GENETICS AND EVOLUTION

infectious disease gave those individuals with a very rare mutation— the sickle- cell allele— an adaptive advantage and the ability to survive and reproduce in these new environmental circumstances. Due to the advantage the heterozygous condition provides, the S allele was maintained and passed from generation to generation. For this reason, sickle- cell anemia predominantly affects those whose descendants came from the malarial environments in large parts of equatorial Africa. Outside of such malarial environments, the S allele never became advantageous.

OTHER HEMOGLOBIN AND ENZYME ABNORMALITIES Sickle- cell anemia turns out to be just one of a number of hemoglobinopathies and other genetic abnormalities in Africa, Asia, and Europe that provide a strong selective advantage in regions of endemic malaria (Figure 4.19). Heterozygous carriers of abnormal hemoglobins apparently make poor hosts for malarial parasites.

Thalassemia, a genetic anemia found in Europe (especially in Italy and Greece), Asia, and the Pacific, reduces or eliminates hemoglobin synthesis. In some homozygous forms of the mutation, hemoglobin becomes clumped inside the red blood cells. The spleen then destroys the red blood cells, resulting in severe anemia. In the areas around the Mediterranean where the genetic frequency is highest— as high as 80%—the presence of malaria makes a strong case for a selective advantage for heterozygous individuals, for whom the condition and malaria are not lethal.

An association has long been recognized between deficiency of the enzyme glucose- 6-phosphate dehydrogenase (G6PD) and malaria. A recessive hered- itary mutation leads more males than females to lack the gene that is coded to produce this enzyme (see Figure 4.11). Without the G6PD enzyme, a person who takes sulfa- based antibiotics or eats fava beans risks the destruction of red blood cells, severe anemia, and occasionally death. Because of the connection with fava beans, this severe hemolytic disease is called favism. Its 130 genetic variants occur in high frequencies in some populations, the highest being 70% among Kurdish Jews. Heterozygous carriers have a strong selective advantage because they pro- duce some of the enzyme but are protected from malaria (here again, the parasite cannot live in the abnormal red blood cells).

Analysis of genetic data by the anthropologist Sara Tishkoff indicates that the mutation for the disease arose between about 4,000 and 12,000 yBP, at the same time as the abnormal hemoglobins. Populations whose descendants did not encounter malaria do not have the G6pd mutation or abnormal hemoglobins.

Once inside the human, the sporozoites travel through the bloodstream to the liver. In the liver, the sporozoites create thousands of merozoites. A merozoite is a daughter cell that results from asexual reproduction.

The newly produced merozoites enter the bloodstream and infect the red blood cells. Within these cells, the merozoites continue to multiply, eventually causing the cells to rupture. The merozoites then invade other red blood cells in the bloodstream, and the cycle continues.

a Sporozoite: The goal of sporozoite vaccines is to block parasites from entering or growing within human liver cells.

b Merozoite: Vaccines based on merozoite antigens lessen malaria’s severity by hobbling the invasion of new generations of red blood cells or by reducing complications.

c Gametocyte: So-called altruistic gametocyte- based vaccines do not affect human disease but are designed to evoke human antibodies that derail parasite development within the mosquito.

Over time, some of the merozoites develop into male and female gametocytes, which may be transferred to another mosquito that bites the human host. Gametocytes are cells that can divide to produce gametes, or sex cells.

Within the mosquito, sexual reproduction occurs, as the male gamete fertilizes the female gamete. Oocysts, or zygotes, develop and even- tually release sporozoites. These newly formed sporozoites travel to the salivary glands of the mosquito, where they can be transmitted to the next human the mosquito bites.

Merozoites

Host’s liver

Host’s red blood cell

INSIDE HUMAN

VACCINE TARGETS

INSIDE MOSQUITO

Female gametocyte

Female gamete

Male gamete

Oocyst

Male gametocyte

Fertilizationc

Sporozoites

A mosquito bites a human, passing sporozoites to the new host. A sporozoite is a motile form of the parasite.

5 2

FIGURE 4.16 The Spread of Malaria The life cycle of the malarial parasite, Plasmodium falciparum, takes place in two hosts: mosquito and human. Both hosts are needed if the parasite is to survive.

