in the separate groups may lead to pact of various evolutionary factors on the amount and genetic differentiation. pattern of genetic variation in a population and how It is sometimes useful to describe the population these factors influence the future potential for evolu­ structure in a particular geographic framework. For tionary change. Generally, evolution is conceived of as example, within a watershed, there may be separated a forward process, examining and predicting the future fish or groups that have a substantial amount of characteristics of a population. However, rapid accu­ genetic exchange between them. On a larger scale, mulation of DNA sequence data over the past two there may be genetic exchange between adjacent wa­ decades has changed the orientation of much of pop­ tersheds but in smaller amounts than between the ulation genetics from a prospective one investigating groups within a watershed. On an even larger scale, the factors involved in observed evolutionary change to there may be populations in quite separated watersheds a retrospective one inferring evolutionary events that that presumably have little direct exchange but may have occurred in the past. That is, understanding the share some genetic history, depending on the amount evolutionary causes that have influenced the DNA se­ of gene flow among the adjacent groups or occasional quence variation in a sample of individuals, such as the long-distance gene flow. This hierarchical representa­ demographic and mutational history of the ancestors tion is useful in describing the overall relationships of of the sample, has become the focus of much popula­ populations of an organism and in documenting the tion genetics research. spatial pattern of genetic variation. Recently, there has In a determination of DNA variation in a popula­ been increasing interest in landscape and geographic tion, a sample of alleles is examined. Each of these approaches to estimating historical and contemporary alleles may have a different history, ranging from gene flow. In addition, , the joint use of descending from the same ancestral allele, that is, phylogenetic techniques and geographic distributions, identical by descent, in the previous generation to has been used to understand spatial relationships and descending from the same ancestral allele many gen­ distributions of populations within species or closely erations before. The point at which this common an­ related species (Avise, 2000). Copyrighted Material

Population Genetics and Ecology 113

In general, the subdivision of populations assumes 1 that the various subpopulations are always . FST � : Another view assumes that individual population sub­ 4Nem þ 1 divisions at particular sites may become extinct and then later be recolonized from other subpopulations, When Nem is large, the measure FST approaches 0, and resulting in a metapopulation. The dynamics of ex­ when Nem is small, FST can approach 1. The value of tinction and recolonization can make metapopulations FST for a group of populations can be estimated using quite different both ecologically and genetically from the amount and pattern of molecular genetic variation the traditional concept of a subdivided population. over subpopulations. Gene flow is central to understanding evolutionary The availability of molecular and DNA sequence potential and mechanisms in several areas of applied data in many provides a database to deter­ population genetics. First, the potential for movement mine the relationships between populations or species of from genetically modified organisms (GMO) that are not obvious from other traits. It is generally into related wild populations—that is, the gene flow of assumed that molecular genetic data better reflect the into natural populations—can be examined true relationships between groups than other data, such using population genetics. Second, the invasive poten­ as or behavior, because molecular data are tial of nonnative plants and animals into new areas less influenced by selective effects. Furthermore, dif­ may be affected by hybridization (gene flow) between ferences between relationships generated from molec­ nonnative and native organisms as well as adaptive ular data and from other traits provide an opportunity change. Finally, a number of endangered species are to evaluate the effect of selective effects on other traits. composed of only one, or a few, remaining populations Maternally inherited mitochrondrial DNA (mtDNA) with low fitness. Gene flow from other populations of data have been the workhorse for phylogeographic the same species can result in or genetic research because mtDNA does not recombine in most restoration of these populations by introducing new organisms and, as a result, shows a clearer phyloge­ variation that allows removal of detrimental variation netic record than many nuclear genes ( and restoration of adaptive change. DNA and Y are similarly useful). In Estimating the amount of gene flow in most sit­ addition, the effective population size for mtDNA (as uations is rather difficult. Direct estimates of the well as for chloroplast DNA and Y chromosomes) is amount of movement can be obtained in organisms only about one-fourth that of nuclear genes so that where different individuals can be identified or individ­ divergence occurs about four faster than for nu­ ual marks are used. Many approaches have been em­ clear genes. However, this faster rate of divergence and ployed to mark individuals differentially, such as toe potentially differential gene flow for the two may clipping in , leg banding in birds, coded-wire cause the signal for these uniparentally inherited genes tags in fish, and radio transponders in many different to be different from the phylogenetic pattern for nu­ . clear genes, which constitute a very large proportion of However, both movement of individuals and their the . incorporation into the breeding population are nec­ essary for gene flow. Using highly variable genetic 5. SELECTION markers, it is now possible to identify parents geneti­ cally and thereby determine the spatial movement of In the past few years, with the availability of extensive gametes between generations without direct movement DNA sequence data for a number of organisms (par­ information of the parents. Or, individuals can be as­ ticularly ), there has been an intensive search signed to specific populations using genetic mark­ for genomic regions exhibiting a signal of adaptive ers, thereby determining whether they are migrants or (positive Darwinian) selection. Many of the genomic not. regions identified have undergone a ‘‘selective sweep’’ Indirect measures of gene flow using genetic mark­ because of favorable directional selection, as indicated ers are useful to confirm behavioral or other observa­ by low genetic variation in genetic regions closely tions or when these observations are inconclusive or linked to the selected gene or regions. impossible. Most commonly, the number of ­ An elegant example of a selective sweep is adaptive fully breeding migrants between groups is measured in the rock pocket of the southwest­ using techniques to evaluate population structure. ern United States (Hoekstra et al., 2004). The mouse Theoretically, assuming finite subpopulations of size is generally light-colored and on light-colored Ne and a proportion m migrants into each subpopu­ granite rocks, but it also has melanic forms that live lation each generation, then on relatively recent black lava formations in several Copyrighted Material

