Selection to Match Climatic Conditions. Many studies of selection have focused on genes encoding en zymes because in such cases the investigator can directly the consequences to the organism of changes in th frequency of alternative enzyme alleles. Often investiga tors find that enzyme allele frequencies vary latitudinally, 9 with one allele more common in northern populations but progressively less common at more southern locations. A superb example is seen in studies of a fish, the mumm hog, Fundulus heteroclitus, which ranges along the eastern 3 0.4 coast of North America. In this fish, allele frequencies of the gene that produces the enzyme lactase dehydrogenase,9 0.2H which catalyzes the conversion of pyruvate to lactate, vary geographically(figure 20.8). Biochemical studies show that the enzymes formed by these alleles function differ ently at different temperatures, thus explaining their geo- 4442403836343230 graphic distributions. For example, the form of the en zyme that is more frequent in the north is a better catalyst at low temperatures than the enzyme from the south Latitude(Degrees North Moreover, functional studies indicate that at low tempera tures. individuals with the northern allele swim faster and FIGURE 20.8 presumably survive better, than individuals with the alter- Selection to match climatic conditions. Frequency of the cole native allele adapted allele for lactase dehydrogenase in the mummichog (Fundulus heteroclitus)decreases at lower latitudes, which are Selection for Pesticide Resistance. A particularly clearwarmer example of selection in action in natural populations is pro- vided by studies of pesticide resistance in insects. The widespread use of insecticides has led to the rapid evolution of resistance in more than 400 pest species. For example, Pesticide the resistance allele at the pen gene decreases the uptake of o arget site O insecticide, whereas alleles at the kdr and dld-r genes de crease the number of target sites, thus decreasing the bind ing ability of the insecticide(figure 20.9). Other alleles en- 48 hance the ability of the insects'enzymes to identify and detoxify insecticide molecules Single genes are also responsible for resistance in other Resistant nsect cell organisms. The pigweed, Amaranthus bybridus, is one of about 28 agricultural weeds that have evolved resistance (a)Insect cells with resistance allele at pen gene to the herbicide Triazine. Triazine inhibits photosynthe decreased uptake of the pesticide sis by binding to a protein in the chloroplast membrane. Single amino acid substitutions in the gene encoding the protein diminish the ability of Triazine to decrease the plant's photosynthetic capabilities. Similarly, Norway rats are normally susceptible to the pesticide Warfarin, which diminishes the clotting ability of the rat 's blood and leads to fatal hemorrhaging. However, a resistance allele at a ngle gene alters a metabolic pathway and renders War- farin ineffective Five factors can bring about a deviation from the (b )Insect cells with resistance allele at kdr gene proportions of homozygotes and heterozygotes decreased number of target sites for the pesticide predicted by the Hardy-Weinberg principle. Only selection regularly produces adaptive evolutionary FIGURE 20.9 change, but the genetic constitution of individual Selection for pesticide resistance. Resistance alleles at ger populations, and thus the course of evolution, can also like pen and kdr allow insects to be more resistant to pesticides be affected by mutation, gene flow, nonrandom nsects that possess these resistance alleles have become more nating, and genetic drift. through selection Chapter 20 Go ene atons
Selection to Match Climatic Conditions. Many studies of selection have focused on genes encoding enzymes because in such cases the investigator can directly assess the consequences to the organism of changes in the frequency of alternative enzyme alleles. Often investigators find that enzyme allele frequencies vary latitudinally, with one allele more common in northern populations but progressively less common at more southern locations. A superb example is seen in studies of a fish, the mummichog, Fundulus heteroclitus, which ranges along the eastern coast of North America. In this fish, allele frequencies of the gene that produces the enzyme lactase dehydrogenase, which catalyzes the conversion of pyruvate to lactate, vary geographically (figure 20.8). Biochemical studies show that the enzymes formed by these alleles function differently at different temperatures, thus explaining their geographic distributions. For example, the form of the enzyme that is more frequent in the north is a better catalyst at low temperatures than the enzyme from the south. Moreover, functional studies indicate that at low temperatures, individuals with the northern allele swim faster, and presumably survive better, than individuals with the alternative allele. Selection for Pesticide Resistance. A particularly clear example of selection in action in natural populations is provided by studies of pesticide resistance in insects. The widespread use of