A comprehensive atlas of variation in gene expression across diverse tissues of the human body and among individuals is presented in a package of articles published in Nature and Nature Genetics this week. The findings provide new insights into the associations between genetic variation and gene expression in healthy tissue, and could reveal new clues into the molecular origins of diseases.
The human genome encodes instructions for the regulation of gene expression, which varies across different cell types - giving rise to diverse tissues with distinct functions - and across individuals. The genetic variants that drive these differences tend to lie within non-coding regions of the genome, which determine how and when they are expressed. However, studies of how gene regulation and gene expression vary across human tissues and individuals have, thus far, remained limited.
The Genotype Tissue Expression (GTEx) consortium collected and studied more than 7,000 post-mortem samples from 449 otherwise healthy human donors across 44 tissues (42 distinct tissue types). The authors used the samples - which included 31 solid-organ tissues, ten brain subregions, whole blood, and two cell lines derived from donor blood and skin - to study how gene expression varies across different tissues and individuals. Reporting in Nature, they use a strategy called expression quantitative trait loci (eQTL) mapping to show that the majority of human genes are affected by local genetic variation, whereby genetic variants are located close to the affected gene. They also identified 93 genes whose expression is affected by genetic variants located more remotely, including on a different chromosome.
Also in Nature, a second paper examines the role of rare variants in gene expression, while in two further papers, the authors use GTEx data to explore how genetic variants associated with gene expression can regulate the phenomena of RNA editing and X-chromosome inactivation. A related Commentary in Nature Genetics introduces the Enhancing GTEx project, which extends the GTEx project by providing a resource for studying how genetic differences cascade through molecular phenotypes to influence human health.
Together, these findings underscore the value of data from multiple individuals and multiple tissues in efforts to identify the genes and mechanisms that underlie human-disease associated variation. “This involved a heroic, collaborative effort to overcome the ethical, legal and technical challenges associated with obtaining post-mortem samples on a large scale,” write Michelle Ward and Yoav Gilad in an accompanying News & Views article. “The extensive catalogue generated by the GTEx consortium takes us one step closer to decoding the regulatory code of the genome. The consequences of genetic variation on gene expression are gradually becoming clearer.”