Since 2010, an international research team in the Genotype-Tissue Expression (GTEx) project has been investigating how genes are regulated and read in different tissue types. Now the scientists have published the final analysis of their data. Among other things, the results provide information about how individual genetic differences affect the risk of certain diseases. They also reveal how gender affects gene regulation in around 50 different tissue types.
Human genes provide the blueprint for proteins that fulfill many different functions in the body: for example, they transport metabolic products, enable cell movements, ward off infections, catalyze biochemical reactions or give cells structure. In theory, every single cell contains the blueprint for all proteins. Depending on whether this cell is in the brain, in the skin, in the blood or in the heart muscle, very different proteins are required and produced. The genes must therefore be regulated depending on the tissue type. The exact genes whose product is currently required in the respective tissue in the specific situation are read off.
Major project as a basis for further research
The data from an international team of researchers in the GTEx project now show how gene regulation differs from cell to cell, from tissue to tissue and from person to person. The scientists analyzed samples from around 50 different tissue types from 838 donors. The result is a detailed atlas of gene expression. This shows, among other things, how individual genetic differences influence gene regulation and thus also the risk of certain diseases. The researchers present the individual results in 15 publications, including in the journal Science.
“This study is a crowning achievement for which dozens of scientists have pooled their expertise,” says Tuuli Lappalainen from Columbia University, who played a leading role in the research. The collected data represent an important resource for further studies. They make it possible to understand the function of the human genome in more detail, to investigate the genetic basis of diseases more precisely, or to search for new targets for drugs.
Differences between men and women
One important finding is that an unexpected number of genes are influenced by gender. More than a third of all genes are read to different degrees in at least one tissue type in women and men. These genes are involved in a wide variety of biological functions, such as the absorption of drugs, lipid metabolism and the immune system. The individual effects are only minor – often smaller than gender-independent individual variations – but can be observed everywhere in the body.
Part of the differences can be explained by the fact that in women the second X chromosome is often not completely shut down, but a small number of the genes on it are also read. In fact, the clearest gender differences were found in genes located on the X chromosome. However, these made up only four percent of all gender-influenced genes. The far greater part of the genes, which are read to different degrees in women and men, are located on the other chromosomes. According to the researchers, these are presumably controlled by hormones and gender-specific epigenetic changes – deposits on the genome.
Importance for personalized medicine
The results can explain why women and men are differently susceptible to certain diseases, for example, and why some drugs work differently depending on their gender. Although it was previously assumed that hormones, environmental conditions, health behavior and genetic variations play a role, the underlying mechanisms were largely unknown. “These results suggest that gender differences in complex human traits are in part due to gender differences in gene regulation,” says Barbara Stranger of the University of Chicago. “In the future, this knowledge could contribute to personalized medicine, in which we consider gender as a significant component of individual characteristics.” The findings are also relevant for future research: “Our study reveals connections between genes and properties that would have been overlooked in gender-independent analyzes,” says Stranger’s colleague Meritxell Oliva.
In addition to gender, ethnicity is presumably also important, as the GTEx results suggest. However, this shows the limits of the study: Around 85 percent of the samples examined came from white Americans with European roots. In addition, two-thirds of the tissue donors were male and over half were older than 50 years. “In view of these limitations, it is even more surprising – and should be motivating for human geneticists – how many interindividual differences in gene expression there are in the individuals examined,” wrote Melissa Wilson of Arizona State University in a classifying comment in Science. “This should be a call to represent more human variation in future studies.”
Sources: François Aguet (The Broad Institute of MIT and Harvard, Cambridge) et al., Science, doi: 10.1126 / science.aaz1776; Meritxell Oliva (University of Chicago) et al., Science, doi: 10.1126 / science.aba3066