Abstract
Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia. As a result, genes involved in malaria resistance are excellent examples of recent, strong selection. In 1949, Haldane initially suggested that infectious disease could be a strong selective force in human populations. Evidence for the strong selective effect of malaria resistance includes the high frequency of a number of detrimental genetic diseases caused by the pleiotropic effects of these malaria resistance variants, many of which are “loss of function” mutants. Evidence that this selection is recent comes from the genetic dating of the age of a number of these malaria resistant alleles to less than 5,000 years before the present, generally much more recent than other human genetic variants. An approach to estimate selection coefficients from contemporary case–control data is presented. In the situations described here, selection is much greater than 1%, significantly higher than generally observed for other human genetic variation. With these selection coefficients, predictions are generated about the joint change of alleles S and C at the β-globin locus, and for α-thalassaemia haplotypes and S, variants that are unlinked but exhibit epistasis. Population genetics can be used to determine the amount and pattern of selection in the past and predict selection in the future for other malaria resistance variants as they are discovered.
Highlights
Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia [1]
His general review [2] is often cited for this concept, this hypothesis was presented in more detail in 1948 [3] where he suggested that β-thalassaemia heterozygotes had an increased fitness in the presence of malaria
Perhaps related to the high frequency of diseases related to genes conferring resistance to malaria is that many of resistance variants, such as G6PD deficiency, the thalassaemias, sickle-cell anaemia, and ovalocytosis, are “loss of function” mutants and lead to reduced expression or altered gene product
Summary
Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia [1]. Perhaps related to the high frequency of diseases related to genes conferring resistance to malaria is that many of resistance variants, such as G6PD deficiency, the thalassaemias, sickle-cell anaemia, and ovalocytosis, are “loss of function” mutants and lead to reduced expression or altered gene product Sometimes these variants result in disease because of their pleiotropic effects. Age of selective variants Many malaria resistance genetic variants appear to be recent polymorphisms and have been generated in the last 5,000 to 10,000 years or less (see Table 1 and below). When the S and A alleles are at their stable equilibrium, C can enter the population and eventually increase to fixation after about 5,000 years (Figure 1) These results occur because genotype CC has the highest relative fitness of the genotypes. Notice that the amount of epistasis between the genes is high, the time for these changes to occur is quite long
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