Population genetics of malaria resistance in humans

Abstract

The high mortality and widespread impact of malaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best-known case studies of strong positive selection in modern humans. I begin by reviewing JBS Haldane's initial contribution to the potential of malaria genetic resistance in humans. Further, I discuss the population genetics aspects of many of the variants, including globin, G6PD deficiency, Duffy, ovalocytosis, ABO and human leukocyte antigen variants. Many of the variants conferring resistance to malaria are 'loss-of-function' mutants and appear to be recent polymorphisms from the last 5000-10 000 years or less. I discuss estimation of selection coefficients from case-control data and make predictions about the change for S, C and G6PD-deficiency variants. In addition, I consider the predicted joint changes when the two β-globin alleles S and C are both variable in the same population and when there is a variation for α-thalassemia and S, two unlinked, but epistatic variants. As more becomes known about genes conferring genetic resistance to malaria in humans, population genetics approaches can contribute both to investigating past selection and predicting the consequences in future generations for these variants.

Figure 1

The increase in frequency of allele A- at the G6PD locus when it begins at a frequency of 0.01 and fitness of females BB, BA- and A-A- and males B and A- are for females 1—s_f, 1, and 1 and for males 1—s_m and 1 (solid line), for females 1—s_f, 1, and 1—s_f and for males 1 and 1 (broken line), and for females 1—s_f, 1, and 1—2s_f and for males 1 and 1 -s_m (dotted line), where s_f=0.046 and s_m=0.058 (estimated from the data of Ruwende et al., 1995).

Figure 2

The increase in frequency of allele C when it begins at a frequency of 0.01 (short, broken line), when S also begins at a frequency of 0.01 (solid lines), and when S begins at its equilibrium frequency of 0.0895 (long, broken line) (after Hedrick, 2004). The change in frequency of S is also given for the last two situations.

Figure 3

The change in the frequency of S where the initial frequency is 0.01 and the change in the frequency of −α where the initial frequency is either 0.55 or 0.65 using the relative fitness levels in Table 9b.