Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development
Yuqi Qiu,
Thomas Arbogast,
Sandra Martin Lorenzo,
Hongying Li,
Shih C. Tang,
Ellen Richardson,
Oanh Hong,
Shawn Cho,
Omar Shanta,
Timothy Pang,
Christina Corsello,
Curtis K. Deutsch,
Claire Chevalier,
Erica E. Davis,
Lilia M. Iakoucheva,
Yann Herault,
Nicholas Katsanis,
Karen Messer,
Jonathan Sebat
Affiliations
Yuqi Qiu
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA
Thomas Arbogast
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
Sandra Martin Lorenzo
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
Hongying Li
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA
Shih C. Tang
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Ellen Richardson
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
Oanh Hong
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Shawn Cho
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Omar Shanta
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Electrical Engineering, University of California, San Diego, La Jolla, CA 92093, USA
Timothy Pang
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Christina Corsello
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children’s Hospital, San Diego, CA 92123, USA
Curtis K. Deutsch
Eunice Kennedy Shriver Center UMMS, Charlestown and Worcester, MA, USA
Claire Chevalier
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
Erica E. Davis
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
Lilia M. Iakoucheva
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA
Yann Herault
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
Nicholas Katsanis
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
Karen Messer
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA
Jonathan Sebat
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have “mirror” effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes. : Using 3D morphometric imaging, Qiu et al. demonstrate that large copy-number variants (CNVs) of 16p11.2 have significant effects on craniofacial structure that are conserved in humans and model organisms, and they demonstrate that these craniofacial phenotypes are attributable to the dosage effects of multiple genes within the CNV region.
