Polygenic adaptation and convergent evolution on growth and cardiac genetic pathways in African and Asian rainforest hunter-gatherers.

Different human populations facing similar environmental challenges have sometimes evolved convergent biological adaptations, for example, hypoxia resistance at high altitudes and depigmented skin in northern latitudes on separate continents. The "pygmy" phenotype (small adult body size), characteristic of hunter-gatherer populations inhabiting both African and Asian tropical rainforests, is often highlighted as another case of convergent adaptation in humans. However, the degree to which phenotypic convergence in this polygenic trait is due to convergent versus population-specific genetic changes is unknown. To address this question, we analyzed high-coverage sequence data from the protein-coding portion of the genomes of two pairs of populations: Batwa rainforest hunter-gatherers and neighboring Bakiga agriculturalists from Uganda and Andamanese rainforest hunter-gatherers and Brahmin agriculturalists from India. We observed signatures of convergent positive selection between the rainforest hunter-gatherers across the set of genes with "growth factor binding" functions ([Formula: see text]). Unexpectedly, for the rainforest groups, we also observed convergent and population-specific signatures of positive selection in pathways related to cardiac development (e.g., "cardiac muscle tissue development"; [Formula: see text]). We hypothesize that the growth hormone subresponsiveness likely underlying the adult small body-size phenotype may have led to compensatory changes in cardiac pathways, in which this hormone also plays an essential role. Importantly, in the agriculturalist populations, we did not observe similar patterns of positive selection on sets of genes associated with growth or cardiac development, indicating our results most likely reflect a history of convergent adaptation to the similar ecology of rainforests rather than a more general evolutionary pattern.

Extending Genome-Wide Association Study Results to Test Classic Anthropological Hypotheses: Human Third Molar Agenesis and the "Probable Mutation Effect".

A genome-wide association study (GWAS) identifies regions of the genome that likely affect the variable state of a phenotype of interest. These regions can then be studied with population genetic methods to make inferences about the evolutionary history of the trait. There are increasing opportunities to use GWAS results-even from clinically motivated studies-for tests of classic anthropological hypotheses. One such example, presented here as a case study for this approach, involves tooth development variation related to dental crowding. Specifically, more than 10% of humans fail to develop one or more permanent third molars (M3 agenesis). M3 presence/absence variation within human populations has a significant genetic component (heritability estimate h 2 = 0.47). The evolutionary significance of M3 agenesis has a long history of anthropological speculation. First, the modern frequency of M3 agenesis could reflect a relaxation of selection pressure to retain larger and more teeth following the origins of cooking and other food-softening behaviors (i.e., the genetic drift hypothesis or, classically, the "probable mutation effect"). Alternatively, commensurate with increasing hominin brain size and facial shortening, M3 agenesis may have conferred an adaptive fitness advantage if it reduced the risk of M3 impaction and potential health complications (i.e., the positive selection hypothesis). A recent GWAS identified 70 genetic loci that may play a role in human M3 presence/absence variation. To begin evaluating the contrasting evolutionary scenarios for M3 agenesis, we used the integrated haplotype score (iHS) statistic to test whether those 70 genetic regions are enriched for genomic signatures of recent positive selection. None of our findings are inconsistent with the null hypothesis of genetic drift to explain the high prevalence of human M3 agenesis. This result might suggest that M3 impaction rates for modern humans do not accurately retrodict those of the preagricultural past. Alternatively, the absence of support for the positive selection hypothesis could reflect a lack of power; this analysis should be repeated following the completion of more comprehensive GWAS analyses for human M3 agenesis.