This is a renewal application for the Yale Center for Mendelian Genomics. The biology linking Mendelian mutations to traits has transformed our understanding of every organ system, identifying therapeutic targets, and allowing preclinical diagnosis and mitigation of disease risk. We know the consequence of mutation of fewer than 3,000 genes. With ~19,000 protein-coding genes, the vast majority of which are conserved across phylogeny, even allowing for 30% lethality, there are doubtless thousands of Mendelian loci awaiting discovery. The full utility of clinical sequencing will not be realized without bette understanding of the consequence of mutation of every gene. The advent of robust exome and genome sequencing allows unprecedented opportunity for discovery of new Mendelian trait loci. In the current cycle, by sequencing more than 7000 exomes from investigators world-wide we have identified 180 new Mendelian trait loci with high confidence, 35 phenotypic expansions, and hundreds more that are likely new trait loci across a range of traits and genetic mechanisms, including de novo mutations, incomplete penetrance, and complex rare recessive traits. Several new loci have immediate therapeutic implications. These results underscore that many new trait loci remain to be described and solved, motivating efforts to complete the human `knock out' map. We now propose, by building upon the current studies and through reduction in high quality exome cost to $330, to identify at least another 500 trait loci via the sequencing of more than 20,000 samples, advancing the understanding of genomes, health and disease.

Public Health Relevance

The vast majority of genomic variation in Mendelian disorders is due to variation in protein coding regions in the genome. Capture and sequencing of these regions allow for rapid identification of disease causing mutations, which will allow us t understand and dissect the biology of these disorders leading to better diagnostic and therapeutic tools. At Yale Center for Mendelian Genomics, we have already collected over 5,000 such samples and now propose to sequence these samples and additional ones available from other institutions using next generation technologies and share this data with the general scientific community.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
2UM1HG006504-05
Application #
9050136
Study Section
Special Emphasis Panel (ZHG1-HGR-P (O1))
Program Officer
Wang, Lu
Project Start
2011-12-05
Project End
2019-11-30
Budget Start
2016-01-14
Budget End
2016-11-30
Support Year
5
Fiscal Year
2016
Total Cost
$2,400,000
Indirect Cost
$962,156
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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