insecticides has led to the rapid evolution of resistance in more than 400 pest species. For example, the resistance allele at the pen gene decreases the uptake of insecticide, whereas alleles at the kdr and dld-r genes decrease the number of target sites, thus decreasing the binding ability of the insecticide (figure 20.9). Other alleles enhance the ability of the insects’ enzymes to identify and detoxify insecticide molecules. Single genes are also responsible for resistance in other organisms. The pigweed, Amaranthus hybridus, is one of about 28 agricultural weeds that have evolved resistance to the herbicide Triazine. Triazine inhibits photosynthesis by binding to a protein in the chloroplast membrane. Single amino acid substitutions in the gene encoding the protein diminish the ability of Triazine to decrease the plant’s photosynthetic capabilities. Similarly, Norway rats are normally susceptible to the pesticide Warfarin, which diminishes the clotting ability of the rat’s blood and leads to fatal hemorrhaging. However, a resistance allele at a single gene alters a metabolic pathway and renders Warfarin ineffective. Five factors can bring about a deviation from the proportions of homozygotes and heterozygotes predicted by the Hardy-Weinberg principle. Only selection regularly produces adaptive evolutionary change, but the genetic constitution of individual populations, and thus the course of evolution, can also be affected by mutation, gene flow, nonrandom mating, and genetic drift. Chapter 20 Genes within Populations 429 1.0 0.8 0.6 0.4 0.2 44 42 40 38 36 34 32 30 Latitude (Degrees North) Frequency of cold-adapted allele FIGURE 20.8 Selection to match climatic conditions. Frequency of the coldadapted allele for lactase dehydrogenase in the mummichog (Fundulus heteroclitus) decreases at lower latitudes, which are warmer. Pesticide molecule Resistant target site Insect cell membrane Target site Target site (a) Insect cells with resistance allele at pen gene: decreased uptake of the pesticide (b) Insect cells with resistance allele at kdr gene: decreased number of target sites for the pesticide FIGURE 20.9 Selection for pesticide resistance. Resistance alleles at genes like pen and kdr allow insects to be more resistant to pesticides. Insects that possess these resistance alleles have become more common through selection
Identifying the Evolutionary Forces Testing the Neutral Theory Maintaining polymorphism Choosing between the adaptive selection theory and the neutral theory is not simple, for they The Adaptive Selection Theory count for much of the data on gene polymorphism in nat As evidence began to accumulate in the 1970s that natural ural populations. A few well-characterized instances where populations exhibit a great deal of genetic polymorphism selection acts on enzyme alleles do not settle the more gen question arose: What evolutionary force is maintaining the ing large-scale patterns of polymorphism sheds light on the polymorphism? As we have seen, there are in principle five difficulty of choosing between the two theories processes that act on allele frequencies: mutation, migra Population size: According to the neutral theory, tion, nonrandom mating, genetic drift, and selection. Be- polymorphism as measured by H should be proportional cause migration and nonrandom mating are not major in- tion size m fluences in most natural populations, attention focused tion rate among neutral alleles u is constant. Thus, H the other three forces The first suggestion, advanced by R. C Lewontin(one should be much greater for insects than humans, as there are far more individuals in an insect population of the discovers of enzyme polymorphism) and many oth- than in a human one. When DNA sequence variation is ers, was that selection was the force acting to maintain the examined, the fruit fly Drosophila melanogaster indeed polymorphism. Natural environments are often quite het exhibits sixfold higher levels of variation, as the theory erogeneous, so selection might reasonably be expected to predicts; but when enzyme polymorphisms are exam pull gene frequencies in different directions within differ ined. levels of variation in fruit flies and humans are ent microhabitats, generating a condition in which many similar. If the level of dNa variation correctly mirrors alleles persist. This proposal is called the adaptive selec- the predictions of the neutral theory, then something tion theory (selection? )is increasing variation at the enzyme level in humans. These sorts of patterns argue for rejection of The Neutral theor the neutral theory A second possibility, championed by the great Japanese The nearly neutral model: One way to rescue the geneticist Moto Kimura, was that a balance between mu neutral theory from these sorts of difficulties is to retreat tation and genetic drift is responsible for maintaining from the assumption of strict neutrality, modifying the polymorphism. Kimura used elegant mathematics to theory to assume that many of the variants are slightly demonstrate that. even in the absence of selection, nat deleterious rather than strictly neutral to