Kellis set to guide MIT group in next stage of GTEx project, focusing on revealing disease susceptibility roots
Getting Down to the Nitty-Gritty of Genes and Disease: The GTEx Project's Next Phase
The National Institutes of Health (NIH) have poured money into eight new grants as part of a fresh wave of the Genotype-Tissue Expression (GTEx) project. This endeavor aims to scrutinize the impact of genomic diversity on gene expression and, eventually, human illness. The new phase will broaden GTEx's horizons, allowing it to assess a plethora of molecular phenotypes that could, in turn, influence human disease.
These grants target inter-individual differences in DNA accessibility, protein levels, telomere lengths, and DNA modifications from a diverse spectrum of tissue samples that collection kicked off in 2010 and spanned hundreds of individuals.
Manolis Kellis, professor of computer science at MIT and the Broad Institute of MIT and Harvard, will head the MIT project. With a focus on gauging shifts in gene regulatory element activity, Kellis and his team aspire to bridge the divide between genetic variation, gene expression, and human disease. Through direct observation of the outcomes of non-coding variants on gene regulation – even before they affect gene expression levels – they seek to advance our understanding of how genetics informs illness.
Kellis, Alexander Meissner, and Brad Bernstein from Harvard will spearhead this initiative in nine peripheral tissues that have roles in diabetes, heart disease, and cancer. Utilizing a method they've previously employed to analyze the regulatory circuitry of diverse human cell lines and tissues, the team plans to study how these elements vary across individuals.
"Genetic variants don't operate alone," Kellis asserts. "An individual's disease risk is the sum of a myriad of non-coding variants, which interact in multiple tissues, impact various genes, and ultimately impact cellular and organismal functions." This complexity makes it difficult to pinpoint the molecular causes of disease, as our measurements are removed from the molecular consequences of genetic variants. Kellis and his colleagues are thus concentrating on direct measurements of the activity of tens of thousands of regulatory regions in each individual and each tissue, to get a clearer view of the genetic machinery behind disease.
Most genetic variants that contribute to disease don't code for proteins. Instead, they assume subtle regulatory roles, such as modifying gene activity levels or affecting the chemical alterations – epigenomic marks – on DNA that determine which genes are active in specific cells. The resulting information will be made available through the GTEx community portal, serving as a guide for the regulatory models developed by Kellis and the broader computational biology community, and helping them in their pursuit of disease-causing mutations.
Kellis, a former MIT undergraduate and Ph.D. student, has won an array of accolades, including the U.S. Presidential Early Career Award in Science and Engineering (PECASE), the Alfred Sloan Foundation award, and the National Science Foundation CAREER award. His lab strives to build a comprehensive understanding of the human genome, melding computational integration of large-scale functional genomics, epigenomics, and comparative genomics.
Funded by the NIH Common Fund, GTEx's goal is to shed light on the genetic foundation of disease. By recognizing which genetic changes affect gene expression in specific tissues – the ones that may be more pertinent to certain diseases – the project enables researchers to single out molecular pathways involved in disease development. This knowledge boosts the development of targeted therapies and the progress of personalized medicine by unmasking how genetic, environmental, and behavioral factors converge to shape health outcomes.
For more information on the NIH Common Fund, visit http://commonfund.nih.gov.
Insight:In this new phase of the GTEx project, the team aims to uncover regulatory mechanisms by employing advanced techniques like causal network inference and Mendelian randomization. These methods help differentiate direct from indirect effects of genetic variants on gene expression and reveal relationships between expression quantitative trait loci (eQTLs), nearby (cis) and distant (trans) genes across nearly 50 different tissues. This information can support the development of targeted therapies and advancements in personalized medicine by identifying previously unknown regulatory mechanisms.
- The new phase of the Genotype-Tissue Expression (GTEx) project, funded by the National Institutes of Health (NIH), will focus on inter-individual differences in DNA accessibility, protein levels, telomere lengths, and DNA modifications across a diverse range of tissue samples.
- Manolis Kellis, a professor of computer science at MIT and the Broad Institute of MIT and Harvard, will lead an MIT project to assess shifts in gene regulatory element activity, aiming to bridge the divide between genetic variation, gene expression, and human disease.
- The research will concentrate on the regulatory role of most genetic variants that contribute to disease, including modifications of gene activity levels and the chemical alterations on DNA that determine gene activity in specific cells.
- Kellis and his team will study these regulatory elements in nine peripheral tissues that have roles in conditions such as diabetes, heart disease, and cancer.
- The resulting information will be made available through the GTEx community portal, serving as a guide for regulatory models developed by Kellis and the broader computational biology community, and potentially leading to the discovery of disease-causing mutations.
- This advancement in understanding the regulatory mechanisms of genes could support the development of targeted therapies, contribute to the progress of personalized medicine, and provide insights into how genetic, environmental, and behavioral factors influence health-and-wellness and mental-health conditions, including medical-conditions like heart disease and diabetes.
