Ellen E. Quillen

Modeling 3D Facial Shape from DNA

Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.

ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample.

Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome‐wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 × 10−8) and two AD‐related phenotypes: flushing response (minimum P = 4.75 × 10−26) and maximum drinks in a 24‐hr period (minimum P = 1.54 × 10−16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females—despite familial enrichment for AD—for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.

OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans

Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments. Previous studies have identified several genes involved in skin pigmentation differences among African, Asian, and European populations. However, none have examined skin pigmentation variation among Indigenous American populations, creating a critical gap in our understanding of skin pigmentation variation. This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans. Analysis was performed on two samples of Indigenous Americans genotyped on genome-wide SNP arrays. Using four tests for natural selection—locus-specific branch length (LSBL), ratio of heterozygosities (lnRH), Tajima’s D difference, and extended haplotype homozygosity (EHH)—we identified 14 selection-nominated candidate genes (SNCGs). SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground-level ultraviolet radiation. In addition to SLC24A5 and SLC45A2, genes previously associated with European/non-European differences in skin pigmentation, OPRM1 and EGFR were associated with variation in skin pigmentation in New World populations for the first time.

Natural selection for the Duffy-null allele in the recently admixed people of Madagascar

While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa.

Novel Associations of Nonstructural Loci with Paraoxonase Activity

The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.

Iris texture traits show associations with iris color and genomic ancestry.

This study seeks to identify associations among genomic biogeographic ancestry (BGA), quantitative iris color, and iris texture traits contributing to population‐level variation in these phenotypes.

Technical Note: Comparing von Luschan skin color tiles and modern spectrophotometry for measuring human skin pigmentation

Prior to the introduction of reflectance spectrophotometry into anthropological field research during the 1950s, human skin color was most commonly classified by visual skin color matching using the von Luschan tiles, a set of 36 standardized, opaque glass tiles arranged in a chromatic scale. Our goal was to establish a conversion formula between the tile-based color matching method and modern reflectance spectrophotometry to make historical and contemporary data comparable. Skin pigmentation measurements were taken on the forehead, inner upper arms, and backs of the hands using both the tiles and a spectrophotometer on 246 participants showing a broad range of skin pigmentation. From these data, a second-order polynomial conversion formula was derived by jackknife analysis to estimate melanin index (M-index) based on tile values. This conversion formula provides a means for comparing modern data to von Luschan tile measurements recorded in historical reports. This is particularly important for populations now extinct, extirpated, or admixed for which tile-based measures of skin pigmentation are the only data available.

The Evolution of Tanning Needs Its Day in the Sun

abstract Variation in human pigmentation has long been an area of interest in biological anthropology, with the advent of genetic technologies allowing deeper plumbing of its evolutionary history. Genome-wide scans of selection show that pigmentation genes have undergone some of the strongest selection in many geographically distant populations. A variety of hypotheses for the photoprotective effects of melanin have been developed, but these hypotheses, as well as genetic studies, focus nearly exclusively on constitutive (basal) pigmentation levels. Failing to consider the contribution of the ultraviolet radiation (UVR) environment neglects the true interface between humans and our environment. Data drawn largely from dermatology demonstrate that constitutive pigmentation and tanning response are weakly coupled in populations from East Asia and the Americas. This suggests a possible role for persistent, UVR-induced pigmentation as a convergent adaptation akin to the protective effect of constitutive pigmentation. The adaptive potential of tanned skin, particularly in the Americas, where constitutive pigmentation is lower than expected, may fill in an important gap in our understanding of the evolution of skin color.

Evaluation of estimated genetic values and their application to genome-wide investigation of systolic blood pressure

The concept of breeding values, an individuals phenotypic deviation from the population mean as a result of the sum of the average effects of the genes they carry, is of great importance in livestock, aquaculture, and cash crop industries where emphasis is placed on an individuals potential to pass desirable phenotypes on to the next generation. As breeding or genetic values (as referred to here) cannot be measured directly, estimated genetic values (EGVs) are based on an individuals own phenotype, phenotype information from relatives, and, increasingly, genetic data. Because EGVs represent additive genetic variation, calculating EGVs in an extended human pedigree is expected to provide a more refined phenotype for genetic analyses. To test the utility of EGVs in genome-wide association, EGVs were calculated for 847 members of 20 extended Mexican American families based on 100 replicates of simulated systolic blood pressure. Calculations were performed in GAUSS to solve a variation on the standard Best Linear Unbiased Predictor (BLUP) mixed model equation with age, sex, and the first 3 principal components of sample-wide genetic variability as fixed effects and the EGV as a random effect distributed around the relationship matrix. Three methods of calculating kinship were considered: expected kinship from pedigree relationships, empirical kinship from common variants, and empirical kinship from both rare and common variants. Genome-wide association analysis was conducted on simulated phenotypes and EGVs using the additive measured genotype approach in the SOLAR software package. The EGV-based approach showed only minimal improvement in power to detect causative loci.

Extensive Regulatory Changes in Genes Affecting Vocal and Facial Anatomy Separate Modern from Archaic Humans

Changes in gene regulation are broadly accepted as key drivers of phenotypic differences between closely related species. However, identifying regulatory changes that shaped human-specific traits is a very challenging task. Here, we use >60 DNA methylation maps of ancient and present-day human groups, as well as six chimpanzee maps, to detect regulatory changes that emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes affecting vocalization and facial features went through particularly extensive methylation changes. Specifically, we identify silencing patterns in a network of genes (SOX9, ACAN, COL2A1 and NFIX), and propose that they might have played a role in the reshaping of the human face, and in forming the 1:1 vocal tract configuration that is considered optimal for speech. Our results provide insights into the molecular mechanisms that may have shaped the modern human face and voice, and suggest that they arose after the split from Neanderthals and Denisovans.Summary Regulatory changes are broadly accepted as key drivers of phenotypic divergence. However, identifying regulatory changes that underlie human-specific traits has proven very challenging. Here, we use 63 DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes affecting the face and vocal tract went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-affecting genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.Identifying changes in gene regulation that shaped human-specific traits is critical to understanding human adaptation. Here, we use dozens of ancient and present-day DNA methylation maps to detect regulatory changes that emerged in modern humans. We show that genes affecting vocalization and facial features went through particularly extensive changes in methylation. Especially, we identify expansive changes in a network of genes regulating skeletal development (SOX9, ACAN and COL2A1), and in NFIX, which controls facial projection and voice box (larynx) development. We propose that these changes played a key role in shaping the human face, and in forming the human 1:1 vocal tract configuration that is considered optimal for speech. Our results provide insights into the molecular mechanisms that shaped the modern human face and voice, and suggest that they arose after the split from Neanderthals and Denisovans.