A multitude of peer-reviewed studies has come out of the Genotype-Tissue Expression (GTEx) Consortium, a multi-institutional effort that aims to shed new light on various aspects of human genetics. One recent study from the consortium members examined how small changes in the genome, or genetic variants, affect the activity of a gene. Another paper examined a person's risk of developing certain diseases or characteristics because of such variants it is one of fifteen studies involving GTEx that have been recently reported in Science.
The GTEx dataset was generated from RNA sequencing, which provides a snapshot of the genes that are active in a cell. It was performed on 49 post-mortem tissues collected from 838 volunteers: 15,201 RNA-sequencing samples in all.
This final set of studies completes the GTEx project, and now there is an atlas of genetic variants that influence gene expression, cellular changes that may be occurring due to these variations, and how they affect the risk of developing both common and rare diseases.
Since many genetic variants that have been associated with an increased risk of disease do not sit in portions of the genome that code for protein, it's been suggested that these disease risk-associated variants are acting by changing gene regulation. GTEx has helped provide some insight into this hypothesis.
"This study is a crowning collaborative achievement, in which dozens of scientists combined their expertise to build a map of genetic regulatory variation and to understand the core biology of genetic variation," said Dr. Tuuli Lappalainen, Ph.D., Core Faculty Member at the New York Genome Center. "GTEx resources also empower other studies by the genomics community, including disease-specific research, the identification of targets for drug development, and understanding genome function."
The researchers applied a tool called expression quantitative trait locus (eQTL) analysis to find changes in the genetic sequence, or variants, which affect the expression of a gene. They included QTLs that affect how RNA is spliced, which creates different instructions for making a protein. This approach has identified eQTLs and sQTLs for most human genes that are expressed in 49 tissues. The GTEx data was integrated with genome-wide association studies to gain insight into the mechanistic changes induced by alterations in regulation or splicing that promote disease development.
Another GTEx study reported in Science assessed how genetic variants affect gene expression levels in different tissue types. "Our approach allowed mapping genetic variants that affect gene regulation in different cell types for a large number of tissues. This enables better discovery of mechanisms behind genetic variants that affect disease risk," said Sarah Kim-Hellmuth, M.D., Ph.D., a former Postdoctoral Fellow in the Lappalainen lab and first study author.