114 Autecology

Arizona

Arizona, USA 5km Xmas

lava Tule

West Mid

East O’Neill Sonora, Mexico

Substrate color:

Coat color:

Xmas Tule West Mid East O’Neill Figure 1. Six sampling sites (three on dark volcanic rock and three grams) in rock pocket mice across a transect in the Sonoran desert. on light-colored substrate) and coat color frequencies (in pie dia­ (From Hoekstra et al., 2004)

restricted sites. Figure 1 shows the frequencies of the the expected pattern if selection has recently increased normal recessive and dominant melanic forms from its frequency by a selective sweep in the area of black a 35-km transect in southwestern Arizona. Here the lava. frequency of melanics is highly concordant with sub­ Some of best-documented examples of adaptive se­ strate color, that is, high frequencies of melanics in the lection are those resulting from recent changes center of this transect that has approximately 10 km in the environment (Hedrick, 2006), such as develop­ of black lava and lower frequencies of melanics on ment of genetic resistance in pests to chemicals the light-colored substrate sites at either end of the used to control them or genetic resistance in transect. to . The genetic basis of resistance Investigation of molecular variation in the Mc1r may be the result of many genes, mutants at a single or gene, which is known to have variants that produce a few genes, or expansion of gene . Because the dark-colored house mice, was found to correlate nearly molecular basis of many of these adaptive changes is completely with the light and melanic . The known, detailed genetic and evolutionary understand­ melanic and normal alleles were found to differ by four ing is possible. For example, resistance to some insec­ amino acids, and the diversity for the me­ ticides among mosquitoes that are vectors for diseases lanic alleles was 1/20 that for light alleles. The lower such as ( gambiae) and West Nile variation among the melanic alleles is consistent with (Culex pipiens) is the result of a single amino-acid Copyrighted Material

Population Genetics and Ecology 115

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3 Expected heterozygosity dhfr 0.2

0.1

0 89 58 30 17 7.6 4.5 4.2 3.9 1.2 0.1 0.2 - - - - 646 623 537 460 363 252 141 121 143 159 181 239 300 323 359 ------0.52 1.48 4.05 5.87 30.3 39.9 49.2 ------Marker distance (kilobases) from dhfr Figure 2. The observed (solid circles) and expected (lines) het­ dium falciparum, which provides resistance to the antimalarial erozygosity around the dhfr gene in the malaria parasite Plasmo­ drug pyrimethamine. (From Nair et al., 2003) substitution. In C. pipiens, a single nucleotide change, where there is resistance in the malarial parasite to the GGC (glycine) to AGC (serine) at codon 119 in the widely used drug chloroquine. Pyrimethamine was in­ gene for the acetylcholinesterase (ace-1) results troduced to the area along the Thailand-Myanmar in insensitivity to organophosphates. A complete lack border in the mid-1970s, and resistance spread to fix­ of variation within samples among resistant variants of ation in approximately 6 years. Resistance is the result this gene suggests that they have originated and spread of point at the active site of the enzyme quite recently. encoded by the gene dhfr on 4. Ex­ Another of examples of adaptive selection in­ amination of genetic variation at genes near dhfr as clude those resulting from the of host re­ shown in figure 2 showed remarkable reduced hetero­ sistance to pathogens. For example, malaria kills more near dhfr and normal variation further away than one million children each year in alone and (Nair et al., 2003). This pattern of variation is consis­ is the strongest selective pressure in recent human his­ tent with a selective sweep, and the theoretical pattern tory. As a result, selective protection from malaria by expected from a selective sweep is shown by the curve sickle , thalassemia, G6PD, Duffy, and many other in figure 2. genetic variants in the human host provide some of the The major histocompatibility complex (MHC) clearest examples of adaptive variation and diversify­ genes are part of the in vertebrates, and ing selection for resistance (Kwiatkowski, differential selection through resistance to pathogens is 2005). Genomic studies have demonstrated that se­ widely thought to be the basis of their high genetic lection for malarial resistance is strong, up to 10%, and variation (Garrigan and Hedrick, 2003). Variation in that variants conferring resistance to malaria are re­ the genes of the human MHC, known as HLA genes, cent, generally less than 5000 years old, consistent with has been the subject of intensive study for many years the proposed timing of malaria as an important human because of their role in determining acceptance or re­ disease. Often the resistant variants are in different jection of transplanted organs, many autoimmune populations, probably mainly in part because of their diseases, and recognition of pathogens. High HLA recent independent mutation origin. variation allows recognition of more pathogens, con­ Efforts to control the malaria parasite using anti­ sistent with the fact that HLA-B is the most variable malarial drugs have resulted in widespread genetic re­ gene in the . In recent years, there has sistance to these drugs. For example, pyrimethamine is been extensive research examining R (disease resistant) an inexpensive antimalarial drug used in countries genes in plants, a system with similarities to MHC. Copyrighted Material

