Missense variants in health and disease affect distinct functional pathways and proteomics features

Abstract

1Missense variants are present amongst the healthy population, but some of them are causative of human diseases. Therefore, a classification of variants associated with \"healthy\" or \"diseased\" states is not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences, is essential to better distinguish pathogenic from population variants. Here we quantify variant enrichment across full-length proteins, their domains and 3D-structure defined regions. We integrate this with available transcriptomic and proteomic (protein half-life, thermal stability, abundance) data. Using this approach we have mined a rich set of molecular features which enable us to understand the differences underlying pathogenic and population variants: pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing, localise to protein cores and interaction interfaces, and are enriched in more abundant proteins. In terms of their molecular properties, we find that common population variants and pathogenic variants show the greatest contrast. Additionally, in contrary to other studies, we find that rare population variants display features closer to common than pathogenic variants. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants. Such details could be harnessed to predict variant deleteriousness, and prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at http://fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate a large number of missense variants with protein structural information, and to calculate variant enrichment in different protein structural regions.\n\nSignificance StatementOne of the greatest challenges in understanding the genetic basis of diseases is to discriminate between likely harmless and potentially disease-causing sequence variants. To better evaluate the pathogenic potential of missense variants, we developed a strategy to quantitatively measure the enrichment of both disease and non disease-related variants within a protein based on its structural and domain organisation. By integrating available transcriptomics and proteomics data, our approach distinguishes pathogenic from population variants far more clearly than previously possible, and reveals hitherto unknown details of how different proteins exhibit resilience and/or sensitivity towards genetic variants. Our results will help to prioritise variant-enriched proteins for therapeutic targeting; we have created the ZoomVar database, accessible at http://fraternalilab.kcl.ac.uk/ZoomVar, for programmatic mapping of user-defined variants to protein structural and domain information.