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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.

SUBMITTER: Sahni N

PROVIDER: S-EPMC4441215 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other

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Widespread macromolecular interaction perturbations in human genetic disorders.

Sahni Nidhi N Yi Song S Taipale Mikko M Fuxman Bass Juan I JI Coulombe-Huntington Jasmin J Yang Fan F Peng Jian J Weile Jochen J Karras Georgios I GI Wang Yang Y Kovács István A IA Kamburov Atanas A Krykbaeva Irina I Lam Mandy H MH Tucker George G Khurana Vikram V Sharma Amitabh A Liu Yang-Yu YY Yachie Nozomu N Zhong Quan Q Shen Yun Y Palagi Alexandre A San-Miguel Adriana A Fan Changyu C Balcha Dawit D Dricot Amelie A Jordan Daniel M DM Walsh Jennifer M JM Shah Akash A AA Yang Xinping X Stoyanova Ani K AK Leighton Alex A Calderwood Michael A MA Jacob Yves Y Cusick Michael E ME Salehi-Ashtiani Kourosh K Whitesell Luke J LJ Sunyaev Shamil S Berger Bonnie B Barabási Albert-László AL Charloteaux Benoit B Hill David E DE Hao Tong T Roth Frederick P FP Xia Yu Y Walhout Albertha J M AJM Lindquist Susan S Vidal Marc M

Cell 20150401 3

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, suggestin ...[more]

PMID: 25910212

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Project description:IntroductionDown syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. This study aimed to investigate genome-wide methylation patterns in DS newborns compared to non-trisomic newborns.MethodWe analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution.ResultsDifferentially methylated position (DMP) analysis of the uncorrected model detected 19525 significant hits (51,2% hypomethylated). In the corrected model, we found 121953 significant DMPs (49,8% hypomethylated). Independent of the used model we observed a chromosome 21 dosage effect. Moreover, we detected 46 and 145 differentially methylated regions in the uncorrected and corrected model respectively, both showing hypomethylation overrepresentation. Replication analyses of DMPs and DMRs found by Bacalini et al. (2015) showed a large overlap.ConclusionIn this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21. Additional research is necessary to substantiate these hypotheses.

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Widespread macromolecular interaction perturbations in human genetic disorders.

Publications

Widespread macromolecular interaction perturbations in human genetic disorders.

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