116 Autecology

Hedrick, Philip. 2006. Genetic in heteroge­ 6. FUTURE DIRECTIONS neous environments: The age of . Annual Review Because of the widespread availability of DNA se­ of Ecology, Evolution, and 37: 67–93. A quence data in many organisms, the future application summary of the recent empirical and theoretical exam­ of population genetic data and principles in ecology ples of genetic polymorphism maintained by ecological variation. appears almost unlimited. Many basic ecological ques­ Hoekstra, Hopi, Kristen Drumm, and Michael Nachman. tions, such as how many individuals there are in a 2004. of adaptive color polymorphism population, what their relationships are, or whether in pocket mice: Geographic variation in selected and they are immigrants, may be definitively answered in neutral genes. Evolution 58: 1329–1341. A discussion of future years using genetic techniques. Such precise de­ adaptive melanism in pocket mice living on dark lava re­ scriptions may then provide data to understand the sults from amino-acid changes in the Mc1r gene. evolutionary and ecological factors influencing popu­ Kimura, Motoo. 1983. The Neutral Theory of Molecular lation dynamics and distributions. Evolution. : Cambridge University Press. A summary of the neutral theory from the view of its major architect, Motoo Kimura. FURTHER READING Kwiatkowski, Dominic. 2005. How malaria has affected the human genome and what can teach us Allendorf, Fred, and Gordon Luikart. 2007. Conservation about malaria. American Journal of Human Genetics 77: and the Genetics of Populations. Oxford: Blackwell Pub­ 171–192. A review of the many human genes that confer lishing. A recent summary of the application of population resistance to malaria, the strongest selective factor in re­ genetics to conservation. cent . Avise, John. 2000. Phylogeography: The History and For­ Nair, Shalini, Jeff Williams, Alan Brockman, Lucy Paiphun, mation of Species. Cambridge, MA: Mayfong Mayxay, P. N. Newton, J. P. Guthmann, F. M. Press. The joint use of phylogenetic relationships and Smithuis, T. T. Hien, N. J. , F. Nosten, and T. J. geographic patterns to understand evolution. Anderson. 2003. A selective sweep driven by pyrimeth­ Garrigan, Daniel, and Philip Hedrick. 2003. Perspective: amine treatment in southeast Asian malaria parasites. Detecting adaptive molecular evolution, lessons from and Evolution 20: 1526–1536. An the MHC. Evolution 57: 1707–1722. A perspective on the example of the fast development of antimalarial drug re­ strongest example of , MHC, and the sistance by a selective sweep of new resistant variants in gain and loss of balancing selection signals. Plasmodium. Hartl, Daniel, and Andrew Clark. 2007. Principles of Popu­ Singh, Rama, and Marcy Uyenoyama, eds. 2004. The Evo­ lation Genetics, 4th ed. Sunderland, MA: Sinauer As­ lution of —Modern Synthesis. Cam­ sociates. A recent summary of the principles of population bridge: Cambridge University Press. A summary of the con­ genetics. tributions to population biology over recent decades. Hedrick, Philip. 2005. Genetics of Populations, 3rd ed. Bos­ ton: Jones and Bartlett Publishers. A recent and thorough summary of the principles of population genetics.