selection. With ural populations could be expected to contain consider this adjustment, it is possible to explain many of the able polymorphism if mutation rates(generating the vari population-size-dependent large-scale patterns. How ation)were high enough and population sizes(promoting ever, little evidence exists that the wealth of enzyme genetic drift) were small enough. In this proposal, selec- polymorphism in natural populations is in fact slightly ion is not acting, differences between alleles being"neu tral to selection. The proposal is thus called the neutral As increasing amounts of DNA sequence data become theory available, a detailed picture of variation at the DNA level is imura's theory, while complex, can be stated simply emerging. It seems clear that most nucleotide substitutions H=1/(4N+1) that change amino acids are disadvantageous and are elimi- nated by selection. But what about the many protein alleles H, the mean heterozygosity, is the likelihood th that are seen in natural populations? Are they nearly neu- randomly selected member of the population will be het- tral or advantageous? No simple answer is yet available, al erozygous at a randomly selected locus. In a population though the question is being actively investigated. Levels of without selection, this value is influenced by two vari- lymorphism at enzyme-encoding genes may depend ables, the effective population size(N) and the mutation both the action of selection on the gene(the adaptive selec. rate(a. tion theory)and on the population dynamics of the specie The peculiar difficulty of the neutral theory is that the(the nearly neutral theory), with the relative contribution vel of polymorphism, as measured by H, is determined varying from one gene to the next by the product of a very large number, Ne, and a very Adaptive selection clearly maintains some enzyme poly small number, u, both very difficult to measure with pre- morphisms in natural populations. Genetic drift seems to cision. As a result, the theory can account for almost any play a major role in producing the variation we see at the value of H, making it very difficult to prove or disprove. DNA level. For most enzyme-level polymorphism, investi- As you might expect, a great deal of controversy has gators cannot yet choose between the selection theory and resulted he nearly neutral theory. 430 Part vI Evolution
Identifying the Evolutionary Forces Maintaining Polymorphism The Adaptive Selection Theory As evidence began to accumulate in the 1970s that natural populations exhibit a great deal of genetic polymorphism (that is, many alleles of a gene exist in the population), the question arose: What evolutionary force is maintaining the polymorphism? As we have seen, there are in principle five processes that act on allele frequencies: mutation, migration, nonrandom mating, genetic drift, and selection. Because migration and nonrandom mating are not major influences in most natural populations, attention focused on the other three forces. The first suggestion, advanced by R. C. Lewontin (one of the discovers of enzyme polymorphism) and many others, was that selection was the force acting to maintain the polymorphism. Natural environments are often quite heterogeneous, so selection might reasonably be expected to pull gene frequencies in different directions within different microhabitats, generating a condition in which many alleles persist. This proposal is called the adaptive selection theory. The Neutral Theory A second possibility, championed by the great Japanese geneticist Moto Kimura, was that a balance between mutation and genetic drift is responsible for maintaining polymorphism. Kimura used elegant mathematics to demonstrate that, even in the absence of selection, natural populations could be expected to contain considerable polymorphism if mutation rates (generating the variation) were high enough and population sizes (promoting genetic drift) were small enough. In this proposal, selection is not acting, differences between alleles being “neutral to selection.” The proposal is thus called the neutral theory. Kimura’s theory, while complex, can be stated simply: H¯¯ = 1/(4Neµ +1) H¯¯, the mean heterozygosity, is the likelihood that a randomly selected member of the population will be heterozygous at a randomly selected locus. In a population without selection, this value is influenced by two variables, the effective population size (Ne) and the mutation rate ( µ). The peculiar difficulty of the neutral theory is that the level of polymorphism, as measured by H¯¯ , is determined by the product of a very large number, Ne, and a very small number, µ, both very difficult to measure with precision. As a result, the theory can account for almost any value of H¯¯ , making it very difficult to prove or disprove. As you might expect, a great deal of controversy has resulted. Testing the Neutral Theory Choosing between the adaptive selection theory and the neutral theory is not simple, for they both appear to account for much of the data on gene polymorphism in natural populations. A few well-characterized instances where selection acts on enzyme alleles do not settle the more general issue. An attempt to test the neutral theory by examining large-scale patterns of polymorphism sheds light on the difficulty of choosing between the two theories: Population size: According to the neutral theory, polymorphism as measured by H¯¯ should be proportional to the effective population size Ne, assuming the mutation rate among neutral alleles µ is constant. Thus, H¯¯ should be much greater for insects than humans, as there are far more individuals in an insect population than in a human one. When DNA sequence variation is examined, the fruit fly Drosophila melanogaster indeed exhibits sixfold higher levels of variation, as the theory predicts; but when enzyme polymorphisms are examined, levels of variation in fruit flies and humans are similar. If the level of DNA variation correctly mirrors the predictions of the neutral theory, then something (selection?) is increasing variation at the enzyme level in humans. These sorts of patterns argue for rejection of the neutral theory. The nearly neutral model: One way to rescue the neutral theory from these sorts of difficulties is to retreat from the assumption of strict neutrality, modifying the theory to assume that many of the variants are slightly deleterious rather than strictly neutral to selection. With this adjustment, it is possible to explain many of the population-size-dependent large-scale patterns. However, little evidence exists that the wealth of enzyme polymorphism in natural populations is in fact slightly deleterious. As increasing amounts of DNA sequence data become available, a detailed picture of variation at the DNA level is emerging. It seems clear that most nucleotide substitutions that change amino acids are disadvantageous and are eliminated by selection. But what about the many protein alleles that are seen in natural populations? Are they nearly neutral or advantageous? No simple answer is yet available, although the question is being actively investigated. Levels of polymorphism at enzyme-encoding genes may depend on both the action of selection on the gene (the adaptive selection theory) and on the population dynamics of the species (the nearly neutral theory), with the relative contribution varying from one gene to the next. Adaptive selection clearly maintains some enzyme polymorphisms in natural populations. Genetic drift seems to play a major role in producing the variation we see at the DNA level. For most enzyme-level polymorphism, investigators cannot yet choose between the selection theory and the nearly neutral theory. 430 Part VI Evolution
Interactions among Evolutionary orces (Agrostis tenuis) When alleles are not selectively neu- 8 tral,levels of variation retained in a 960mine Non- Mine Non-mine population may be determined by the 3 relative strength of different evolution- ary processes. In theory, for example, if allele B mutates to allele b at a high a enough rate, allele b could be main-%20 tained in the population even if natural selection strongly favored allele B. In nature. however. mutation rates are 020406080100120140160 rarely high enough to counter the ef- Distance in meters fects of natural selection The effect of natural selection also FIGuRE 20.1 may be countered by genetic drift. Degree of copper tolerance in grass plants on and near ancient mine sites. Prevailing Both processes may act to remove vari- winds blow pollen containing nontolerant alleles onto the mine site and tolerant alleles ation from a population. However, beyond the site's borders whereas selection is a deterministic process that operates to increase the representation of alleles that enhance survival and reproductive success, drift is a random process. Thus, in some cases, drift may lead to than in surrounding areas. Heavy metal concentrations are a decrease in the frequency of an allele that is favored by generally toxic to plants, but alleles at certain genes confer loss of a favored allel eme cases, drift may even lead to the resistance. The ability to tolerate heavy metals comes at a selection. In some ext from a population. Remember, how price, however; individuals with the resistance allele exhibit ever, that the magnitude of drift is negatively related to lower growth rates on non-polluted soil. Consequently, we population size; consequently, natural selection is expected would expect the resistance allele to occur with a frequenc to overwhelm drift except when populations are very small. of 100% on mine sites and 0% elsewhere Heavy metal tol- erance has been studied particularly intensively in the slen Gene Flow versus Natural selection der bent grass, Agrostis tenuis, in which researchers have found that the resistance allele occurs at intermediate levels Gene flow can be either a constructive or a constraining in many areas(figure 20. 