Cell INTRODUCTION et al., 2008). This finding suggested that a pre-existing mouse overexpressed, Humans are unique among primates in having colonized nearly might provide insight into 370A's phenotypic consequences every corner of the world; consequently, niche 008). Indeed, trans- pressures likely helped shape the phenotypic varia present-day g, enlarged globin-B a P. falcipa 2005);muta digest milk (Enattah genes dr 2005) Althor s.We tated the chara tional e ces. affect a by exp ther of car ghlights the variation in idat g other candidate those w S persist unknowr difficu native to t date adap A SNP in 51 worldwide particularl of 370A. Haplotype hum subtle p ype adapti g plasin A et al., 200 of the se East Asian ar scalp hair th 200 2009;Park quantify tained whe phenotypes. The bioch that the variant Structural models Domain(DD) required transducer EDARADD we performed a pression of 370A has bee NFkB signaling in vitro re sent-day Han Chinese 62e,69-7 February 1420120eINTRODUCTION Humans are unique among primates in having colonized nearly every corner of the world; consequently, niche-specific selective pressures likely helped shape the phenotypic variation currently evident in Homo sapiens. Identifying the genetic variants that underlie regional adaptations is thus central to understanding present-day human diversity, yet only a few adaptive traits have been elucidated. These include mutations in the Hemo￾globin-B and Duffy antigen genes, driving resistance to P. falciparum and P. vivax malaria, respectively (Kwiatkowski, 2005); mutations in lactase allowing some adult humans to digest milk after the domestication of milk-producing livestock (Enattah et al., 2002); and mutations in SLC24A5 and other genes driving variation in skin pigmentation (Lamason et al., 2005). Although breakthroughs in genomic technology have facili￾tated the identification of hundreds of candidate genetic variants with evidence of recent positive natural selection, validation and characterization of putative genetic adaptations requires func￾tional evidence linking genotypes to phenotypes that could affect an organism’s fitness (Akey, 2009). This is made difficult by experimental challenges in isolating the phenotypic effects of candidate loci and by methodological limitations on the phenotypes that can be readily assessed in humans. Accord￾ingly, the best-characterized human adaptive alleles are typically those whose phenotypic outcomes are easily measured and strongly related to known genetic variation, such as lactase persistence or skin pigmentation. Many genes, however, have unknown or pleiotropic effects, making their adaptive advantage difficult to uncover (Sivakumaran et al., 2011). A promising alter￾native to tackle these difficulties is to study the effects of candi￾date adaptive alleles in animal models. Although such models, particularly using mice, have been used extensively to study human disease alleles, they have not been used to model the subtle phenotypic changes expected to result from human adaptive variation. A compelling candidate human adaptive allele to emerge from genome-wide scans is a derived coding variant of the Ectodys￾plasin A (EDA) receptor (EDAR), EDARV370A (370A) (Sabeti et al., 2007; Grossman et al., 2010). Computational fine-mapping of the selection signal and the restricted occurrence of 370A in East Asian and Native American populations have led to sugges￾tions that 370A was selected in Asia (Bryk et al., 2008). In support of this hypothesis, 370A was shown to associate with increased scalp hair thickness and incisor tooth shoveling in multiple East Asian populations (Fujimoto et al., 2008a, 2008b; Kimura et al., 2009; Park et al., 2012). However, because association studies quantify correlation rather than causation, it remains to be ascer￾tained whether 370A is the genetic change driving the observed phenotypes. The biochemical properties of 370A support the possibility that the variant directly causes the associated phenotypes. Structural models predict that V370A lies in the EDAR Death Domain (DD) required for interaction with the downstream signal transducer EDARADD (Sabeti et al., 2007). Moreover, overex￾pression of 370A has been reported to upregulate downstream NFkB signaling in vitro relative to 370V (Bryk et al., 2008; Mou et al., 2008). This finding suggested that a pre-existing mouse model, in which the ancestral 370V allele is overexpressed, might provide insight into 370A’s phenotypic consequences (Headon and Overbeek, 1999; Mou et al., 2008). Indeed, trans￾genic mice expressing multiple copies of 370V have thicker hair shafts as seen in humans with the 370A allele (Fujimoto et al., 2008a, 2008b; Mou et al., 2008). In addition, these animals exhibit increased mammary gland branching, enlarged mammary glands and hyperplastic sebaceous and Meibomian glands that secrete hydrophobic films as a barrier to water loss in the skin and eyes, respectively (Chang et al., 2009). These latter phenotypes led to the proposal that the 370A variant may have been selected in response to cold and arid environ￾mental conditions (Chang et al., 2009). Evaluating which forces may have contributed to the spread of 370A requires knowledge of both the environmental context in which this variant was selected and its phenotypic effects. We therefore employed a multi-disciplinary approach to test the role of 370A in recent human evolution. This included modeling to reconstruct the evolutionary history of 370A, and a knockin mouse model to examine its direct phenotypic consequences. Analysis of the mouse knockin revealed phenotypes not previously reported in human genetic studies, which we further characterized in a Han Chinese cohort. This work highlights the utility of modeling nonpathological human genetic variation in mice, providing a framework for assessing other candidate adaptive human alleles. RESULTS Single Origin of 370A in Central China Using both newly generated and publicly available data, we examined 280 SNPs flanking the 370A SNP in 51 worldwide populations in order to assess the origin of 370A. Haplotype analysis supports a single origin of the derived allele (Figure 1A), with the mutation lying on a unique, nearly unbroken haplotype extending more than 100 kb among both East Asians and Native Americans (Figure S1 available online). To estimate the allele’s geographic and temporal origin, we performed more than one million spatially explicit demic forward simulations modeling the appearance and spread of 370A in Asia (Itan et al., 2009) (Modeling the Origins and Spread of 370A in an Approximate Bayesian Computation Framework). We used approximate Bayesian computation (ABC) (Beaumont et al., 2002) to compare simulated to observed allele frequencies and to estimate key evolutionary and demographic parameters (Fagundes et al., 2007; Itan et al., 2009; Ray et al., 2010). This analysis estimated the 370A allele originated in central China (Figure 1B) between 13,175 and 39,575 years BP (95% credible interval), with a mode of 35,300 years BP and a median of 30,925 years BP. The estimated selection coefficient has a 95% credible interval between 0.030 and 0.186, with a mode of 0.122 and a median of 0.114 (Figures S2, S3, and S4, and Tables S1, S2, S3, and S4, and Modeling the Origins and Spread of 370A in an Approximate Bayesian Computation Framework). As a separate calculation of the age of 370A, we performed a maximum likelihood inference analysis using the allele frequency spectrum of 1,677 nearby SNPs in present-day Han Chinese 692 Cell 152, 691–702, February 14, 2013 ª2013 Elsevier Inc