Natural Selection: Advantageous Characteristics, Survival, and Reproduction | 89

a Sporozoite: The goal of sporozoite vaccines is to block parasites from entering or growing within human liver cells.

b Merozoite: Vaccines based on merozoite antigens lessen malaria’s severity by hobbling the invasion of new generations of red blood cells or by reducing complications.

c Gametocyte: So-called altruistic gametocyte- based vaccines do not affect human disease but are designed to evoke human antibodies that derail parasite development within the mosquito.

Merozoites

Host’s liver

Host’s red blood cell

INSIDE HUMAN

VACCINE TARGETS

INSIDE MOSQUITO

Female gametocyte

Female gamete

Male gamete

Oocyst

Male gametocyte

Fertilizationc

Sporozoites

A mosquito bites a human, passing sporozoites to the new host. A sporozoite is a motile form of the parasite.

5 2

FIGURE 4.16 The Spread of Malaria The life cycle of the malarial parasite, Plasmodium falciparum, takes place in two hosts: mosquito and human. Both hosts are needed if the parasite is to survive.

FIGURE 4.17 Bantu Expansion Beginning by about 1000 BC, Bantu people began a series of migrations, originating in central Africa and pushing southward eventually into southern Africa. In addition to agriculture, they carried the mutation for the sickle- cell allele.

Bantu Khoisan

hemoglobinopathies A group of related genetic blood diseases characterized by abnormal hemoglobin.

thalassemia A genetic blood disease in which the hemoglobin is improperly synthesized, causing the red blood cells to have a much shorter life span.

glucose- 6-phosphate dehydrogenase (G6PD) An enzyme that aids in the proper functioning of red blood cells; its deficiency, a genetic condition, leads to hemolytic anemia.

(a) (b)

FIGURE 4.18 The Spread of Malaria As the Bantu cleared forests for agricultural fields, (a) pools of stagnant water (b) became an ideal breeding ground for mosquito larvae, which carried the malarial parasites.

90 | CHAPTER 4 Genes and Their Evolution: Population Genetics

Today, for example, malaria appears throughout the tropical regions of the Amer- icas, but Native Americans are 100% homozygous for normal alleles at the G6pd and hemoglobin loci. That these particular genes do not appear to have mutated in the New World strongly suggests that malaria was introduced to North and South America only after the Europeans’ arrival. Indeed, the introduction of malaria and other Old World diseases— by either Spaniards or their African slaves— likely played an instrumental role in the precipitous decline in the native populations.

If malaria had been introduced in the Americas much earlier than the last few centuries— say thousands of years ago— and the mutations occurred, there might have been time for a natural selection to develop for the mutations. If the mutations did appear before the Europeans’ arrival, however, they would have exhibited a clear selective disadvantage in the absence of malaria and been weeded out of the gene pool. Thus, red blood cell polymorphisms in the abnormal hemoglobin and G6pd loci reflect the fundamental interactions among environment, genes, and culture that have resulted in the modern human genome. The genes provide an important record about human evolution and the role of natural selection in shaping genetic variation.

Genetic Drift: Genetic Change due to Chance One of the four forces of evolution (see “The Evolutionary Synthesis, the Study of Populations, and the Causes of Evolution” in chapter 2), genetic drift, is random change in allele frequency over time. Provided that no allele confers a selective advantage over another, a random change can lead to a change in gene frequency, such as one allele being lost and the other becoming fixated— or fixed, the only allele of its kind, in the population. This force, this kind of change, makes possible the measuring of evolution as a statistical probability.

Hb C Hb E Hb S

FIGURE 4.19 Distribution of Hemoglobinopathies This map shows the distribution of hemoglobin E in Southeast Asia. People with hemoglobin E, an uncommon but severe blood abnormality, may have mild hemolytic anemia or other mild effects. Like hemoglobin S, hemoglobin C appears primarily in equatorial Africa. Like hemoglobin E, hemoglobin C has generally minor effects, most often mild hemolytic anemia.

Genetic Drift: Genetic Change due to Chance | 91

Coin tosses can demonstrate the effects of genetic drift (Table 4.4). Imagine that heads and tails are two alleles in a population. If there are only two members of the population (two coin tosses), there is a great chance that both will be heads. In effect, the “heads” allele will become fixed in the small population, while the “tails” allele will be lost. As the population size (number of coin tosses) increases, it becomes less likely that one allele will become fixed and the other lost. In very large populations (1 million coin tosses), both alleles may be present in equal proportions.