10). The explanation relates to the force. On one hand, gene flow can increase the adaptedness reproductive system of this grass in which pollen, the male of a species by spreading a beneficial mutation that arises in gamete(that is, the floral equivalent of sperm), is dispersed one population to other populations within a species On by the wind. As a result, pollen-and the alleles it carries- the other hand, gene flow can act to impede adaptation can be blown for great distances, leading to levels of gene within a population by continua ally importing inferior all flow between mine sites and unpolluted areas high enough les from other populations. Consider two populations of to counteract the effects of natural selection species that live in different environments. In this situation general, the extent to which gene flow can hinder the natural selection might favor different alleles-B and b-in effects of natural selection should depend on the relative the different populations. In the absence of gene flow and strengths of the two processes In species in which gene other evolutionary processes, the frequency of B would be flow is generally strong, such as birds and wind-pollinated expected to reach 100% in one population and 0% in the plants, the frequency of the less favored allele may be rela two populations, then the less favor oing on between the tively high, whereas in more sedentary species which ex- other. However, if gene flow were go nu- hibit low levels of gene flow, such as salamanders, the fa ally be reintroduced into each population. As a result, the vored allele should occur at a frequency near 100% frequency of the two alleles in each population would re- flect a balance between the rate at which gene flow brings the inferior allele into a population versus the rate at which Evolutionary processes may act to either natural selection removes it maintain genetic variation within a population. Allele A classic example of gene flow opposing natural selec- equency sometimes may reflect a balance between tion occurs on abandoned mine sites in great britain, Al opposed processes, such as gene flow and natural though mining activities ceased hundreds of years ago, the selection. In such cases, observed frequencies w concentration of metal ions in the soil is still much greater depend on the relative strength of the processe Chapter 20 Go ene hin Populations 431
Interactions among Evolutionary Forces When alleles are not selectively neutral, levels of variation retained in a population may be determined by the relative strength of different evolutionary processes. In theory, for example, if allele B mutates to allele b at a high enough rate, allele b could be maintained in the population even if natural selection strongly favored allele B. In nature, however, mutation rates are rarely high enough to counter the effects of natural selection. The effect of natural selection also may be countered by genetic drift. Both processes may act to remove variation from a population. However, whereas selection is a deterministic process that operates to increase the representation of alleles that enhance survival and reproductive success, drift is a random process. Thus, in some cases, drift may lead to a decrease in the frequency of an allele that is favored by selection. In some extreme cases, drift may even lead to the loss of a favored allele from a population. Remember, however, that the magnitude of drift is negatively related to population size; consequently, natural selection is expected to overwhelm drift except when populations are very small. Gene Flow versus Natural Selection Gene flow can be either a constructive or a constraining force. On one hand, gene flow can increase the adaptedness of a species by spreading a beneficial mutation that arises in one population to other populations within a species. On the other hand, gene flow can act to impede adaptation within a population by continually importing inferior alleles from other populations. Consider two populations of a species that live in different environments. In this situation, natural selection might favor different alleles—B and b—in the different populations. In the absence of gene flow and other evolutionary processes, the frequency of B would be expected to reach 100% in one population and 0% in the other. However, if gene flow were going on between the two populations, then the less favored allele would continually be reintroduced into each population. As a result, the frequency of the two alleles in each population would reflect a balance between the rate at which gene flow brings the inferior allele into a population versus the rate at which natural selection removes it. A classic example of gene flow opposing natural selection occurs on abandoned mine sites in Great Britain. Although mining activities ceased hundreds of years ago, the concentration of metal ions in the soil is still much greater than in surrounding areas. Heavy metal concentrations are generally toxic to plants, but alleles at certain genes confer resistance. The ability to tolerate heavy metals comes at a price, however; individuals with the resistance allele exhibit lower growth rates on non-polluted soil. Consequently, we would expect the resistance allele to occur with a frequency of 100% on mine sites and 0% elsewhere. Heavy metal tolerance has been studied particularly intensively in the slender