title: Widespread macromolecular interaction perturbations in human genetic disorders.
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.
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Song
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authors.lastname: Yi
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Mikko
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authors.lastname: Taipale
authors.affiliation: Program in Systems Biology, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Fuxman Bass
authors.affiliation: Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada.
authors.forename: Jasmin
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authors.lastname: Coulombe-Huntington
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Fan
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authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jian
authors.initials: J
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Jochen
authors.initials: J
authors.lastname: Weile
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Karras
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Departments of Physics, Biology and Computer Science, Northeastern University, Boston, MA 02115, USA.
authors.forename: István A
authors.initials: IA
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Atanas
authors.initials: A
authors.lastname: Kamburov
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Irina
authors.initials: I
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authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Mandy H
authors.initials: MH
authors.lastname: Lam
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: George
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authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Vikram
authors.initials: V
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Departments of Physics, Biology and Computer Science, Northeastern University, Boston, MA 02115, USA.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Departments of Physics, Biology and Computer Science, Northeastern University, Boston, MA 02115, USA.
authors.forename: Yang-Yu
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Yachie
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Quan
authors.initials: Q
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yun
authors.initials: Y
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Palagi
authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Adriana
authors.initials: A
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dawit
authors.initials: D
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Amelie
authors.initials: A
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authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Biophysics, Harvard University, Cambridge, MA 02139, USA.
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authors.initials: DM
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.initials: AA
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xinping
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.initials: AK
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authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.initials: MA
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Département de Virologie, Unité de Génétique Moléculaire des Virus ARN (GMVR), Institut Pasteur, UMR3569, Centre National de la Recherche Scientifique, and Université Paris Diderot, Paris, France.
authors.forename: Yves
authors.initials: Y
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authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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authors.initials: ME
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kourosh
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authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Shamil
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authors.lastname: Sunyaev
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mathematics and Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Berger
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Departments of Physics, Biology and Computer Science, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Albert-László
authors.initials: AL
authors.lastname: Barabási
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Charloteaux
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Hao
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G 1Z8, Canada.
authors.forename: Frederick P
authors.initials: FP
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Bioengineering, Faculty of Engineering, McGill University, Montreal, QC H3A 0C3, Canada.
authors.forename: Yu
authors.initials: Y
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authors.affiliation: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Program in Systems Biology, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Albertha J M
authors.initials: AJM
authors.lastname: Walhout
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA. Electronic address: lindquist@wi.mit.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.affiliation: Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marc_vidal@dfci.harvard.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004194:Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020125:Mutation, Missense; D016366:Open Reading Frames; D017510:Protein Folding; D060066:Protein Interaction Maps; D055550:Protein Stability; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins