Resistance to malaria in humans: the impact of strong, recent selection

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.

Polygenic patterns of adaptive introgression in modern humans are mainly shaped by response to pathogens

“…We postulate that introgression could have been the source of several 323 adaptive variants increasing the fitness of individuals in an environment where malaria is 324 endemic. Since malaria resistance alleles typically appeared after the Neolithic transition 325 (Hedrick 2012), these alleles could have been present in archaic populations for a long 326 time, evolving neutrally in the absence of malaria and been positively selected only once 327 the disease appeared (Laval, et al 2019). Alternatively, archaic populations living in 328 tropical areas could have been exposed to similar endoparasites, which is possible as 329 malaria parasites infect many vertebrates including great apes, which are the most likely 330 origin of the parasite transmission to humans (Prugnolle, et al 2011).…”

Molecular interactions governing host-specificity of blood stage malaria parasites

“…Indeed, P. vivax pathogenicity has favored the proliferation of a mutation in the DARC promoter, which abrogates expression of this protein on human erythrocytes [56,57]. This allele, which arose less than 33,000 years ago [58], can now be found at >95% frequency in parts of sub-Saharan Africa and underlies the near complete absence of P. vivax in human populations on the African continent [59]. …”

Human Genomic Loci Important in Common Infectious Diseases: Role of High-Throughput Sequencing and Genome-Wide Association Studies

“…is hypothesis suggests that some human diseases such as thalassemia are polymorphisms which provide heterozygote advantage because of the trade-o s between the advantages of resistance to malaria and negative e ects due to the disease [77], where the hemoglobin S (HbS) homozygote disadvantage is recompensed through the malaria resistance of the heterozygote (HbAS) in regions of malaria endemicity [78,79]. e ∆32 mutation at the CCR5 locus is a wellstudied example of natural selection acting in humans.…”