5 Case Studies of Natural Selection in Human

Ms. Gangaina Kameih

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Learning outcomes

 

After studying this module:

  • You would know the illustrative examples of several types of selection, particularly those that show evidence of rapid evolutionary change in recent human evolution.
  • You shall be able to understand the given different methods of analysis and different lessons regarding natural selection.

 

TABLE OF CONTENTS

 

1.  Introduction

2.  Hemoglobin S and Malaria

2.1 Balancing Selection

2.2 Culture Change and evolution of Hemoglobin S

3.  Duffy Blood Group and Malaria

4.  CCR5-Δ32 Gene mutation and Disease Resistance

5.  Lactase Persistence and Human Diet

6.  The evolution of skin color

7.  Genetic Adaptation to High Altitude Population

 

 

1. Introduction

 

The total genetic material of a given population is termed gene pool. Several factors can alter the equilibrium of gene frequencies in the gene pool. One of such factor is Natural selection. Selection is the non random differential retaining of favoured genotypes. Unlike mutation which operates directly on gene to alter its frequency, selection indirectly alters a gene frequency by acting on its carriers as a function of their ability to reproduce viable offspring. For example, if individuals carrying gene A are more successful in reproduction than individuals carrying gene B, the frequency of the former gene will tend to increase generation after generation at the expense of the latter. Any trait which gives an organism a better chance at survival in a given environment will increase that organisms’ ability to grow and reproduce, and it will increase the proportion of gene for that trait in the gene pool. By the same token, any gene which confers a disadvantage to its carrier within its environment will decrease that organism’s chance of survival to reproductive age and thus decrease the frequency of that gene in the gene pool. This is the principle underline natural selection.

 

Since modern humans evolved in Africa about 200kya and migrated across different regions of the world (Lachance & Tishkoff, 2013), the rapid change are not as a result of natural selection but are instead changes in environmental conditions i.e. a primarily shift in infectious disease and nutrition, an unfortunate truth is that many humans continue to live in impoverished environments without proper health care or diet, and do not share with the existence of different conditions enjoyed by those living in other parts of society or the world. Changes due to cultural adaptation appear to be more rapid than changes due to genetic adaptation. Natural selection shapes the human population over time. Here are some case study which gives an idea about how does it work and shows the evidence of evolutionary change in recent human evolution since the initial beginnings of agriculture.

 

2. Haemoglobin S and Malaria

 

The story of natural selection and haemoglobin molecule is a classic example in anthropology, providing an excellent example of balancing selection, rapid genetic change, and the effect of cultural and ecological influences on selection. Haemoglobin is a protein of the blood that transports oxygen to tissues throughout the body (different tissues). Normal haemoglobin consists of 4 protein chains i.e. 2 identical chains of alpha (α) and Beta (β). The alpha chains are 141 amino acids in length, and gene is on chromosome 16. The beta chains are 146 amino acids in length, and the gene is on chromosome 11 (Mielke et al. 2011). Here, we deal with the beta chain only.

 

The normal form of β haemoglobin gene is known as the A allele and people with AA genotype have haemoglobin functions normally in transferring oxygen. SS genotype results in manifestation of disease Sickle cell anaemia where a single mutation replaces the sixth amino acid of the beta chain Glutamic Acid with amino acid Valine. The disease can cause the red blood cells to become distorted and change the levels of oxygen and the donut shape turn to the shape of sickle (hence the name sickle cell). The deformed blood cells do not carry oxygen effectively, causing serious problems throughout the body’s tissues and organs, and typically leading to death before adulthood without substantial medical intervention.

 

With respect to natural selection, relative fitness is assigned to different genotypes (AA, AS and SS). The genotype AA is reported to have highest relative fitness, genotype AS slightly lower relative fitness whereas the genotype SS is expected to have the lowest fitness. A main focus is laid on A and S alleles, because S allele is harmful in the homozygous case and a selection against allele is done. Allele S is mutant and has the lowest frequency. Data from many human populations certainly fit this prediction. For example, the allele frequencies in a number of populations throughout the world are A=1 and S=0. In some other cases, S is not zero, but is very low, such as in Portugal (S=0.0005), Libya (S=0.0002), and the Bantu of South Africa (S=0.0006) (Roychoudhary and Nei 1988).