How does such statistical probability translate to populations? Now imagine that before the election of your student government you have been asked to predict the winners. The best way for you to predict would be to ask each voting- eligible student how he or she planned to vote. It is highly likely that the outcome of such a comprehensive poll would be close to the actual election results. The shortcom- ings of this approach might include the very large size of the target population. No one would interview, for example, 50,000 students! The second- best approach would be to select a sample, preferably a random sample that represented the entire student body. If you selected five students out of the 50,000, chances are very slim that those five would represent all the ethnic, national, regional, and economic backgrounds of the student body. In fact, chances are very high that this sample (.01% of the total population) would provide a voting outcome very different from the actual one. If you interviewed 500 students (1% of the population), the chances of representation would be much greater; and if you chose 5,000 students (10% of the population), they would be greater still. The larger the sample size, the greater the probability of an accurate prediction.

Variations in human populations work the exact same way, except that genetic drift operates over a period of time rather than at a single point. The probability of an allele’s frequency changing in a relatively short period of time increases with

TABLE 4.4 Heads versus Tails: Genetic Drift and Probability

Coin Tosses Heads Tails Heads: Tails Rat io

2 2 0 2:0

10 4 6 4:6

50 22 28 11:14

100 55 45 11:9

200 199 201 199:201

500 253 247 253:247

1,000 501 499 501:499

5,000 2,500 2,500 1:1

10,000 5,000 5,000 1:1

100,000 50,000 50,000 1:1

500,000 250,000 250,000 1:1

1,000,000 500,000 500,000 1:1

92 | CHAPTER 4 Genes and Their Evolution: Population Genetics

decreasing population size. The larger the population, the less divergence from the original gene frequency over time (Figure 4.20).

How does this effect play out in real life? Among humans, for example, genetic drift might occur in a small group that is endogamous, discouraging reproduc- tion outside the group. (An exogamous society extends reproduction outside its community.) Within such a group, the chances are great that the frequencies of genetic markers will differ from those of a larger population. When the Dunkers, a small religious sect that discourages outside marriage (and thus reproduction), first emigrated from Germany to Pennsylvania, in 1719, the group included just 28 members. Over the next few decades, several hundred more arrived in Pennsylvania; the breeding population remained quite small. Comparisons of contemporary blood type percentages among Dunkers, Germans, and Americans reflect significant changes in the Dunkers and a likely lack of change in the larger populations (Figure 4.21). That is, blood type frequencies among Germans and Americans remain basically the same as they were in the 1700s. The Dunkers’ original frequencies were probably much like those of the Germans, but the small

endogamous Refers to a population in which individuals breed only with other members of the population.

exogamous Refers to a population in which individuals breed only with non- members of their population.

founder effect The accumulation of random genetic changes in a small population that has become isolated from the parent population due to the genetic input of only a few colonizers.

G en

e fre

qu en

cy (%

)

Number of generations

100

200 10 30 40 50 0

FIGURE 4.20 Genetic Drift over Time The effects of genetic drift appear in this graph, which plots the frequencies over time (by generations) of one gene in three differently sized populations. Assume that population A is the smallest of the three and that population C is the largest. At the start, each population has the gene at 50% frequency. Around 38 generations, population A has drifted significantly; the gene is fixed at 100% frequency, a 50% increase. At 50 generations, population B has also drifted. Its gene frequency has declined by 40%. Although the frequency in population C has changed over time, it is still approximately 50% after 50 generations, owing to the largeness of the population.

(a) ABO Blood Type Frequencies (b) MN Blood Type Frequencies

Pe rc

en ta

Populations

AmericansGermansDunkers

Pe rc

en ta

Populations

AmericansGermansDunkers

A B AB O MM MN NN 70

FIGURE 4.21 Genetic Drift in the Dunker Population Comparisons of ABO and MN blood type frequencies among Dunkers, Germans, and Americans reveal genetic drift: (a) Dunkers have a higher percentage of blood type A and lower percentages of blood types O, B, and AB than do Germans and Americans; (b) Dunkers have a higher percentage of blood type M and lower percentages of MN and N.

Gene Flow: Spread of Genes across Population Boundaries | 93

Dunker population meant a much greater chance for genetic drift. The frequencies diverged dramatically over time simply due to chance.

