Journal Article

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations

Wierbowski, Shayne D., Liang, Jin, Wei, Xiaomu, Keinan, Alon, Clark, Andrew G., Liang, Siqi, Yu, Haiyuan, Schimenti, John C., Rivera-Erick, Christen A., Tran, Tina N., Das, Jishnu, Fragoza, Robert, Mort, Matthew, Yao, Li, Beltran, Juan F., Ye, Kaixiong, Stenson, Peter D., Cooper, David N., Wang, Ting-Yi

2019

Overview

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual’s genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations. Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/70 / 49/47 / 631/208/457/649/2219 / 631/208/737 / 631/337/475/2290 / 631/553 / 82/111 / Alleles / Animals / Base Sequence / Disease - genetics / Disruption / Frequency spectrum / Gene frequency / Gene Frequency - genetics / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genetic Variation / Genetics, Population / Genome, Human / Genomes / HEK293 Cells / Human populations / Humanities and Social Sciences / Humans / Mice / multidisciplinary / Mutation / Mutation, Missense - genetics / Nucleotides / Phenotype / Polymorphism, Single Nucleotide - genetics / Population genetics / Populations / Protein Binding - genetics / Protein interaction / Proteins / Science / Science (multidisciplinary)