Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders

被引：400

作者：

Sahni, Nidhi ^{[1
,2
,3
,4
]}

Yi, Song ^{[1
,2
,3
,4
]}

Taipale, Mikko ^{[5
]}

Bass, Juan I. Fuxman ^{[6
]}

Coulombe-Huntington, Jasmin ^{[7
]}

Yang, Fan ^{[1
,2
,3
,8
,9
,10
,11
]}

Peng, Jian ^{[12
]}

Weile, Jochen ^{[1
,2
,3
,8
,9
,10
,11
]}

Karras, Georgios I. ^{[5
]}

Wang, Yang ^{[1
,2
,3
,4
]}

Kovacs, Istvan A. ^{[1
,2
,3
,13
,14
,15
,16
]}

Kamburov, Atanas ^{[2
,3
,4
]}

Krykbaeva, Irina ^{[5
]}

Lam, Mandy H. ^{[10
]}

Tucker, George ^{[12
]}

Khurana, Vikram ^{[5
]}

Sharma, Amitabh ^{[1
,2
,3
,13
,14
,15
,16
]}

Liu, Yang-Yu ^{[2
,3
,13
,14
,15
,16
]}

Yachie, Nozomu ^{[1
,2
,3
,8
,9
,11
]}

Zhong, Quan ^{[2
,3
,4
]}

Shen, Yun ^{[1
,2
,3
,4
]}

Palagi, Alexandre ^{[2
,3
,4
]}

San-Miguel, Adriana ^{[2
,3
,4
]}

Fan, Changyu ^{[1
,2
,3
,4
]}

Balcha, Dawit ^{[1
,2
,3
,4
]}

Dricot, Amelie ^{[1
,2
,3
,4
]}

Jordan, Daniel M. ^{[17
,18
]}

Walsh, Jennifer M. ^{[2
,3
,4
]}

Shah, Akash A. ^{[2
,3
,4
]}

Yang, Xinping ^{[2
,3
,4
]}

Stoyanova, Ani K. ^{[2
,3
,4
]}

Leighton, Alex ^{[12
]}

Calderwood, Michael A. ^{[1
,2
,3
,4
]}

Jacob, Yves ^{[2
,3
,4
,19
,20
]}

Cusick, Michael E. ^{[1
,2
,3
,4
]}

Salehi-Ashtiani, Kourosh ^{[2
,3
,4
]}

Whitesell, Luke J. ^{[5
,21
,22
]}

Sunyaev, Shamil ^{[17
,23
]}

Berger, Bonnie ^{[12
,24
]}

Barabasi, Albert-Laszlo ^{[1
,2
,3
,13
,14
,15
,16
,25
]}

Charloteaux, Benoit ^{[1
,2
,3
,4
]}

Hill, David E. ^{[1
,2
,3
,4
]}

Hao, Tong ^{[1
,2
,3
,4
]}

Roth, Frederick P. ^{[1
,2
,3
,8
,9
,11
,26
]}

Xia, Yu ^{[2
,3
,7
]}

Walhout, Albertha J. M. ^{[2
,3
,6
,10
]}

Lindquist, Susan ^{[5
,27
]}

Vidal, Marc ^{[1
,2
,3
,4
]}

机构：

[1] Dana Farber Canc Inst, Genom Anal Network, Perturbat Ctr Excellence Genom Sci CEGS, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[5] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[6] Univ Massachusetts, Sch Med, Program Mol Med, Program Syst Biol, Worcester, MA 01605 USA

[7] McGill Univ, Fac Engn, Dept Bioengn, Montreal, PQ H3A 0C3, Canada

[8] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada

[9] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada

[10] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[11] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[12] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA

[13] Northeastern Univ, Ctr Complex Network Res CCNR, Boston, MA 02115 USA

[14] Northeastern Univ, Dept Phys, Boston, MA 02115 USA

[15] Northeastern Univ, Dept Biol, Boston, MA 02115 USA

[16] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA

[17] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dept Med, Boston, MA 02115 USA

[18] Harvard Univ, Program Biophys, Cambridge, MA 02139 USA

[19] CNRS, Dept Virol, Unite Genet Mol Virus ARN GMVR, Inst Pasteur,UMR3569, Paris, France

[20] Univ Paris Diderot, Paris, France

[21] MIT, Dept Biol, Cambridge, MA 02139 USA

[22] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[23] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[24] MIT, Dept Math & Elect Engn & Comp Sci, Cambridge, MA 02139 USA

[25] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[26] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada

[27] Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

CELL | 2015年 / 161卷 / 03期

基金：

美国国家科学基金会; 加拿大自然科学与工程研究理事会;

关键词：

ONE-HYBRID ASSAYS; SEQUENCE VARIATION; MUTATIONS; EXPRESSION; CHAPERONE; DISEASE; MYOGENESIS; RECEPTORS; STABILITY; DATABASE;

D O I：

10.1016/j.cell.2015.04.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

引用

页码：647 / 660

页数：14

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