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

Cell Reports (Sep 2019)

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

Journal volume & issue: Vol. 28, no. 13
pp. 3320 – 3328.e4

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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