 

Such frequencies are consistent with a model of selection against an allele, and would simply be a good example of such selection if not for the fact that a number of human populations do not fit the general model of natural selection. Some populations in the world have higher frequencies of the S allele that range from 0.01 to over 0.20 (Roychoudhary and Nei 1988). These frequencies are much higher than expected under a model of selection against the S allele. How could the frequency of a harmful allele be higher than expected? There are two possible answers. One is genetic drift. By chance, the frequencies of harmful alleles can drift upward given certain levels of population size and fitness values. The other explanation is balancing selection. When there is selection for the heterozygote, we have a situation where having only one copy of an allele actually confers higher fitness than someone with two copies, or someone with only one copy (Relethford, 2012).

 

2.1 Balancing Selection: Balancing selection refers to a selective process by which multiple alleles get added and are maintained in the gene pool of a population. A moderate to higher frequency of S allele are found in the populations in parts of West Africa and South Africa, as well as parts of Middle East, and India. Populations that have a history of malarial epidemics tend to have a higher frequency of S allele and can be best explained by balancing selection. Malaria, an infectious disease is one of the harmful disease recorded in human history of which the parasite Plasmodium falciparum is the most fatal of all the four different of malarias. Presence of an S allele renders the red cell inhospitable to the malaria parasite, thus protecting the individual from its effects. Thus in a malarial environment, the heterozygous AS has the highest fitness followed by the AA genotype, and the SS genotype still has the lowest fitness.

 

The fitness difference among the SS and AA genotype can be seen by an example provided by Bodmer and Cavali-Sforza (1976) from the Yoruba of Nigeria inhabiting the malarial environment. The observed genotype numbers in adults were AA=9365, AS=2993 and SS=29) for a total of 12387 adults, where 21723 A alleles and 3,051 S alleles, for a total of 24774 alleles. Hardy Weinberg proportions can be easily computed and will give the genotypic and allelic frequencies.

 

Allele frequency   Allele a Allele S

 

21723/24774                       3051/24774

 

=0.877                                     =0.123

 

Genotypic frequencies

 

AA= p2(12,387)= (0.877)2(12387)

 

=9527.2

 

AS=2pq (0.877)(0.123)(12387)

 

=2672.4

 

SS=q2(12387)= (0.123) 2(12387)

 

=187.4

 

The absolute fitness for the various genotypes can be observed

 

AA=9365/9527= 0.983

 

AS= 2993/2672.4= 1.120

 

SS=29/187.4= 0.155

 

The absolute fitness can be further used to calculate relative fitness

 

AA= 0.983/1.120=0.878

 

AS=1.120/1.120=1

 

SS=0.155/1.120=0.138

 

The selection coefficients (obtained by subtracting the relative fitness from 1) for the homozygotes are s=1-wAA= 1-0.878=0.122

t=1-wSS=1-0.138= 0.862

 

We can now derive the expected equilibrium frequencies using the equations from models of natural selection

 

p= t/s+t =0.862/0.122+0.862 =0.876

 

q= s/s+t =0.122/0.122+0.862 =0.124

 

These values are almost identical with the observed allele frequencies, suggesting that this population has reached equilibrium under balancing selection.

 

2.2 Culture Change and evolution of Hemoglobin S: The case of Hemoglobin S provides a classic example of balancing selection. Likewise, it also provides a classic example of how culture affects genetic evolution in human populations. The frequency of haemoglobin S increasing in parts of Africa because of practising agriculture can be depicted in this scenario (Livingstone 1958; Bodmer and Cavalli-Sforza 1976). The mosquito species that spreads malaria do not thrive in dense forest such as western Africa before the introduction of agriculture. Because there would be no selective advantage for heterozygotes, and the frequency of S would be very low, as it is today in populations where there is no problem of malaria.

 

With the introduction of agriculture, forest were cleared for planting shifting cultivation and subsequent changes to soil chemistry reduced water absorption led to an increased in sunlit areas and pools of stagnant water, which are ideal conditions for spreading mosquitoes. As the malaria population grew in humans, the balance between mutation and selection changed. Now those with the heterozygote had the highest fitness because they had resistance to malaria at the same time did not suffer from sickle cell anemia. The frequency of s would have increased as the heterozygotes were selected. However, as the frequency of S (=q) increases, so does the frequency of those with the SS homozygote (=q2), who are then selected against, causing the increase in S to slow down and then stop to reach an equilibrium.