FOUNDER EFFECT: A SPECIAL KIND OF GENETIC DRIFT Founder effect, one form of genetic drift, occurs when a small group (fewer than several hundred members) of a large parent population migrates to a new region and is reproductively isolated. The new region is either unoccupied or occupied by species with which the small group cannot breed. Because the founding population is so small, there is a very good chance that its genetic composition is not representative of the parent population’s. Thanks to the founder effect, as the founding population grows its gene pool diverges even further from the source (Figure 4.22). For example, around 12,000 yBP a very small number of individuals— perhaps just a few hundred— migrated from eastern Asia to North America (this movement is among the topics of chapter 12). Today, Native Amer- icans have very high frequencies of type O blood— in many places the frequency is 100%—while eastern Asian populations have among the world’s lowest frequencies of it. This discrepancy strongly suggests that the original east Asian immigrants, the founding “Native Americans,” had a higher frequency of type O blood than their parent population had.

Founder effect has also been documented in several genetic diseases that affect humans. Among the best known is a type of microsatellite called Hun- tington’s chorea, a genetic abnormality caused by an autosomal dominant gene (Figure 4.23). The gene is located on chromosome 4 at the locus that codes for the Huntington protein, and a person needs only one allele from a parent to have the disease. At the end of the normal gene is a sequence of three DNA bases, CAG (the code for valine). If the sequence is repeated numerous times, usually more than 35 times, the individual has the mutation. Huntington’s chorea causes degenera- tion of parts of the brain that control body movement and abilities such as speech production, triggering involuntary jerky movements of the arms and legs as well as dementia. These multiple and debilitating symptoms normally do not manifest until late in life or after the reproductive years, usually after about age 40. For- tunately, the disease is quite rare, affecting only five to eight people per 100,000.

Why had such a debilitating disease not been removed from the gene pool via natural selection? Since the effects of the gene are not expressed until later in life, people might not have known they had the disease until after they had passed on the detrimental allele to their offspring (Figure 4.24).

Today, most human populations are not small and isolated, and they interbreed relatively freely with surrounding groups. Whenever interbreeding occurs across population boundaries, gene flow occurs.

Gene Flow: Spread of Genes across Population Boundaries Another force of evolution, gene flow (or admixture; see “The Evolutionary Synthesis, the Study of Populations, and the Causes of Evolution” in chapter 2) is the transfer of genes across population boundaries. Simply, members of two

FIGURE 4.22 Founder Effect The large circle on the left represents a parent population, from which a very small proportion is removed to begin a new population. Over time, the founding population grows, and its gene pool looks less and less like that of the parent population.

FIGURE 4.23 Huntington’s Chorea The woman in the wheelchair suffers from Huntington’s chorea, a degenerative genetic disorder.

Huntington’s chorea A rare genetic disease in which the central nervous system degenerates and the individual loses control over voluntary movements, with the symptoms often appearing between ages 30 and 50.

admixture The exchange of genetic mate- rial between two or more populations.

94 | CHAPTER 4 Genes and Their Evolution: Population Genetics

populations produce offspring (Figure 4.25). The key determinant for the amount of gene flow is accessibility to mates— the less the physical distance between pop- ulations, the greater the chance of gene flow. While mutation increases genetic variation between two populations over time, gene flow decreases such variation. Anthropologists and geneticists have found that for many kinds of biological traits, ranging from cranial shapes to blood types to microsatellite DNA markers (see “Polymorphisms: Variations in Specific Genes” in chapter 3), similarity increases the closer one population is to another population.

Migration does not necessarily bring about gene flow. For example, when east Asians first migrated to North America (see “Founder Effect: A Special Kind of Genetic Drift,” above), they reached a continental landmass where no humans had ever lived. Written records suggest that Vikings first traveled from Greenland to Newfoundland around AD 1000, but there is no evidence that they interbred with the native people. The first significant gene flow involving Native Americans and Europeans seems to have occurred when or soon after Christopher Columbus and his crew arrived in the New World, in 1492. From that point on, gene flow in the Americas, North and South, has been extensive.

Gene flow and genetic variation are also highly influenced by social structure (Figure 4.26). Endogamous societies— for example, Australian aborigines— have relatively little genetic diversity because few individuals migrate into the commu- nity and thus little new genetic material is introduced. Exogamous societies have relatively high genetic diversity because proportionately more genetic material is brought into the gene pool.

Gene flow has always affected human evolution, but its effects have increased greatly over time. Originally, human populations tended to be small and isolated (among the topics of chapter 13). Only during the last 10,000 years, with the development of agriculture and with major population increases, have humans had widespread interaction.

