Extending genome-wide association study (GWAS) results to test classic anthropological hypotheses: Human third molar agenesis and the â•Ÿprobable mutation effectâ•Ž

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 = 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 the risk of M3 impaction and potential health complications was reduced (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 don’t accurately retrodict those of the pre-agricultural 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.