bent grass, Agrostis tenuis, in which researchers have found that the resistance allele occurs at intermediate levels in many areas (figure 20.10). The explanation relates to the reproductive system of this grass in which pollen, the male gamete (that is, the floral equivalent of sperm), is dispersed by the wind. As a result, pollen—and the alleles it carries— can be blown for great distances, leading to levels of gene flow between mine sites and unpolluted areas high enough to counteract the effects of natural selection. In general, the extent to which gene flow can hinder the effects of natural selection should depend on the relative strengths of the two processes. In species in which gene flow is generally strong, such as birds and wind-pollinated plants, the frequency of the less favored allele may be relatively high, whereas in more sedentary species which exhibit low levels of gene flow, such as salamanders, the favored allele should occur at a frequency near 100%. Evolutionary processes may act to either remove or maintain genetic variation within a population. Allele frequency sometimes may reflect a balance between opposed processes, such as gene flow and natural selection. In such cases, observed frequencies will depend on the relative strength of the processes. Chapter 20 Genes within Populations 431 Index of copper tolerance Distance in meters Nonmine Mine Non-mine 0 20 40 0 20 40 60 80 100 120 140 160 0 20 40 60 Prevailing wind Bent grass (Agrostis tenuis) FIGURE 20.10 Degree of copper tolerance in grass plants on and near ancient mine sites. Prevailing winds blow pollen containing nontolerant alleles onto the mine site and tolerant alleles beyond the site’s borders
Heterozygote Advantage Sickle cell anemia is often fatal. Until therapies developed to more effectively treat its symptoms, almost In the previous pages, natural selection has been discussed all affected individuals died as children. Even today, 31% as a process that removes variation from a population by fa- of patients in the United States die by the age of 15. The voring one allele over others at a genetic locus. However, if disease occurs because of a single amino acid change, re- heterozygotes are favored over homozygotes, then natural peated in the two beta chains of the hemoglobin molecule selection actually will tend to maintain variation in the In this change, a valine replaces the usual glutamic acid at population. The reason is simple. Instead of tending to re- a location on the surface of the protein near the oxygen- nove less successful alleles from a population, such het- binding site. Unlike glutamic acid, valine is nonpolar(hy- erozygote advantage will favor individuals with copies of drophobic). Its presence on the surface of the molecule th alleles, and thus will work to maintain both alleles in creates a"sticky"patch that attempts to escape from the the population. Some evolutionary biologists believe that polar water environment by binding to another similar heterozygote advantage is pervasive and can explain the patch. As long as oxygen is bound to the hemoglobin mol- high levels of polymorphism observed in natural popula ecule there is no problem, because the hemoglobin atoms tions. Others, however, believe that it is relatively rare shield the critical area of the surface. When oxygen levels fall, such as after exercise or when an individual is stressed Sickle cell anemia oxygen is not so readily bound to hemoglobin and the ex- The best documented example of heterozygote advantage globin molecules, eventually producin on other hemo- posed sticky patch binds to similar patch g long, fibrous is sickle cell anemia, a hereditary disease affecting hemo- clumps(figure 20. 11). The result is a deformed, " sickle globin in humans. Individuals with sickle cell anemia ex- shaped"red blood cell hibit symptoms of severe anemia and contain abnormal Individuals who are heterozygous or homozygous for red blood cells which are irregular in shape, with a great the valine-specifying allele(designated allele S) are said to number of long and sickle-shaped cells. The disease is possess the sickle cell trait. Heterozygotes produce some particularly common among African Americans. In chap- sickle-shaped red blood cells, but only 2% of the number ter 13, we noted that this disorder, which affects roughly seen in homozygous individuals. The reason is that in het 3 African Americans out of every 1000, is associated with erozygotes, one-half of the molecules do not contain va recessive allele. Using the Hardy-V finberg line at the critical location. Consequently, when a mole equation, you can calculate the frequency of the sickle cell cule produced by the non-sickle cell allele is added to the allele in the African-American population; this frequenc chain, there is no further "sticky"patch available to add is the square root of 0.003, or approximately 0.054. In additional molecules and chain elongation stops. Hence, contrast, the frequency of the allele among white Ameri- most chains in heterozygotes are too short to produce cans is only about 0.001 sickling of the cell. FIGURE 20.11 Why the sickle cell mutation causes hemoglobin to clump. The sickle cell mutation changes the sixth amino acid in the hemoglobin B chain(position B6) from glutamic acid (very polar) to valine (nonpolar). The unhappy result is that the nonpolar valine at position B6, protruding from a corner of the hemoglobin molecule fits into a nonpolar pocket on the opposite side of another hemoglobin molecule, causing the two molecules to clump together. As each molecule has both a B6 valine and an opposite nonpolar pocket, long hains form. When polar glutamic acid (the normal allele)occurs at position B6, it is not attracted to the nonpolar C Irving ge 432 Part vI Evolution
Heterozygote Advantage In the previous pages, natural selection has been discussed as a process that removes variation from a population by favoring one allele over others at a genetic locus. However, if heterozygotes are favored over homozygotes, then natural selection actually will tend to maintain variation in the population. The reason is simple. Instead of tending to remove less successful alleles from a population, such heterozygote advantage will favor individuals with copies of both alleles, and thus will work to maintain both alleles in the population. Some evolutionary biologists believe that heterozygote advantage is pervasive and can explain the high levels of polymorphism observed in natural populations. Others, however, believe that it is relatively rare. Sickle Cell Anemia The best documented example of heterozygote advantage is sickle cell anemia, a hereditary disease affecting hemoglobin in humans. Individuals with sickle cell anemia exhibit symptoms of severe anemia and contain abnormal red blood cells which are irregular in shape, with a great number of long and sickle-shaped cells. The disease is particularly common among African Americans. In chapter 13, we noted that this disorder, which affects roughly 3 African Americans out of every 1000, is associated with a particular recessive allele. Using the Hardy–Weinberg equation, you can calculate the frequency of the sickle cell allele in the African-American population; this frequency is the square root of 0.003, or approximately 0.054. In contrast, the frequency of the allele among white Americans is only about 0.001. Sickle cell anemia is often fatal. Until therapies were developed to more effectively treat its symptoms, almost all affected individuals died as children. Even today, 31% of patients in the United States die by the age of 15. The disease occurs because of a single amino acid change, repeated in the two beta chains of the hemoglobin molecule. In this change, a valine replaces the usual glutamic acid at a location on the surface of the protein near the oxygenbinding site. Unlike glutamic acid, valine is nonpolar (hydrophobic). Its presence on the surface of the molecule creates a “sticky” patch that attempts to escape from the polar water environment by binding to another similar patch. As long as oxygen is bound to the hemoglobin molecule there is no problem, because the hemoglobin atoms shield the critical area of the surface. When oxygen levels fall, such as after exercise or when an individual is stressed, oxygen is not so readily bound to hemoglobin and the exposed sticky patch binds to similar patches on other hemoglobin molecules, eventually producing long, fibrous clumps (figure 20.11). The result is a deformed, “sickleshaped” red blood cell. Individuals who are heterozygous or homozygous for the valine-specifying allele (designated allele S) are said to possess the sickle cell trait. Heterozygotes produce some sickle-shaped red blood cells, but only 2% of the number seen in homozygous individuals. The reason is that in heterozygotes, one-half of the molecules do not contain valine at the critical location. Consequently, when a molecule produced by the non-sickle cell allele is added to the chain, there is no further “sticky” patch available to add additional molecules and chain elongation stops. Hence, most chains in heterozygotes are too short to produce sickling of the cell. 432 Part VI Evolution Val 6 FIGURE 20.11 Why the sickle cell mutation causes hemoglobin to clump. The sickle cell mutation changes the sixth amino acid in the hemoglobin β chain (position B6) from glutamic acid (very polar) to valine (nonpolar). The unhappy result is that the nonpolar valine at position B6, protruding from a corner of the hemoglobin molecule, fits into a nonpolar pocket on the opposite side of another hemoglobin molecule, causing the two molecules to clump together. As each molecule has both a B6 valine and an opposite nonpolar pocket, long chains form. When polar glutamic acid (the normal allele) occurs at position B6, it is not attracted to the nonpolar pocket, and no clumping occurs. Copyright © Irving Geis
