New GTEx project tackles DNA’s genetic ‘switchboard’

May 15, 2015

The link between inherited DNA variation and numerous diseases has been well established, but an important question still looms – What are the precise mechanisms linking genetic variation to disease? Despite decades of research and the development of sophisticated tools, important gaps remain in understanding human genetic processes, which vary widely across the organs and tissues of the body.

Described in an article published May 8 in the journal Science, the Genotype-Tissue Expression (GTEx) project, funded by the National Institutes of Health, aims to fill these gaps by looking at ways genetic variation affects gene expression.

Dr. Andrew Nobel

Andrew Nobel, PhD, professor of biostatistics at The University of North Carolina at Chapel Hill’s Gillings School of Global Public Health and study co-author, said the research is analogous to deciphering genetic “recipes.”

“Our DNA acts like a cookbook, containing recipes for distinct tissues – such as skin, blood, lung, heart and brain – which we all share,” said Nobel, who is also professor of statistics and operations research in the UNC College of Arts and Sciences. “Unlike an ordinary cookbook, the recipes in DNA have been broken up into microscopic instructions and spread throughout our chromosomes. Some of these instructions are unique to specific tissues or tissue groups, while others are shared by most, or all, tissues. Understanding how different genetic instructions are carried out in different tissues is an important scientific problem, and an important first step in understanding mechanisms that link genetic variation and disease.’’

Fred Wright, PhD, professor of statistics and biological sciences at N.C. State University and study co-author, agreed.

“We have little understanding of how genetic variants actually cause disease because we haven’t been able to look at the gene expression part of the equation,” Wright said. “GTEx aims to fill the knowledge gap between the DNA you’re born with and actual disease outcomes.”

Another way to think of DNA is as the “controller of a giant genetic switchboard,” Nobel said. “When DNA switches on a gene, the gene produces proteins with specific functions. In the case of many common diseases, relatively small changes in protein output can have profound effects upon disease risk.”

The GTEx project took samples of a large variety of tissues from 175 recently deceased individuals, measuring gene expression in those tissues. First, researchers established that nearly normal gene activity persists for several hours after death. Then the major task of connecting variation in DNA to expression began. This is where Wright, Nobel and their team came in – to find meaningful correlations within the wealth of experimental and biological data.

The researchers found that DNA variants that affect expression tend to do so either in one tissue alone, or in all the examined tissues. Groups within the GTEx project now are comparing results of the model to each variant-disease association, helping further narrow which genes the variants affect – and in which tissue. The work may bring scientists one step closer to personalized therapies for numerous diseases.

“We found that DNA variants affecting expression tend to do so either in very few tissues or in almost all tissues,” Nobel, who is also a professor of statistics and operation research in the College of Liberal Arts and Sciences, said. “As data from more tissues become available, we expect a more complex picture to emerge, in which we identify variants affecting the expression of blocks of biologically related tissues.”

Nobel said that researchers within GTEx are now comparing their results and those of other analysis groups to existing studies of variant-disease association, with the immediate goal of better identifying variants and genes associated with known diseases.

“It may be some way off, but a long-term goal of the GTEx project, and our analysis, is to facilitate personalized (targeted) therapies for numerous diseases,” he said.