Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation.
Using robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriched for genes mutated in neurological Mendelian disorders. We thus conclude that carefully orchestrated developmental processes are under strong constraint in early brain development, and perturbations caused by mutation have adverse outcomes subject to strong purifying selection. Our findings demonstrate that selective forces can act on groups of genes involved in the same process, supporting the notion that purifying selection can act coordinately on multiple genes. Our approach provides a statistically robust, interpretable way to identify the tissues and developmental times where groups of disease genes are active.
Department of Neurology, Yale School of Medicine, New Haven Connecticut, United States of America.
Jinmyung
J
Choi
Department of Neurology, Yale School of Medicine, New Haven Connecticut, United States of America.
Parisa
0000-0003-2273-1034
P
Shooshtari
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America.
Kaitlin E
KE
Samocha
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Mark J
MJ
Daly
Department of Neurology, Yale School of Medicine, New Haven Connecticut, United States of America.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Genetics, Yale School of Medicine, New Haven CT, United States of America.
Chris
0000-0002-7772-5910
C
Cotsapas
D053263:Gene Regulatory Networks / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D016678:Genome / Q000235:genetics*; D006624:Hippocampus / Q000196:embryology*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics*