New insights into how DNA differences influence gene activity, disease susceptibility

Researchers funded by the National Institutes of Health Genotype-Tissue Expression (GTEx) project have created a new and much-anticipated data resource to help establish how differences in an individual's genomic make-up can affect gene activity and contribute to disease. The new resource will enable scientists to examine the underlying genomics of many different human tissues and cells at the same time, and promises to open new avenues to the study and understanding of human biology.


GTEx investigators reported initial findings from a two-year pilot study in several papers. These efforts provide new insights into how genomic variants - inherited spelling differences in the DNA code - control how, when and how much genes are turned on and off in different tissues, and can predispose people to diseases such as cancer, heart disease and diabetes.


'GTEx was designed to sample as many tissues as possible from a large number of individuals in order to understand the causal effects of genes and variants, and which tissues contribute to predisposition to disease,' said Emmanouil Dermitzakis, Ph.D., professor of genetics at the University of Geneva Faculty of Medicine, Switzerland, and a corresponding author on the main Science paper. 'The number of tissues examined in GTEx provides an unprecedented depth of genomic variation. It gives us unique insights into how people differ in gene expression in tissues and organs.'


In the main paper, researchers analysed the gene activity readouts of more than 1,600 tissue samples collected from 175 individuals and 43 different tissues types. One way that researchers evaluate gene activity is to measure RNA, which is the readout from the genome's DNA instructions. Investigators focused much of their analyses on samples from the nine most available tissue types: fat, heart, lung, skeletal muscle, skin, thyroid, blood, and tibial artery and nerve.


The genomic blueprint of every cell is the same, but what makes a kidney cell different from a liver cell is the set of genes that are turned on (expressed) and off over time and the level at which those genes are expressed. GTEx investigators used a methodology - expression quantitative trait locus (eQTL) analysis - to gauge how variants affect gene expression activity. An eQTL is an association between a variant at a specific genomic location and the level of activity of a gene in a particular tissue. One of the goals of GTEx is to identify eQTLs for all genes and assess whether or not their effects are shared among multiple tissues.


Investigators discovered a set of variants with common activity among the different tissue types. In fact, about half of the eQTLs for protein-coding genes were active in all nine tissues. They identified approximately 900 to 2,200 eQTL genes - genes linked to nearby genomic variants - for each of the nine tissues studied, and 6,486 eQTL genes across all the tissues. 'We didn't know how specific this regulation would be in different tissues,' said co-corresponding author Kristin Ardlie, Ph.D., who directs the GTEx Laboratory Data Analysis and Coordination Center at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. 'The analysis showed a large number of variants whose effects are common across tissues, and at the same time, there are subsets of variants whose effects are tissue-specific.'


Comparing tissue-specific eQTLs with genetic disease associations might help provide insights into which tissues are the most relevant to a disease. The researchers also found a great deal of eQTL sharing among tissues, which can help explain how genomic variants affect the different tissues in which they are active.

National Human Genome research Institute