Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Neha Arora
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Harold S Matthews
Department of Human Genetics, KU Leuven, Leuven, Belgium; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium
Karissa Hansen
Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
Maram Bader
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Susan Walsh
Department of Biology, Indiana University Indianapolis, Indianapolis, United States
Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, United States; Department of Human Genetics, University of Pittsburgh, Pittsburgh, United States
Seth M Weinberg
Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, United States; Department of Human Genetics, University of Pittsburgh, Pittsburgh, United States; Department of Anthropology, University of Pittsburgh, Pittsburgh, United States
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Peter Claes
Department of Human Genetics, KU Leuven, Leuven, Belgium; Medical Imaging Research Center, University Hospitals Leuven, Leuven, Belgium; Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium; Murdoch Children’s Research Institute, Melbourne, Australia
Licia Selleri
Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States; Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States
Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.
