Recent Adaptive Acquisition by African Rainforest Hunter-Gatherers of the Late Pleistocene Sickle-Cell Mutation Suggests Past Differences in Malaria Exposure

Abstract

The hemoglobin b S sickle mutation is a textbook case in which natural selection maintains a deleterious mutation at high frequency in the human population. Homozygous individuals for this mutation develop sickle-cell disease, whereas heterozygotes benefit from higher protection against severe malaria. Because the overdominant b S allele should be purged almost immediately from the population in the absence of malaria, the study of the evolutionary history of this iconic mutation can provide important information about the history of human exposure to malaria. Here, we sought to increase our understanding of the origins and time depth of the b S mutation in populations with different lifestyles and ecologies, and we analyzed the diversity of HBB in 479 individuals from 13 populations of African farmers and rainforest hunter-gatherers. Using an approximate Bayesian computation method, we estimated the age of the b S allele while explicitly accounting for population subdivision, past demography, and balancing selection. When the effects of balancing selection are taken into account, our analyses indicate a single emergence of b S in the ancestors of present-day agriculturalist populations $22,000 years ago. Furthermore, we show that rainforest hunter-gatherers have more recently acquired the b S mutation from the ancestors of agriculturalists through adaptive gene flow during the last $6,000 years. Together, our results provide evidence for a more ancient exposure to malarial pressures among the ancestors of agriculturalists than previously appreciated, and they suggest that rainforest hunter-gatherers have been increasingly exposed to malaria during the last millennia.

Human Immunology through the Lens of Evolutionary Genetics

“…A recent study revisited the history of the balancing selection acting on the HBB gene in Africa and showed that the sicklecell mutation first appeared in the ancestors of present-day farmers more than 20,000 ya (Laval et al, 2019). It was then acquired by rainforest hunter-gatherers through adaptive admixture over the last 6,000 years.…”

Global consumption and international trade in deforestation-associated commodities could influence malaria risk

“…The inter-relationship between malaria parasites and human hosts is associated with adaptive mutations in the human genome. A recent study that focused on the evolution of human populations that were highly exposed to malaria provides an additional argument in favour of the association between deforestation and malaria 6 .…”

Role of rs454214 in Personality mediated Depression and Subjective Well-being

“…It was recently found that homozygotes of βS sickle mutation can lead to sickle-cell disease while heterozygotes contribute to higher protection 33 . The heterozygotes of CHRNA4 polymorphism (rs1044396) showed higher activity during cognitive engagement than the homozygotes in the cingulo-opercular (CO) network 34 .…”