From the Literature

Scientists working on a far-reaching collaborative project to understand how variation in individuals’ DNA sequences affects gene expression in different tissues have published their latest insights, providing important information that may help uncover molecular mechanisms of genetic traits and diseases. The research is helping to crack the regulatory code of the human genome. “We have identified genetic sequence variants, or differences in DNA sequence between individuals, that affect expression for nearly every gene in the human genome,” said coauthor Alexis Battle, PhD, an assistant professor in the Department of Computer Science at Johns Hopkins University. “In this project, we specifically measure and describe the effects of these genetic differences on a large, diverse set of tissues, from brain to artery to heart, and show that genetic changes affect different tissues in unique ways.” When Dr Battle and her colleagues, who are all participating in the GTEx project (Genotype-Tissue Expression (GTEx) that was established in 2010, examined gene expression across 44 human tissues from 449 individuals, they identified 152 869 expression quantitative trait loci—or regions with genetic variations that influence gene expression—that lie within 1 Mb of target gene start sites. These cisexpression quantitative trait loci control nearly 20 000 genes, representing ≈80% of all protein-coding genes. GTEx is supported by the National Institutes Health’s Common Fund and administered by the National Human Genome Research Institute, the National Institute of Mental Health, and the National Cancer Institute. As described in their Nature paper, the scientists also identified interchromosomal genetic effects for 93 genes and 112 loci, allowing them to compare the local and distal impacts of genetic changes. Most of the transexpression quantitative trait loci, which control genes from afar, regulated genes in only 1 tissue or in a subset of related tissues. Experiments are underway to evaluate the functional properties of the numerous expression quantitative trait loci identified in this study. As part of the eGTEx project (Enhanced GTEx), scientists are collecting additional measurements from the GTEx samples, ranging from epigenetics to protein abundance. This will enable scientists to understand both upstream mechanisms and downstream consequences of regulatory changes across tissues. “Our results will help researchers understand the biological mechanisms underlying complex traits including cardiac diseases,” said Dr Battle. “Based on genome-wide association studies, there are numerous genetic variants known to be associated with cardiac traits but where the cellular mechanism is not understood. Our data can help identify which genes and tissues are affected by each variant, elucidating mechanism and potentially even suggesting candidate drug targets.” Three other studies from the GTEx project were published in the same issue of Nature. One specifically examined rare variants’ effects on gene expression, with a focus on individuals with extremely high or extremely low expression of a particular gene compared with the population. The study found that many individuals displaying abnormally high or low levels of gene expression in particular tissues have rare variants near the affected genes, and it provides a computational method for evaluating which rare variants in an individual genome are most likely to have regulatory effects. Another study that focused on X-chromosome inactivation found that ≈25% of genes on the X chromosome escape inactivation, providing a basis for sex-specific differences in gene expression. A third study that looked at how variants associated with altered gene expression can regulate RNA editing process found that RNA editing levels vary among organs, especially in nonrepetitive stretches of sequence. In addition to GTEx data, the research included hundreds of other primate and mouse samples, making it the most comprehensive atlas of RNA editing in tissues and species, and it has already uncovered unexpected and novel insights on the dynamic regulation of RNA editing. From the Literature