An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders

被引：53

作者：

Chen, Siwei ^{[1
,2
,3
]}

Fragoza, Robert ^{[1
,2
,3
]}

Klei, Lambertus ^{[4
]}

Liu, Yuan ^{[1
,2
]}

Wang, Jiebiao ^{[5
]}

Roeder, Kathryn ^{[5
,6
]}

Devlin, Bernie ^{[4
]}

Yu, Haiyuan ^{[1
,2
]}

机构：

[1] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA

[2] Cornell Univ, Weill Inst Cell & Mol Biol, Ithaca, NY USA

[3] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA

[4] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[5] Carnegie Mellon Univ, Dept Stat & Data Sci, Pittsburgh, PA 15213 USA

[6] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA

来源：

NATURE GENETICS | 2018年 / 50卷 / 07期

基金：

美国国家科学基金会;

关键词：

AUTISM SPECTRUM DISORDERS; DE-NOVO MUTATIONS; SEVERE INTELLECTUAL DISABILITY; PROTEIN INTERACTION NETWORK; CONGENITAL HEART-DISEASE; COPY-NUMBER VARIATION; TOPOLOGICAL FEATURES; INTERACTION DATABASE; GENETIC-DISEASE; UPDATE;

D O I：

10.1038/s41588-018-0130-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Identifying disease-associated missense mutations remains a challenge, especially in large-scale sequencing studies. Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network and test our approach by analyzing similar to 2,000 de novo missense mutations found in autism subjects and their unaffected siblings. Interaction-disrupting de novo missense mutations are more common in autism probands, principally affect hub proteins, and disrupt a significantly higher fraction of hub interactions than in unaffected siblings. Moreover, they tend to disrupt interactions involving genes previously implicated in autism, providing complementary evidence that strengthens previously identified associations and enhances the discovery of new ones. Importantly, by analyzing de novo missense mutation data from six disorders, we demonstrate that our interactome perturbation approach offers a generalizable framework for identifying and prioritizing missense mutations that contribute to the risk of human disease.

引用

页码：1032 / +

页数：11

共 71 条

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