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 hippoc...

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Bibliographic Details
Published in:PLoS genetics 2016-06, Vol.12 (6), p.e1006121-e1006121
Main Authors: Choi, Jinmyung, Shooshtari, Parisa, Samocha, Kaitlin E, Daly, Mark J, Cotsapas, Chris
Format: Article
Language:English
Subjects:
Biology and Life Sciences
Computer and Information Sciences
Disease
Fetal brain
Funding
Gene expression
Gene mutation
Gene Regulatory Networks - genetics
Genetic aspects
Genetic Diseases, Inborn - genetics
Genetic Variation - genetics
Genome - genetics
Genomes
Growth
Health aspects
Hippocampus - embryology
Humans
Medical Subject Headings-MeSH
Medicine and Health Sciences
Models, Genetic
Mutation
Mutation - genetics
Physical Sciences
Protein Interaction Maps - genetics
Proteins
Standard deviation
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006121