Multilayer View of Pathogenic SNVs in Human Interactome through In Silico Edgetic Profiling

Journal of Molecular Biology
Hongzhu CuiDmitry Korkin

Abstract

Non-synonymous mutations linked to the complex diseases often have a global impact on a biological system, affecting large biomolecular networks and pathways. However, the magnitude of the mutation-driven effects on the macromolecular network is yet to be fully explored. In this work, we present a systematic multi-level characterization of human mutations associated with genetic disorders by determining their individual and combined interaction-rewiring, "edgetic," effects on the human interactome. Our in silico analysis highlights the intrinsic differences and important similarities between the pathogenic single-nucleotide variants (SNVs) and frameshift mutations. We show that pathogenic SNVs are more likely to cause gene pleiotropy than pathogenic frameshift mutations and are enriched on the protein interaction interfaces. Functional profiling of SNVs indicates widespread disruption of the protein-protein interactions and synergistic effects of SNVs. The coverage of our approach is several times greater than the recently published experimental study and has the minimal overlap with it, while the distributions of determined edgotypes between the two sets of profiled mutations are remarkably similar. Case studies reveal the cen...Continue Reading

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Citations

Mar 11, 2020·Scientific Reports·Evans KatakaDmitrij Frishman

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