Robust classification of protein variation using structural modelling and large-scale data integration

Evan H. Baugh, Riley Simmons-Edler, Christian L. Müller, Rebecca F. Alford, Natalia Volfovsky, Alex E. Lash, Richard Bonneau

Research output: Contribution to journalArticlepeer-review

Abstract

Existing methods for interpreting protein variation focus on annotating mutation pathogenicity rather than detailed interpretation of variant deleteriousness and frequently use only sequence-based or structure-based information. We present VIPUR, a computational framework that seamlessly integrates sequence analysis and structural modelling (using the Rosetta protein modelling suite) to identify and interpret deleterious protein variants. To train VIPUR, we collected 9477 protein variants with known effects on protein function from multiple organisms and curated structural models for each variant from crystal structures and homology models. VIPUR can be applied to mutations in any organism's proteome with improved generalized accuracy (AUROC. 83) and interpretability (AUPR. 87) compared to other methods. We demonstrate that VIPUR's predictions of deleteriousness match the biological phenotypes in ClinVar and provide a clear ranking of prediction confidence. We use VIPUR to interpret known mutations associated with inflammation and diabetes, demonstrating the structural diversity of disrupted functional sites and improved interpretation of mutations associated with human diseases. Lastly, we demonstrate VIPUR's ability to highlight candidate variants associated with human diseases by applying VIPUR to de novo variants associated with autism spectrum disorders.

Original languageEnglish (US)
Pages (from-to)2501-2513
Number of pages13
JournalNucleic acids research
Volume44
Issue number6
DOIs
StatePublished - Feb 28 2016

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Robust classification of protein variation using structural modelling and large-scale data integration'. Together they form a unique fingerprint.

Cite this