Principal Investigator Manolis Kellis (Kamvysselis)
Project Website http://commonfund.nih.gov/GTEx/index
The National Institutes of Health (NIH) has awarded eight grants as part of a new phase of the Genotype-Tissue Expression (GTEx) project to study the role that genomic variation plays in modulating gene expression and, ultimately, human disease. This new phase enhances GTEx to measure, in addition to gene expression levels, a diversity of molecular phenotypes that may ultimately influence human disease. The new grants explore inter-individual variation in DNA accessibility, protein levels, telomere lengths, and DNA modifications from diverse tissue samples whose collection began in 2010 across hundreds of individuals.
Professor Kellis will lead the MIT project. The goal is to measure changes in gene regulatory element activity in order to bridge the gap between genetic variation, gene expression, and human disease, by directly measuring the consequences of non-coding variants on gene regulation even before they affect gene expression levels.
Specifically, Kellis and his collaborators Alexander Meissner and Brad Bernstein from Harvard will work to characterize the epigenomic effects of genetic variation in nine peripheral tissues with roles in diabetes, heart disease, and cancer. The group will take an epigenomics approach that they previously used to study the regulatory circuitry of diverse human cell lines and tissues, and apply it to study how these elements vary across individuals.
This strategy is based on the recognition that most genetic variants linked to disease don’t code for proteins, but instead have subtle gene regulatory roles, such as altering gene activity levels, or affecting the chemical modifications — epigenomic marks — made to DNA that influence which genes are active in which cells. The resulting information will be widely disseminated through the GTEx community portal, and used to guide the regulatory models developed by Kellis and the broader computational biology community, to guide their search for disease-causing mutations.
The NIH Common Fund, which supports the GTEx, encourages collaboration and supports a series of high impact, trans-NIH programs. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone.