One way humans adapted to malaria in wet, tropical Africa was through the A/S polymorphism at the j-Hb locus, an adaptation that confers malarial resistance to only about 20% of the population. In general, many loci can contribute to how an individual responds to its environment in determining the phenotype of fitness. As a consequence, adaptation to a new environment is usually a polygenic process, with genetic variation at many loci responding to natural selection. This is certainly the case for malarial adaptation in human populations. We will now examine a few of the other loci involved in this adaptation.
Glucose-6-phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme coded for by the X-linked G6PD locus. The G6PD enzyme is essential for a cell's capacity to withstand oxidant stress (Ruwende and Hill 1998), as mentioned in Chapter 4. Over 300 independent mutations have been identified that lead to a common phenotype of a deficiency of the enzyme G6PD. G6PD deficiency affects over 400 million persons worldwide, mostly living in malarial regions. This geographical distribution implies that G6PD deficiency has risen in frequency through natural selection with malaria as the selective agent. This hypothesis is supported by data from in vitro studies that demonstrate impaired growth of P. falciparum parasites in G6PD-deficient red blood cells. In wet, tropical Africa, the allele A- is the most common allele at the G6PD locus that results in an enzyme deficiency. Studies conducted in East and West Africa provide strong evidence that the A- allele is associated with a significant reduction in the risk of severe malaria for both G6PD A- female heterozygotes and male hemizygotes. The effect of female homozygotes for A- on severe malaria remains unclear but can probably be assumed to be similar to that of comparably deficient male hemizygotes.
If a person does not have the A/S genotype at the j-Hb locus in a malarial region, the person could still be protected against malaria through the G6PD A- allele. Thus, the Bantu-speaking peoples adapted to malaria as they expanded into wet, tropical Africa with the Malaysian agricultural complex not only by the C and S alleles at the j - Hb locus but also by the A- allele at the G6PD locus. However, as with the S allele, there are fitness tradeoffs associated with the A- and other G6PD-deficient alleles. Although reducing the red blood cell's capacity to withstand oxidant stress provides resistance to the malarial parasite by causing premature lysis of infected cells, it also makes the red blood cells subject to lysis when exposed to oxidizing agents, thereby resulting in hemolytic anemia. For example, about 25% of the people with G6PD deficiency experience an adverse reaction to eating fava beans, a bean containing strong oxidizing agents. This sensitivity, known as favism, can result in death. Thus, the adaptation to one environmental agent (malaria) is counterbalanced by the interactions with other environmental agents (oxidizing agents), and these two antagonistic effects are weighted through the average excess to determine the frequency of the G6PD-deficient alleles. Such deficient alleles vary tremendously in frequency from one human population to the next as a function of malaria and oxidizing agents in the diet or environment, ranging from 0.001 in nonmalarial regions such as Japan or northern Europe to 0.62 in Kurdish Jews living in historical malarial regions (Ruwende and Hill 1998).
There are even more loci involved in malarial adaptation in humans. The first genetic syndrome suggested to be a malarial adaptation in humans was thalassemia (Haldane 1949). All normal hemoglobins are tetramers of two pairs of unlike globin chains (Weatherall 2001). Adult hemoglobin (HbA) has two a chains and two j chains, so HbA can be symbolized as a2 j2. To obtain efficient production of HbA, it is necessary that a chains should be produced in about the same quantity as j chains. We have already discussed the j - Hb locus on chromosome 11 that encodes for the j chain. As shown in Figure 2.5, the j-Hb locus normally exists as a single copy of the gene per chromosome. In contrast, the a-Hb locus that codes for the a chain generally exists as two tandem copies (a-Hb1 and a-Hb2) on chromosome 16. Normally, the rates of transcription and translation at these three loci are adjusted to produce an equal balance of a and j chains in the adult human. Thalassemia occurs when that balance is disrupted, and a large number of mutations at either the a-Hb loci and the j - Hb locus can lead to thalassemia. For example, some 80 different deletions and point mutations can induce a-thalassemia, including a deletion of one or both of the duplicated copies of a-Hb, a frame shift mutation in one of the copies or any point mutation that results in an inactive a chain. Over 200 mutations have been discovered that induce j-thalassemia, including deletions of all or part of the jj-Hb gene, point mutations that inactivate the production of functional j chains, promoter mutations that lower the amount of transcription, mutations that alter posttranscriptional processing such as mutations that create or destroy exon/intron splice sites (including both noncoding mutations in the introns and silent mutations in the exons), and 3' mutations that alter the signal for the 3' cleavage site of the primary transcript (followed normally by polyadenylation). All of these mutations can result in an imbalance between a and j chains that in turn results in a spectrum of phenotypic effects ranging from no clinical symptoms to lethal anemia but also to resistance to the malarial parasite. In general, the severity of the thalassemia depends upon the degree of imbalance. Homozygotes for mutations inducing thalassemia generally have deleterious clinical symptoms, whereas heterozygotes generally have mild to no deleterious clinical symptoms.
Thalassemic heterozygotes appear to have an advantage against P. falciparum malaria as well (Weatherall 2001). As a consequence, the global distribution of thalassemia is largely coincident with the distribution of falciparum malaria. For example, the African populations that we discussed earlier with respect to the S and C alleles at the j - Hb locus and the A-allele at the G6PD locus also have a high frequency of j-thalassemia due to 5' point mutations and a high frequency of a-thalassemia due to a deletion of one of the copies of a-Hb. Hence, the adaptation to malaria in these Bantu-speaking populations involves changes in allele frequencies at a-Hb, j - Hb, and G6PD. However, the list does not end here, as malarial-resistant variants have been associated also with the ApoE locus (Woznaik et al. 2003), the acid phosphatase 1 locus (Bottini et al. 2001a), the major histocompatibility complex loci (Chapter 1), the tumor-necrosis factor-a locus, the intercellular adhesion molecule I locus, and others (Weatherall 2001).
Different human populations have adapted to malaria using different combinations of these alleles and loci. We have already pointed out how some western African populations adapted to malaria through jj-Hb S and others through j - Hb C, and different alleles representing independent mutation events are in high frequencies in different human populations living in malarial regions across the globe at the other loci involved in malarial adaptation. This pattern illustrates three general points about adaptation through natural selection:
1. The course of adaptation is always constrained by the available genetic variation. Whether or not a human population adapts to malaria through S or C at the j - Hb locus depends upon which variants were available to the population due to mutation and/or gene flow. Natural selection is only selection on existing variation that arises by mutation and spreads by gene flow. Natural selection acts upon genetic variation but does not directly create it.
2. Even uniform selective pressures produce divergent adaptive responses because selection operates upon variation whose creation and initial frequencies are profoundly influenced by randomfactors such as mutation and drift. The randomness of the mutation and recombination processes that create variation in the first place and the randomness of drift influencing the frequencies of newly created variation cause much variation among populations in the state of their initial gene pools and array of available genetic variation. This heterogeneity can lead to diverse selective outcomes among different populations adapting to the same environmental influence.
FUNDAMENTAL THEOREM OF NATURAL SELECTION: UNMEASURED GENOTYPES
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