Vukelic Adrijana, Cohen Jacob A, Sullivan Alexis P, Perry George H
1 Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, USA.
2 Department of Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
Hum Biol. 2017 Apr;89(2):157-169. doi: 10.13110/humanbiology.89.2.03.
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 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.
全基因组关联研究（GWAS）可识别基因组中可能影响感兴趣表型可变状态的区域。然后可以使用群体遗传学方法对这些区域进行研究，以推断该性状的进化历史。利用GWAS结果（即使是来自临床研究的结果）来检验经典人类学假设的机会越来越多。本文作为这种方法的一个案例研究，给出的一个例子涉及与牙列拥挤相关的牙齿发育变异。具体而言，超过10%的人不会萌出一颗或多颗恒牙第三磨牙（第三磨牙缺失）。人类群体中第三磨牙的有无变异具有显著的遗传成分（遗传力估计值h = 0.47）。第三磨牙缺失的进化意义在人类学领域一直备受猜测。首先，现代第三磨牙缺失的频率可能反映出在烹饪和其他食物软化行为出现后，保留更多更大牙齿的选择压力有所放松（即遗传漂变假说，或者经典的“可能的突变效应”）。另外，随着古人类脑容量的增加和面部缩短，如果第三磨牙缺失降低了第三磨牙阻生和潜在健康并发症的风险，那么它可能带来了适应性的健康优势（即正选择假说）。最近的一项GWAS识别出70个可能在人类第三磨牙有无变异中起作用的基因位点。为了开始评估第三磨牙缺失的不同进化情形，我们使用综合单倍型评分（iHS）统计量来检验这70个基因区域是否富集了近期正选择的基因组特征。我们的研究结果均未与用遗传漂变零假设来解释人类第三磨牙高缺失率的情况相矛盾。这一结果可能表明，现代人类的第三磨牙阻生率并不能准确追溯到农业出现之前的过去。或者，缺乏对正选择假说的支持可能反映出检验效力不足；在完成针对人类第三磨牙缺失更全面的GWAS分析后，应重复此分析。