Normal red blood cells Sickled red blood cells le in africa malania in arnica 5-10% 口10-20% FIGURE 20.1 Frequency of sickle cell allele and distribution of Plasmodium falciparum malaria.(a)The red blood cells of people homozygous for the sickle cell allele collapse into sickled shapes when the oxygen level in the blood is low. (b)The distribution of the sickle cell allele in Africa coincides closely with that of P falciparum malaria Malaria and Heterozygote Advantage Consequently, even though most homozygous recessive The average incidence of the S allele in the Central African individuals die before they have children, the sickle cell al population is about 0.12, far higher than that found among lected for) because of its association with resistance to African Americans From the Hardy-Weinberg principle, malaria in heterozygotes and also, for reasons not yet fully heterozygous at the S allele, and 1 in 100 develops the fatal understood, with increased fertility in female heterozygotes form of the disorder. People who are homozygous for the having the sickle cell allele in the heterozygous condition ally die before they reach reproductive age. Why is the s has adaptive value (figure 20. 12). Among African Amer allele not eliminated from the Central African population by selection, rather than being maintained at such high ley- some 15 generations in a country where malaria has been els?People who are heterozygous for the sickle cell allele relatively rare and is now essentially absent, the environ causes of illness and death in Central Africa, especially Consequently, no adaptive value counterbalances the ill: among young children--in the areas where the allele is tion is acting to eliminate the s allele. Only 1 in 375 common. The reason is that when the parasite that causes malaria, Plasmodium falciparum, enters a red blood cell,it African Americans develop sickle cell anemia, far less than leads to cell sickling even in heterozygotes. Such cells.g causes extremely low oxygen tension in the cell, wl in Central africa quickly filtered out of the bloodstream by the spleen, thus eliminating the parasite(the spleens filtering effect is what anemia in homozygotes, is maintained by heter ell he hemoglobin allele S, responsible for sic leads to anemia in homozygotes as large numbers of red dvantage in Central Africa, where heterozygotes for blood cells are removed). he s allele are resistant to malaria Chapter 20 Genes within Popul
Malaria and Heterozygote Advantage The average incidence of the S allele in the Central African population is about 0.12, far higher than that found among African Americans. From the Hardy–Weinberg principle, you can calculate that 1 in 5 Central African individuals are heterozygous at the S allele, and 1 in 100 develops the fatal form of the disorder. People who are homozygous for the sickle cell allele almost never reproduce because they usually die before they reach reproductive age. Why is the S allele not eliminated from the Central African population by selection, rather than being maintained at such high levels? People who are heterozygous for the sickle cell allele are much less susceptible to malaria—one of the leading causes of illness and death in Central Africa, especially among young children—in the areas where the allele is common. The reason is that when the parasite that causes malaria, Plasmodium falciparum, enters a red blood cell, it causes extremely low oxygen tension in the cell, which leads to cell sickling even in heterozygotes. Such cells are quickly filtered out of the bloodstream by the spleen, thus eliminating the parasite (the spleen’s filtering effect is what leads to anemia in homozygotes as large numbers of red blood cells are removed). Consequently, even though most homozygous recessive individuals die before they have children, the sickle cell allele is maintained at high levels in these populations (it is selected for) because of its association with resistance to malaria in heterozygotes and also, for reasons not yet fully understood, with increased fertility in female heterozygotes. For people living in areas where malaria is common, having the sickle cell allele in the heterozygous condition has adaptive value (figure 20.12). Among African Americans, however, many of whose ancestors have lived for some 15 generations in a country where malaria has been relatively rare and is now essentially absent, the environment does not place a premium on resistance to malaria. Consequently, no adaptive value counterbalances the ill effects of the disease; in this nonmalarial environment, selection is acting to eliminate the S allele. Only 1 in 375 African Americans develop sickle cell anemia, far less than in Central Africa. The hemoglobin allele S, responsible for sickle cell anemia in homozygotes, is maintained by heterozygote advantage in Central Africa, where heterozygotes for the S allele are resistant to malaria. Chapter 20 Genes within Populations 433 Sickle cell allele in Africa 1-5% 5-10% 10-20% P.falciparum malaria in Africa Malaria (b) (a) Normal red blood cells Sickled red blood cells FIGURE 20.12 Frequency of sickle cell allele and distribution of Plasmodium falciparum malaria. (a)The red blood cells of people homozygous for the sickle cell allele collapse into sickled shapes when the oxygen level in the blood is low. (b) The distribution of the sickle cell allele in Africa coincides closely with that of P. falciparum malaria