PolyDoms: a whole genome database for the identification of non-synonymous coding SNPs with the potential to impact disease

Abstract

As knowledge of human genetic polymorphisms grows, so does the opportunity and challenge of identifying those polymorphisms that may impact the health or disease risk of an individual person. A critical need is to organize large-scale polymorphism analyses and to prioritize candidate non-synonymous coding SNPs (nsSNPs) that should be tested in experimental and epidemiological studies to establish their context-specific impacts on protein function. In addition, with emerging high-resolution clinical genetics testing, new polymorphisms must be analyzed in the context of all available protein feature knowledge including other known mutations and polymorphisms. To approach this, we developed PolyDoms (http://polydoms.cchmc.org/) as a database to integrate the results of multiple algorithmic procedures and functional criteria applied to the entire Entrez dbSNP dataset. In addition to predicting structural and functional impacts of all nsSNPs, filtering functions enable group-based identification of potentially harmful nsSNPs among multiple genes associated with specific diseases, anatomies, mammalian phenotypes, gene ontologies, pathways or protein domains. PolyDoms, thus, provides a means to derive a list of candidate SNPs to be evaluated in experimental or epidemiological studies for impact on protein functions and disease risk associations. PolyDoms will continue to be curated to improve its usefulness.

Figure 1

Schematic representation of PolyDoms data resources, work-flow and features.

Figure 2

PolyDoms feature displays. (A) PolyDoms image of a nsSNP model of the protein KCNH2. Numbers in the image indicate the amino acid residue positions from the corresponding RefSeq protein sequence. The pink, yellow and green blocks over the protein sequence represent the three known domains derived from the NCBI's CDD. Vertical lines represent nsSNPs. The color codes indicate the predictions—gray represents an nsSNP predicted as deleterious and/or damaging; yellow indicates mutation (based on OMIM/SwissChange); orange indicates an nsSNP that has been predicted as deleterious and/or damaging and also reported as a mutation. (B) The summary view gives the basic sequence annotations along with an expandable list of diseases, GO terms, mammalian phenotypes and Pathways associated with the queried gene. (C) Tabular description of nsSNP predictions based on PolyPhen and SIFT analysis and LS-SNP annotations (refer to B above for descriptions of color codes). (D) Tabular list of allelic variants derived from OMIM and SwissChange. (E) Top five relevant abstracts, when available, related to queried gene polymorphisms and disease association. The list is generated dynamically and therefore is up-to-date with current literature. (F) List of protein–protein interactions (from NCBI Entrez Gene).