Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders
Author(s)
Peng, Jian; Tucker, George Jay; Leighton, Alexander T.; Berger Leighton, Bonnie
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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.
Date issued
2015-04Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Massachusetts Institute of Technology. Department of MathematicsJournal
Cell
Publisher
Elsevier
Citation
Sahni, Nidhi, Song Yi, Mikko Taipale, Juan I. Fuxman Bass, Jasmin Coulombe-Huntington, Fan Yang, Jian Peng, et al. “Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders.” Cell 161, no. 3 (April 2015): 647–660.
Version: Author's final manuscript
ISSN
0092-8674
1097-4172