 

3. Duffy Blood Group and Malaria

 

A number of genetic traits show evidence of natural selection because of malaria, including other haemoglobin alleles, genetic diseases known as thalassemias, and the enzyme Glucose-6-phosphate dehydrogenase (G6PD) which even lead to human mortality. Duffy blood group is also one such trait, and Duffy blood group is defined by the presence of antigens on the surface of red blood cells. The gene of duffy blood group is present on the chromosome 1 and consist of three codominant alleles: Fy0 or Fy(a−b−) (coding for the absence of any Duffy antigen), Fya (coding for a antigen) and Fyb (coding for b antigen). Individuals who are homozygous for the Duffy negative allele cannot be infected by the plasmodium vivax, which causes vivax malaria (Chaudhuri et al. 1993). A selection for the Duffy negative alleles are expected to be there in populations experiencing vivax malaria, ultimately leading to fixation of this allele.

 

The highest frequencies of Duffy negative alleles is found in central and South Africa reaching a value of 1.0 (100%) in number of populations. Moderate to high frequencies is found in northern Africa and the Middle East, at low frequencies in parts of India, and at or close to zero in native populations throughout the rest of the world (Roychoudhary and Nei 1988). The most extreme variation possible in a species is where an allele ranges from 0 to 1 in various populations, and such a range in values typically indicates selection across different environments. Those homozygous for the Duffy negative allele cannot be infected by vivax malaria. Therefore, we expect a close relationship between the prevalence of vivax malaria and the frequency of Duffy negative allele i.e., the longer vivax malaria has been around, the higher the frequency of the advantageous Duffy negative allele.

 

Support for natural selection for the Duffy negative allele come from the molecular studies that have examined DNA sequences at and near the location of the Duffy blood group gene. The evidence shows for the Duffy blood group and neighbouring DNA sequences that reduced variation for those with the Duffy negative allele, confirming that selection has taken place (Hamblin and Di Rienzo 2000; Hamblin et al. 2002). However, does this mean that the selection initially resulted from adaptation to vivax malaria? Not necessarily. Livingstone (1984) presents another hypothesis that can also explain the negative correlation between Duffy negative allele frequency and prevalence of vivax malaria. He suggests that there was already a high frequency of the Duffy negative allele in some other disease. Consequently, these populations were already resistant to vivax malaria when it spread into Africa, but because almost everyone was immune, the disease never took hold. This alternative continues to be a possibility, although estimates of the date of the initial Duffy negative mutation from coalescent analysis suggest that it arose fairly recently, at about the same time as the origin of agriculture and the spread of malaria (Seixas et al. 2002). If so, then vivax malaria was responsible for fixation of the Duffy negative allele in Africa.

 

4. CCR5-Δ32 Gene mutation and Disease Resistance

 

On a micro-evolutionary level, we can see the same thing when looking at variation of the CCR5-Δ32 mutation. The CCR5 gene (short for C-C chemokine receptor 5) is located on chromosome 3. This gene is responsible for the CCR5 protein, which functions in resistance to certain infectious diseases. A mutation of the CCR5 gene results in the deletion of a 32-bp section of the DNA sequence of CCR5, and is known as CCR5-Δ32 (delta 32) mutation. In European populations Δ32 mutation has a frequency of 0-14% but it is absent in rest of the world (Stephens et al. 1998). Statistical analysis of DNA sequences near this locus provides strong support that the distribution of this allele has been shaped by natural selection (Bamshad et al. 2002).

 

Herozygotes with one CCR5-Δ32 allele show partial resistance to HIV, and homozygotes show almost complete resistance to AIDS (Galvani and Slatkin 2003). However, AIDS has been known only a short time in human history and therefore it could not have been responsible for the initial elevation of this mutant allele in some European populations. Most likely higher frequencies of CCR5- Δ32 arose because of selection related to some other disease such as bubonic plaque known as Black Death that ravaged Europe from 1346 to 1352 and small pox, another major historical disease.

 

Further insight into the evolution of the CCR5-Δ32 allele comes from analysis of ancient DNA from human skeletal remains. Hummel et al. (2005) extracted DNA sequences from 14 skeletons from a mass grave of black death victims in Germany in 1350 and found that the allele frequency of CCR5-Δ32 (=0.142) was not significantly different from a control group of famine victims from Germany in 1316 that did not have the plaque (allele frequency=0.125). If individuals with CCR5-Δ32 were less likely to be infected with bubonic plaque, then the allele frequency of CCR5-Δ32 in the Black Death mass grave should be significantly lower than in the control group, which is not the case.

 

Hummel et al. (2005) also found out evidence for the CCR5-Δ32 allele in 4 of 17 Bronze Age skeletons from Germany dating back 2900 years. The results show that the mutant allele was common in Europe over 2000 years before the Black Death. They conclude that bubonic plaque was not likely to have been a major factor in the evolution of CCR5-Δ32, and that smallpox is a more likely causal factor. There is a possibility that other infectious disease might have also contributed to changes in CCR5- Δ32 over time. At any event, this example shows again how adaptive relationships that we see today (in this case, AIDS resistance) cannot be used to explain the origin and evolution of a mutant allele.

 

5. Lactase Persistence and Human Diet

 

So far, the case studies presented above have focused on disease. Adaptation to disease through natural selection makes sense as disease directly affects one’s probability of survival. However, let us consider a different sort of selection, evidence of adaptation to changing diet. Human infants are nourished through breastfeeding. Infant mammals produce the enzyme lactase, which allow lactose (milk sugar) to be broken down and digested. The typical pattern in mammals is to shut down the lactase production after the infant is weaned. After this, the mammal can no longer easily digest lactose.

 

Today, many humans have developed lactose intolerant, that they cannot produce the lactase after about 5 years of age. The physical effect of lactose intolerance can vary and include flatulence, bloating, cramps, distention, and acute diarrhoea. The interesting fact is that although many people are lactose intolerant while others have no trouble in digesting lactose as they continue producing lactase enzyme throughout their lifetimes. The gene controlling lactase activity is present on the chromosome2.   There are two lactase activity alleles: LCT*R (lactase restriction that codes for shut off of lactase production after weaning) and LCT*P (lactase persistence allele that codes for continued lactase production) apart from some minor mutations that are found in low frequencies. The LCT*P allele is dominant, so individuals with one persistence allele (genotype LCT*P/ LCT*R) or two persistence alleles (genotypes LCT*P/ LCT*P) can more easily digest lactose. The recessive homozygotes (LCT*R/ LCT*R) are lactose-intolerant (Mielke et al. 2011).

 

Lactase persistence has an interesting geographic distribution. It is found highest in northern Europe, and moderate in southern Europe and the Middle East. It is found very low in African and Asian populations on average, although some African populations, such as Fulani and the Tutsi, have moderate to high frequencies (Leonard 2000; Tiskoff et al. 2007). Variation in Africa is particularly revealing because some populations are found with high frequencies of lactase persistence, and some are found with very low levels (and thus have a high prevalence of people who are lactose-intolerant).

 

The critical factor that explains global variation in lactose persistence is diet. Populations indulged in dairy farming tend to have higher frequencies of the lactase persistence allele. The fact can very well be explained by natural selection where lactase persistence was selected for the populations engaged in dairy farming because of the nutritional advantage among individuals who are able to digest the milk. A European cattle study revealed that the geographic distribution of various protein genes was correlated with levels of lactase persistence in humans and the locations of prehistoric sites associated with the early adoption of cattle farming (Beja-Pereira et al. 2003). As humans adapted to a diet (include milk), they also selected cattle that provided better quantity and quality milk. The estimated age of lactose persistence fits the archaeological evidence for the origin of the age of domestication of cattle. Cattle farming began in northern Africa and the Middle East between 7500 and 9000 years ago, which fits with the estimated age of 8000-9000 years for the T-13910 mutation in Europeans. Earlier age estimate of 2700-6800 years for the C-14010 mutation in Africa fits the younger age of 3300-4500 years ago for the cattle domestication in sub-Saharan Africa (Tisskoff et al. 2007).

 

It is clear from both the European and African evidence that the increase in lactase persistence occurred in a very short time in an evolutionary sense. All of these changes, genetic and cultural, took place only within the last 10,000 years, which is a high degree of evolutionary change.

 

6. The evolution of skin color

 

Human skin colour (pigmentation) is a quantitative trait that shows an immense amount of variation between human groups around the world, ranging from very dark to extremely light. The wide range of skin colour is affected by natural selection, and the specific geographical distribution of skin color is another. Skin color tends to be darker at or near the equator, and decrease with increasing distance from the equator, both north and south as the amount of ultraviolet (UV) varies with distance. UV radiation is strongest at the equator and diminishes with increasing distance. Skin color, levels of UV radiation, and distance from the equator are all highly correlated (Jablonski and Chaplin 2000). Pigmented skin acts as a protective barrier against UV radiation, therefore dark skin are preferable in areas at or near the equator. Although vitamin D hypothesis, the cold injury hypothesis, and the sexual hypothesis have their own different views, they all have one thing in common i.e., they all agree that the evolution of light skin was due to natural selection. In fact, there might have been multiple paths of selection for light skin in human populations.

 

7. Adaptation to High Altitude

 

A change in the adaptability was observed among the humans, as our ancestors expanded out of Africa and spread across the world. One particular challenge occurred in adapting themselves to high altitude and overcome the physiological stress. Some population live as high as 5400m above sea level (Beal 2007). When a low native enters a high altitude environment, the hypoxic conditions can be encountered by various individuals and an adaptive response is further generated like increase in the red blood cells and increased respiration, increased chest dimension, greater lung volume relative to high altitude. Some adaptation occurs in infants and children who move to high altitude through a process known as developmental acclimatization, where there are changes in the body during the growth process when adapting to an environmental stress. Those who move to high altitude show an increase in aerobic capacity compared with those that stay at low altitude. Further, the younger the child who moves to high altitude, the greater is the change (Frisancho 1993).

 

There are some genetic influences on high altitude environment, then some physiologic and biochemical traits as a result of natural selection. As can be seen from the genetic make-up of the respiratory components of the Tibetan and the Andean populations are significantly different. Andean population is the native inhabitants of the Andean plateau in South America, who descended from human populations moving into the region about 11,000 years ago. The other group i.e., Tibetan population is the native inhabitants of the Tibetan plateau, who colonized the area about 25,000 years ago. These two populations differ in the level of oxygen in the blood, the level of oxygen saturation in the blood and levels of haemoglobin concentration. The important lesson here is that there may be different paths of selection that operate differently depending on the types of genetic variation available, which in turn is influenced by variation in mutation and genetic drift. Besides multiple adaptive solutions, genetic studies of high altitude adaptation provide another example of the rapid pace of recent human evolution, because the high-altitude populations have been in those environments only within recent evolutionary history (Relethford 2012).

 

Summary

 

Studies based on Human genetic and morphological variation have allowed us to understand a number of significant examples of natural selection in today human evolution, with illustrative examples showing adaptation within only the past 200kya years. One of the classic examples of natural selection in human populations is the change in allele frequencies of hemoglobin S, which is selected for the malarial environments. Here, the fitness of the heterozygote (AS) relative to the AA genotype (susceptibility to malaria) and SS genotype (presence of sickle cell anemia), is also a classic example of balancing selection.

 

Other genetic studies also show a significance implication of infectious disease in recent natural selection. The fixation of the Duffy negative allele is a genetic adaptation related to the spread of vivax malaria. The association of the Δ32 mutation of the CCR5-Δ32 gene with resistance to HIV/AIDS is interesting, but the evolutionary history of this allele suggests an initial adaptation to a different disease, perhaps small pox.

 

Several examples of natural selection are related to other aspects of human evolution such as changes in diet. The rapid increase in lactase persistence allele allow those who possess this allele to digest milk even as adult, occurred independently in different human populations as an adaptation for increased nutrition available from dairy farming, a recent innovation. A striking example of environmental adaptation is the wide distribution of human skin color, reflecting different stresses associated with various levels of UV radiation. Other genetic changes reflect the propensity of our ancestors to adapt genetically at high altitude environments to the physiologic stress of lowered amount of oxygen, although in different way.

 

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References

 

Suggested readings

 

  • Bamshad, M. J., Mummidi, S., Gonzalez, E., Ahuja, S. S., Dunn, D. M., Watkins, W. S., … & Ahuja, S. K. (2002). A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proceedings of the National Academy of Sciences, 99(16), 10539-10544.
  • Beall, C. M. (2007). Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proceedings of the National Academy of Sciences, 104(suppl 1), 8655-8660.
  • Beja-Pereira, A., Luikart, G., England, P. R., Bradley, D. G., Jann, O. C., Bertorelle, G., … & Erhardt, G. (2003). Gene-culture coevolution between cattle milk protein genes and human lactase genes. Nature genetics, 35(4), 311-313.
  • Bodmer, W. F., & Cavalli-Sforza, L. L. (1976). Genetics, evolution, and man(pp. 559-603). San Francisco: WH Freeman.
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  • Frisancho, A. R. (1993). Human adaptation and accommodation. University of Michigan Press.
  • Galvani, A. P., & Slatkin, M. (2003). Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele.Proceedings of the National Academy of Sciences, 100(25), 15276-15279.
  • Hamblin, M. T., & Di Rienzo, A. (2000). Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. The American Journal of Human Genetics, 66(5), 1669-1679.
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  • Hummel, S., Schmidt, D., Kremeyer, B., Herrmann, B., & Oppermann, M. (2005). Detection of the CCR5-Δ32 HIV resistance gene in Bronze Age skeletons. Genes and immunity, 6(4), 371-374.
  • Jablonski, N. G., & Chaplin, G. (2000). The evolution of human skin coloration.Journal of human evolution, 39(1), 57-106.
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