NEW YORK (GenomeWeb) – Researchers have published the first analyses from the initial pilot stage of the Genotype-Tissue Expression (GTEx) project, an effort coordinated by the National Human Genome Research Institute to investigate the genetic basis of variation in transcript abundance, or gene expression, across different body tissues.
The results appeared today in Science in three separate studies, which together offer novel insights into the link between genetic variants and gene expression, the distribution of gene expression across tissues, and the effect of truncated protein variants on this tissue-specific expression.
Overall, GTEx will eventually compare whole-genome sequence variation with RNA sequencing data from about 1,000 postmortem donors across more than 50 tissue types.
The hope is that a better understanding of the functional consequences of genetic variation will help researchers uncover how the thousands of disease-associated variants discovered in GWAS and other studies affect disease risk among healthy people.
Despite dramatic advances in our understanding of the association of genetic alterations with disease, and that the majority of common polymorphisms associated with disease risk act by modulating gene expression, scientists still understand precious little about precisely how genetic changes affect the expression of genes across different individuals and in different tissues of the body.
The main GTEx report, authored by the consortium as a whole, provides a comprehensive look at the role of regulatory variants and the tissues in which they act across the project's 175 pilot subjects.
The investigators performed 76-base-pair, paired-end mRNA sequencing on a total of 1,641 samples from 43 tissue sites, including 29 solid-organ tissues, 11 brain subregions, whole blood, and two cell lines derived from donor blood and skin samples.
In addition to reporting the patterns of expression of 53,934 transcribed genes across the different studied tissues, the team also attempted to uncover novel expression quantitative trait loci (eQTLs).
In a perspective accompanying the three studies in Science, the Georgia Institute of Technology's Greg Gibson wrote that one of the major contributions of these first GTEx papers is a quantification of the relative contributions of these eQTLs in different tissues.
Overall, the consortium's main study found that around half of all identified cis-eQTLs — eQTLs that act in cis to the gene — particularly those proximal to a promoter, were active across the majority of tissues. The other half tended to be specific to just one or two tissues.
The study also found evidence for the existence of loci that appear to influence the co-regulation of multiple genes.
According to the authors, genes often appear to be organized into expression groups or modules. Even if located on different chromosomes, certain collections of genes tend to have similar expression levels.
In the GTEx pilot study, investigators detected 117 of these modules made up of between 25 and about 400 transcripts. While most genes appeared to remain in the same module or switched their allegiance only to other modules with similar gene expression across different tissues, the researchers did see that a significant number of genes — 3,965 genes or 21 percent of the total —switched to modules with clearly different expression levels.
The team then looked for neighboring SNPs that were correlated with these module membership switches, what they call module-switching QTLs (modQTLs).
Overall, they found 2,102 modQTLs associated with statistically significant switching between dissimilar gene modules, suggesting that genetic variation for the identified genes leads to changes in multi-tissue regulatory processes.
Alongside the main publication, researchers from the consortium also published two additional studies. In one, a group led by Marta Melé of the Center for Genomic Regulation in Barcelona, provided an added overview of differences in the transcriptome across different tissues and across individuals in the pilot cohort.
According to the authors, the analysis found that tissues exhibit characteristic transcriptional signatures that are dominated by a relatively small number of genes. Few, however, are exclusive to a particular tissue.
In a final paper, researchers led by the Wellcome Trust Centre for Human Genetics' Manuel Rivas also reported specifically on the effect that protein-truncating variants have on transcription across tissues.
When data from the full GTEx study of closer to 1,000 individuals is available in about two years, the expectation is that the results will confirm these early discoveries in the pilot cohort, and will also allow greater understanding of individual mechanisms, for example the modQTL architecture controlling genes' movement from one expression module to another.
More ambitious GTEx projects moving forward might also include "evaluating how genetic regulatory effects vary in the context of disease and across environments [using] genotype-tissue expression from patients who have chronic diseases or have lived with different lifestyles or environmental exposures such as toxins or severe socioeconomic stress," Gibson wrote.
Even more distant is the hope that the project will be a springboard for incorporating information about the connection between DNA sequence and gene expression into the practice of personalized medicine.
"Although there is justifiable excitement about the ability of DNA sequencing to identify the causes of congenital abnormalities, to predict the progression of tumors, and to personalize the prescription of drugs, the static genome has its limitations," Gibson wrote. "If, 20 years from now, gene expression profiling is incorporated side-by-side with genotype analysis as a standard component of medical diagnostics, the GTEx project will be seen to have brought us closer to realization of this vision."
According to Gibson, the most obvious immediate implication of the GTEx results in this vein is that they validate important inferences from other studies, namely that disease-associated variants appear to be enriched in the vicinity of genes that are more active in a particular disease-relevant tissue, for example neurons in psychiatric disorders.
"GTEx provides direct evidence that this is the case, and the project's accompanying portal allows anyone to look up in which tissue a disease variant influences the expression of a nearby gene in a particular direction," he wrote.