The GTEx project is a step forward towards understanding the human genome
The first results of the work of the consortium for the study of tissue genotypes (Genotype-Tissue Expression, GTEx) open up to specialists a new vision of how genomic variations regulate the activation or inactivation of genes in various tissues, as well as how this can make people predisposed to diseases such as cancer, heart disease and diabetes mellitus.
Despite the fact that all cells of the body have identical genetic material, the vast majority of them are specific to a particular tissue or organ. This is due to the regulation of gene expression. In other words, each cell uses a certain set of genes, according to the instructions encoded in which it acquires its specificity. The goal of the GTEx project, launched in 2010 by the US National Institutes of Health, is to create a reference database and a tissue bank that will allow scientists to study the influence of genomic variants on gene activity and predisposition of people to various diseases.
One of the first studies conducted within the framework of this project by the laboratory of Professor Roderic Guigo from the Center for Genomic Regulation in Barcelona, together with colleagues from Harvard University and the Massachusetts Institute of Technology, was devoted to studying the variability of gene expression in the genomes of different individuals, as well as in different organs and tissues. The results obtained by the authors indicate that much more pronounced differences in gene activity are characteristic of organs and tissues, and not for individuals. Interindividual variations account for approximately 5% of the entire spectrum of gene activity variability.
The genes showing the most pronounced expression variability between individuals are related to gender, ethnicity, and age. Thus, gender-related differences extend to more than 750 genes, the vast majority of which are expressed by mammary gland cells. At the same time, differences in gene expression between people of African and European descent are concentrated in skin cells. The authors also note that the expression levels of approximately 2,000 genes corresponding to 10% of the total genetic material vary significantly depending on age. This list includes genes associated with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
The relationship between gene expression and tissue specificity was less clear than expected. For example, assuming that the cells included in the structure of the same tissue are similar to each other, the researchers expected to identify tissue-specific profiles of gene expression. However, despite the fact that tissues and organs do have specific profiles of gene activity, the authors identified only single genes expressed exclusively in any particular tissue or organ.
As part of the project, the researchers plan to analyze the largest possible number of samples of various tissues obtained during autopsies and operations to extract organs from a large number of cadaveric donors. They have already collected samples of more than 30 types of tissues and are currently analyzing DNA and RNA isolated from these samples. By the end of 2015, it is planned to analyze about 20,000 tissue samples from about 1,000 cadaver donors.
Traditionally, to study the role of genomic variants in the development of various diseases, scientists conduct genome-wide studies of associations. By comparing thousands of genomic variants of people with a particular disease with thousands of genomic variants of people without this disease, they can isolate associations between diseases and genomic variants, as well as certain regions of the genome. However, these associations do not always explain what certain genomic variants do and what effect they have on the biological mechanisms and development of the disease. At the same time, the data obtained within the framework of GTEx allows us to ask previously impossible questions about genetic variants and their effect on gene expression both in individual and in many tissues at once.
Articles of the GTEX Consortium The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans, as well as Mele et al. The human transcriptome across tissues and individuals and Rivas et al. The effect of predicted protein-truncating genetic variants on the human transcriptome is published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Centre for Genomic Regulation:
Gene expression is key to understanding differences between individuals and disease susceptibility.
12.05.2015