In silico functional profiling of human disease-associated and polymorphic amino acid substitutions
- 5 January 2010
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 31 (3), 335-346
- https://doi.org/10.1002/humu.21192
Abstract
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 http://profile.mutdb.org/. Hum Mutat 31:1–12, 2010.Keywords
This publication has 89 references indexed in Scilit:
- Identification, analysis, and prediction of protein ubiquitination sitesProteins-Structure Function and Bioinformatics, 2009
- Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosisThe EMBO Journal, 2009
- Common vs. rare allele hypotheses for complex diseasesCurrent Opinion in Genetics & Development, 2009
- Functional annotations improve the predictive score of human disease-related mutations in proteinsHuman Mutation, 2009
- Assessment of functional effects of unclassified genetic variantsHuman Mutation, 2008
- In silico analysis of missense substitutions using sequence-alignment based methodsHuman Mutation, 2008
- Improving the prediction accuracy of residue solvent accessibility and real‐value backbone torsion angles of proteins by guided‐learning through a two‐layer neural networkProteins-Structure Function and Bioinformatics, 2008
- Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humansHuman Mutation, 2007
- Protein recognition motifs: Design of peptidomimetics of helix surfacesPeptide Science, 2007
- Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical featuresPeptide Science, 1983