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In silico functional profiling of human disease-associated and polymorphic amino acid substitutions

Mort, Matthew Edwin, Evani, Uday S., Krishnan, Vidhya G., Kamati, Kishore K., Baenziger, Peter H., Bagchi, Angshuman, Peters, Brandon J., Sathyesh, Rakesh, Li, Biao, Sun, Yanan, Xue, Bin, Shah, Nigam H., Kann, Maricel G., Cooper, David Neil ORCID:, Radivojac, Predrag and Mooney, Sean D. 2010. In silico functional profiling of human disease-associated and polymorphic amino acid substitutions. Human Mutation 31 (3) , pp. 335-346. 10.1002/humu.21192

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An important challenge in translational bioinformatics is to understand how genetic variation gives rise to molecular changes at the protein level that can precipitate both monogenic and complex disease. To this end, we compiled datasets of human disease-associated amino acid substitutions (AAS) in the contexts of inherited monogenic disease, complex disease, functional polymorphisms with no known disease association, and somatic mutations in cancer, and compared them with respect to predicted functional sites in proteins. Using the sequence homology-based tool SIFT to estimate the proportion of deleterious AAS in each dataset, only complex disease AAS were found to be indistinguishable from neutral polymorphic AAS. Investigation of monogenic disease AAS predicted to be nondeleterious by SIFT were characterized by a significant enrichment for inherited AAS within solvent accessible residues, regions of intrinsic protein disorder, and an association with the loss or gain of various posttranslational modifications. Sites of structural and/or functional interest were therefore surmised to constitute useful additional features with which to identify the molecular disruptions caused by deleterious AAS. A range of bioinformatic tools, designed to predict structural and functional sites in protein sequences, were then employed to demonstrate that intrinsic biases exist in terms of the distribution of different types of human AAS with respect to specific structural, functional and pathological features. Our Web tool, designed to potentiate the functional profiling of novel AAS, has been made available at

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RB Pathology
Uncontrolled Keywords: Amino acid substitutions ; AAS ; Missense mutations ; Translational bioinformatics ; Disease mechanism ; Association study ; SNP
Publisher: Wiley Blackwell
ISSN: 1059-7794
Last Modified: 05 Nov 2022 15:17

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