Hunting for genes that shape human faces: Initial successes and challenges for the future

Weinberg, Seth M.; Roosenboom, Jasmien; Shaffer, John R.; Shriver, Mark D.; Wysocka, Joanna; Claes, Peter

doi:10.1111/ocr.12268

Cited by 26 publications

(19 citation statements)

References 32 publications

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“…We then queried whether any genes within 0.25 Mb of the SNP or genome scan LOD peaks are known to be associated with craniofacial development or phenotypes (Table 3). As with human facial shape GWAS [42], LOD peaks tended to be located in non-coding regions. While the focal genes we identified all have known roles in skeletal or craniofacial development, they also tend to be developmentally ubiquitous.…”

Section: Association Mappingmentioning

confidence: 94%

“…Quantitative genetics analyses [32,36,37] as well as expression and epigenomic atlases of facial development both strongly point to the potential for hundreds or thousands of genetic loci with as-yet-undetected QTL variance contributions [38][39][40]. Increased sample sizes, greater mapping resolution, and the development of new experimental lines all have the potential to expand the facial shape QTL library and increase the precision of variant localization [41][42][43].…”

Section: Introductionmentioning

confidence: 99%

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Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

et al. 2020

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The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and Xchromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal and facial development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTL's peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.

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Section: Association Mappingmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

et al. 2020

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“…This resulted in 364 height‐related SNPs. Rather than including loci from new GWAS studies, for example for human facial variation (reviewed by Weinberg et al, 2019), we restricted our studies to those used by Sheehan and Nachman (2014) to ensure comparability between these studies.…”

Section: Methodsmentioning

confidence: 99%

Elevated diversity in loci linked to facial morphology is consistent with the hypothesis that individual facial recognition is important across hominoids

Steiper

Grube

Gagnon

2021

American J Phys Anthropol

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Objectives: The ability to use visual signals to identify individuals is an important feature of primate social groups, including humans. Sheehan and Nachman (2014) showed that loci linked to facial morphology had elevated levels of diversity and interpreted this as evidence that the human face is under frequency-dependent selection to enhance individual recognition (Nature Communications 5). In our study, we tested whether this pattern is found in non-human ape species, to help understand whether individual recognition might also play a role in species other than humans. Materials and methods: We examined levels of genetic diversity in an available population genomic dataset of humans, chimpanzees, bonobos, gorillas, and orangutans for three sets of loci, (1) loci linked to facial morphology, (2) loci linked to height, and (3) neutrally evolving regions. We tested whether loci linked to facial morphology were more variable than loci linked to height or neutrally evolving loci in each of these species. Results: We found significantly elevated diversity in loci linked to facial morphology in chimpanzees, gorillas, and Sumatran and Bornean orangutans. Discussion: Our findings closely parallel those of Sheehan and Nachman and are consistent with the idea that selection for facial diversity and individual recognition has not only shaped the evolution of the human face, but it has similarly shaped the evolution of most of our closest primate relatives. We also discuss alternative hypotheses for this pattern.

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“…Significant progress has been made in elucidating the genetic basis of human facial traits 1 – 3 . Genome-wide association studies (GWASs) have identified and replicated numerous common genetic variants associated with normal-range facial morphology 4 – 13 (see implicated genes by facial regions in Fig S1 ); yet these variants cumulatively explain only a small fraction of the heritable phenotypic variation.…”

Section: Introductionmentioning

confidence: 99%

Impact of low-frequency coding variants on human facial shape

Liu

Alhazmi

Matthews

et al. 2021

Sci Rep

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The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

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Hunting for genes that shape human faces: Initial successes and challenges for the future

Cited by 26 publications

References 32 publications

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

Elevated diversity in loci linked to facial morphology is consistent with the hypothesis that individual facial recognition is important across hominoids

Impact of low-frequency coding variants on human facial shape

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