title: In silico functional profiling of human disease-associated and polymorphic amino acid substitutions.
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/.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.forename: Uday S
authors.initials: US
authors.lastname: Evani
authors.forename: Vidhya G
authors.initials: VG
authors.lastname: Krishnan
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Kamati
authors.forename: Peter H
authors.initials: PH
authors.lastname: Baenziger
authors.forename: Angshuman
authors.initials: A
authors.lastname: Bagchi
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Peters
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sathyesh
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.forename: Yanan
authors.initials: Y
authors.lastname: Sun
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Nigam H
authors.initials: NH
authors.lastname: Shah
authors.forename: Maricel G
authors.initials: MG
authors.lastname: Kann
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Predrag
authors.initials: P
authors.lastname: Radivojac
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006031:Glycosylation; D006801:Humans; D020407:Internet; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D020539:Sequence Analysis, Protein
chemical_list: D000596:Amino Acids