Widespread macromolecular interaction perturbations in human genetic disorders

Nidhi Sahni, Song Yi, Mikko Taipale, Juan I. Fuxman Bass, Jasmin Coulombe-Huntington, Fan Yang, Jian Peng, Jochen Weile, Georgios I. Karras, Yang Wang, István A. Kovács, Atanas Kamburov, Irina Krykbaeva, Mandy H. Lam, George Tucker, Vikram Khurana, Amitabh Sharma, Yang Yu Liu, Nozomu Yachie, Quan Zhong & 28 others Yun Shen, Alexandre Palagi, Adriana San-Miguel, Changyu Fan, Dawit Balcha, Amelie Dricot, Daniel M. Jordan, Jennifer M. Walsh, Akash A. Shah, Xinping Yang, Ani K. Stoyanova, Alex Leighton, Michael A. Calderwood, Yves Jacob, Michael E. Cusick, Kourosh Salehi-Ashtiani, Luke J. Whitesell, Shamil Sunyaev, Bonnie Berger, Albert László Barabási, Benoit Charloteaux, David E. Hill, Tong Hao, Frederick P. Roth, Yu Xia, Albertha J.M. Walhout, Susan Lindquist, Marc Vidal

    Research output: Contribution to journalArticle

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)647-660
    Number of pages14
    JournalCell
    Volume161
    Issue number3
    DOIs
    StatePublished - Apr 23 2015

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    Inborn Genetic Diseases
    Medical Genetics
    Alleles
    Proteins
    Protein folding
    Mutation
    Protein Stability
    Protein Folding
    Missense Mutation
    Assays
    Transcription Factors
    Genes
    Phenotype
    DNA

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Sahni, N., Yi, S., Taipale, M., Fuxman Bass, J. I., Coulombe-Huntington, J., Yang, F., ... Vidal, M. (2015). Widespread macromolecular interaction perturbations in human genetic disorders. Cell, 161(3), 647-660. https://doi.org/10.1016/j.cell.2015.04.013

    Widespread macromolecular interaction perturbations in human genetic disorders. / Sahni, Nidhi; Yi, Song; Taipale, Mikko; Fuxman Bass, Juan I.; Coulombe-Huntington, Jasmin; Yang, Fan; Peng, Jian; Weile, Jochen; Karras, Georgios I.; Wang, Yang; Kovács, István A.; Kamburov, Atanas; Krykbaeva, Irina; Lam, Mandy H.; Tucker, George; Khurana, Vikram; Sharma, Amitabh; Liu, Yang Yu; Yachie, Nozomu; Zhong, Quan; Shen, Yun; Palagi, Alexandre; San-Miguel, Adriana; Fan, Changyu; Balcha, Dawit; Dricot, Amelie; Jordan, Daniel M.; Walsh, Jennifer M.; Shah, Akash A.; Yang, Xinping; Stoyanova, Ani K.; Leighton, Alex; Calderwood, Michael A.; Jacob, Yves; Cusick, Michael E.; Salehi-Ashtiani, Kourosh; Whitesell, Luke J.; Sunyaev, Shamil; Berger, Bonnie; Barabási, Albert László; Charloteaux, Benoit; Hill, David E.; Hao, Tong; Roth, Frederick P.; Xia, Yu; Walhout, Albertha J.M.; Lindquist, Susan; Vidal, Marc.

    In: Cell, Vol. 161, No. 3, 23.04.2015, p. 647-660.

    Research output: Contribution to journalArticle

    Sahni, N, Yi, S, Taipale, M, Fuxman Bass, JI, Coulombe-Huntington, J, Yang, F, Peng, J, Weile, J, Karras, GI, Wang, Y, Kovács, IA, Kamburov, A, Krykbaeva, I, Lam, MH, Tucker, G, Khurana, V, Sharma, A, Liu, YY, Yachie, N, Zhong, Q, Shen, Y, Palagi, A, San-Miguel, A, Fan, C, Balcha, D, Dricot, A, Jordan, DM, Walsh, JM, Shah, AA, Yang, X, Stoyanova, AK, Leighton, A, Calderwood, MA, Jacob, Y, Cusick, ME, Salehi-Ashtiani, K, Whitesell, LJ, Sunyaev, S, Berger, B, Barabási, AL, Charloteaux, B, Hill, DE, Hao, T, Roth, FP, Xia, Y, Walhout, AJM, Lindquist, S & Vidal, M 2015, 'Widespread macromolecular interaction perturbations in human genetic disorders', Cell, vol. 161, no. 3, pp. 647-660. https://doi.org/10.1016/j.cell.2015.04.013
    Sahni N, Yi S, Taipale M, Fuxman Bass JI, Coulombe-Huntington J, Yang F et al. Widespread macromolecular interaction perturbations in human genetic disorders. Cell. 2015 Apr 23;161(3):647-660. https://doi.org/10.1016/j.cell.2015.04.013
    Sahni, Nidhi ; Yi, Song ; Taipale, Mikko ; Fuxman Bass, Juan I. ; Coulombe-Huntington, Jasmin ; Yang, Fan ; Peng, Jian ; Weile, Jochen ; Karras, Georgios I. ; Wang, Yang ; Kovács, István A. ; Kamburov, Atanas ; Krykbaeva, Irina ; Lam, Mandy H. ; Tucker, George ; Khurana, Vikram ; Sharma, Amitabh ; Liu, Yang Yu ; Yachie, Nozomu ; Zhong, Quan ; Shen, Yun ; Palagi, Alexandre ; San-Miguel, Adriana ; Fan, Changyu ; Balcha, Dawit ; Dricot, Amelie ; Jordan, Daniel M. ; Walsh, Jennifer M. ; Shah, Akash A. ; Yang, Xinping ; Stoyanova, Ani K. ; Leighton, Alex ; Calderwood, Michael A. ; Jacob, Yves ; Cusick, Michael E. ; Salehi-Ashtiani, Kourosh ; Whitesell, Luke J. ; Sunyaev, Shamil ; Berger, Bonnie ; Barabási, Albert László ; Charloteaux, Benoit ; Hill, David E. ; Hao, Tong ; Roth, Frederick P. ; Xia, Yu ; Walhout, Albertha J.M. ; Lindquist, Susan ; Vidal, Marc. / Widespread macromolecular interaction perturbations in human genetic disorders. In: Cell. 2015 ; Vol. 161, No. 3. pp. 647-660.
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    abstract = "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.",
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