During the current grant period, we have developed two models of the impact of missense SNPs on protein function in vivo. Through this work, and that of others, we now have a clearer understanding of the molecular mechanisms that lead to monogenic disease. We have also developed a web resource which integrates our results with a large range of other information relevant to disease. Goals for next phase fall into three categories: (1) Exploiting the present results to address basic questions concerning the relationship between genetic variation and disease. Specifically: What is the distribution of mechanisms by which mis-sense SNPs influence protein function;how common are epistatic (non-linear) interactions between SNPs with the same protein molecule and across protein-protein interfaces;what are the characteristics of the approximately 1500 proteins involved in monogenic disease, versus all the others;which SNPs are most significant in directly and indirectly affecting particular biological processes and susceptibility to common diseases? (2) Improving and extending SNP analysis methods, both to obtain a more extensive and reliable set of deleterious mis-sense SNPs, and to include analysis of SNPs that influence disease susceptibility through other processes. New models will be developed for effects on transcription, message processing and translation. Available database information will be augmented by a combination of literature analysis and soliciting input from appropriate members of the scientific community. (3) Maintain and enhance the web resource to increase its utility to the research community. Functionality will be extended to allow users to input their own SNPs and receive a real time analysis from both models;a user annotation interface will be developed, to capture knowledge on the role of amino acids altered mis-sense SNPs, as well as which genes are most relevant to disease, and what buffering mechanisms shield the phenotype from particular deleterious SNPs;additional information sources will be incorporated, including SNP analysis by others. Relevance to public health: Many common human diseases, such as heart attack, Alzheimer, asthma and diabetes, are partly inherited, through specific DNA features. At present, there is no common disease for which these inheritance mechanisms are understood. This work will provide specific insight into a number of diseases, and improved understanding of the inheritance process.

Agency
National Institute of Health (NIH)
Institute
National Library of Medicine (NLM)
Type
Research Project (R01)
Project #
7R01LM007174-09
Application #
7842564
Study Section
Biomedical Library and Informatics Review Committee (BLR)
Program Officer
Ye, Jane
Project Start
2001-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$290,690
Indirect Cost
Name
University of Maryland College Park
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Pal, Lipika R; Yu, Chen-Hsin; Mount, Stephen M et al. (2015) Insights from GWAS: emerging landscape of mechanisms underlying complex trait disease. BMC Genomics 16 Suppl 8:S4
Cao, Chen; Moult, John (2014) GWAS and drug targets. BMC Genomics 15 Suppl 4:S5
Feiglin, Ariel; Moult, John; Lee, Byungkook et al. (2012) Neighbor overlap is enriched in the yeast interaction network: analysis and implications. PLoS One 7:e39662
Shi, Zhen; Sellers, Jenn; Moult, John (2012) Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. Proteins 80:61-70
Shi, Zhen; Moult, John (2011) Structural and functional impact of cancer-related missense somatic mutations. J Mol Biol 413:495-512
Gorlatova, Natalia; Chao, Kinlin; Pal, Lipika R et al. (2011) Protein characterization of a candidate mechanism SNP for Crohn's disease: the macrophage stimulating protein R689C substitution. PLoS One 6:e27269
Yue, Peng; Moult, John (2006) Identification and analysis of deleterious human SNPs. J Mol Biol 356:1263-74
Yue, Peng; Melamud, Eugene; Moult, John (2006) SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 7:166
Yue, Peng; Li, Zhaolong; Moult, John (2005) Loss of protein structure stability as a major causative factor in monogenic disease. J Mol Biol 353:459-73
Wang, Zhen; Moult, John (2003) Three-dimensional structural location and molecular functional effects of missense SNPs in the T cell receptor Vbeta domain. Proteins 53:748-57