Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8 ). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure

Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure

Limb development genes underlie variation in human fingerprint patterns

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning

Mitochondrial DNA Evidence for a Diversified Origin of Workers Building Mausoleum for First Emperor of China

Variant studies on ancient DNA have attempted to reveal individual origin. Here, based on cloning sequencing and polymerase chain reaction-restriction fragment length polymorphisms, we analyzed polymorphisms in the first hypervariable region and coding regions of mitochondrial DNA of 19 human bone remains which were excavated from a tomb near the Terra Cotta Warriors and dated some 2,200 years before present. With the aim of shedding light on origins of these samples who were supposed to be workers building the mausoleum for the First Emperor of China, we compared them with 2,164 mtDNA profiles from 32 contemporary Chinese populations at both population and individual levels. Our results showed that mausoleum-building workers may be derived from very diverse sources of origin

The adaptive variant EDARV370A is associated with straight hair in East Asians

Hair straightness/curliness is a highly heritable trait amongst human populations. Previous studies have reported European specific genetic variants influencing hair straightness, but those in East Asians remain unknown. One promising candidate is a derived coding variant of the ectodysplasin A receptor (EDAR), EDARV370A (370A), associated with several phenotypic changes of epidermal appendages. One of the strongest signals of natural selection in human genomes, 370A, has risen to high prevalence in East Asian and Native American populations, whilst being almost absent in Europeans and Africans. This striking frequency distribution and the pleiotropic nature of 370A led us to pursue if hair straightness, another epidermal appendage-related phenotype, is affected by this variant. By studying 1,718 individuals from four distinctive East Asian populations (Han, Tibetan, Mongolian, and Li), we found a significant association between 370A and the straight hair type in the Han (p = 2.90 × 10−6), Tibetan (p = 3.07 × 10−2), and Mongolian (p = 1.03 × 10−5) populations. Combining all the samples, the association is even stronger (p = 5.18 × 10−10). The effect of 370A on hair straightness is additive, with an odds ratio of 2.05. The results indicate very different biological mechanisms of straight hair in Europe and Asia, and also present a more comprehensive picture of the phenotypic consequences of 370A, providing important clues into the potential adaptive forces shaping the evolution of this extraordinary genetic variant.Organismic and Evolutionary Biolog

Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration

<div><p>Human facial morphology is a combination of many complex traits. Little is known about the genetic basis of common facial morphological variation. Existing association studies have largely used simple landmark-distances as surrogates for the complex morphological phenotypes of the face. However, this can result in decreased statistical power and unclear inference of shape changes. In this study, we applied a new image registration approach that automatically identified the salient landmarks and aligned the sample faces using high density pixel points. Based on this high density registration, three different phenotype data schemes were used to test the association between the common facial morphological variation and 10 candidate SNPs, and their performances were compared. The first scheme used traditional landmark-distances; the second relied on the geometric analysis of 15 landmarks and the third used geometric analysis of a dense registration of ∼30,000 3D points. We found that the two geometric approaches were highly consistent in their detection of morphological changes. The geometric method using dense registration further demonstrated superiority in the fine inference of shape changes and 3D face modeling. Several candidate SNPs showed potential associations with different facial features. In particular, one SNP, a known risk factor of non-syndromic cleft lips/palates, rs642961 in the <i>IRF6</i> gene, was validated to strongly predict normal lip shape variation in female Han Chinese. This study further demonstrated that dense face registration may substantially improve the detection and characterization of genetic association in common facial variation.</p></div

Facial shape comparisons among the genotype female groups of rs642961.

<p>The average shapes of the different genotype groups of rs642961 were compared pair-wisely, either for the point-wise distances, represented as color gradients in the left column; or for the contrast of the facial profile lines in the right column. The first, second and third rows denote the comparisons of CC/TT, CT/TT and CC/CT, respectively. In A, C and E, the higher intensity of the color gradient indicates greater point-wise distance. The first genotype group average face as the reference face (e.g, CC in the CC:TT comparison). The white color indicate no difference between reference face and compared face. The cold (or warm) colors indicate that the average shape of the reference face in a comparison is inside (or outside) of the compared face. In B, D and F, the red profile line is the average shape of the first genotype, and the blue line denotes the second genotype.</p

The 10 candidate SNPs selected from the literature.

<p>All the positions are using NCBI build 36.3 as reference. Chr chromosome. The two alleles in a SNP are given in the format of (wild type/derived type).</p