FIGURE 4.25 Gene Flow New genetic material can be introduced into a population through gene flow from another population. Say, for example, that a population in one place has genes for only brown hair. Members of that population interbreed with an adjacent population, which has genes for only blond hair. After interbreeding for a generation, both populations have genes for blond and brown hair. As a result, when people from either population interbreed with yet another population, they may contribute alleles for brown, blond, or both.

Generation 1 Generation 2

D ive

rs ity

1.00

.95

.90

.85

.80

.75 Matrilocal mtDNA

Patrilocal mtDNA

Matrilocal Y chromosome

Patrilocal Y chromosome

mtDNA and Y chromosome variation

FIGURE 4.26 Social Structure in mtDNA and Y Chromosome Diversity In patrilocal societies, generally speaking, males stay in the birthplace, females migrate out, and female mates come from elsewhere. In matrilocal societies, females stay in the birthplace, males migrate out, and male mates come from elsewhere. To test the hypothesis that the out- migration of females and the out- migration of males produce different patterns of genetic diversity, the geneticist Hiroki Oota and colleagues studied six groups in Thailand, three of them patrilocal and three matrilocal. They found predictable patterns in the diversity of mtDNA and of Y chromosomes. Since mtDNA is passed from mother to daughter and son, the patrilocal groups showed high mtDNA variation (brought about by females moving into new villages) and the matrilocal groups showed low mtDNA variation (brought about by females remaining in place). Since the Y chromosome is passed from father to son, the patrilocal societies showed low Y chromosome variation (from males not migrating) and the matrilocal societies showed high Y chromosome variation (from males moving to new villages and introducing new Y chromosomes).

FIGURE 4.24 Nancy Wexler Wexler, whose mother died of Huntington’s chorea, here stands in front of a chart showing genetic histories she tracked in studying the disease.

Gene Flow: Spread of Genes across Population Boundaries | 95

Generation 1 Generation 2

D ive

rs ity

1.00

.95

.90

.85

.80

.75 Matrilocal mtDNA

Patrilocal mtDNA

Matrilocal Y chromosome

Patrilocal Y chromosome

mtDNA and Y chromosome variation

96 | CHAPTER 4 Genes and Their Evolution: Population Genetics

Specific genetic markers in living populations, such as the ABO blood group system, provide evidence of gene flow across large regions. For example, the fre- quencies of type B blood change gradually from eastern Asia to far western Europe (Figure 4.27). This clinal— that is, sloping— trend was first noted, in the early 1940s, by the American geneticist Pompeo Candela, who made the case that the gradient from east to west reflects significant gene flow that occurred as Mongol populations migrated westward from AD 500 to 1500. That is, if Mongols had higher frequencies of the B allele, they might have passed on that allele as they interbred with local populations.

Subsequent data on blood groups, however, have revealed sharp distinctions in frequencies between adjacent populations. These distinctions suggest that, in addition to gene flow, genetic drift within small, isolated groups contributed to the frequency variations.

This chapter and the previous one have discussed inheritance, the genetic code, and genetic change in terms of evolution. Prior to the emergence of evolutionary approaches to the study of human variation, many scientists believed that human variation could be understood through discrete categories called races. The next chapter will address the study of biological diversity, the uses and misuses of biolog- ical classification, and the ways that variation in living people reflects adaptations to diverse and sometimes extreme environments across the earth.

<6% 6–9%

9–12% 12–15%

>15%

FIGURE 4.27 B Blood Type Distribution The frequency of blood type B ranges from 30% in eastern Asia to almost 0% in far western Europe. The main factor contributing to this change was probably gene flow between populations in an east- to- west direction (shown by arrow).

What Causes Evolution?

Evolution is caused by one or a combination of four forces: mutation, natural selection, genetic drift, and gene flow. Although all four forces are important, natural selection accounts for most evolution.

Cause Definition Examples

Mutation Heritable change in structure or amount of DNA

Sickle- cell anemia Huntington’s chorea Klinefelter’s syndrome Down syndrome

Natural selection

Favoring of individuals with characteristics that enhance survival and reproduction

Sickle- cell anemia Industrial melanism Thalassemia G6PD deficiency Lactase deficiency

Genetic drift Genetic change due to chance

Klinefelter’s syndrome Blood types Hemophilia Achromatopsia Porphyria

Gene flow Transfer of genes across population boundaries

Blood types

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