The Genotype-Tissue Expression project
A more personal gene expression catalogue
We meet a new frontier in biomedical research with publications from the Genotype-Tissue Expression (GTEx) Consortium, that of cataloguing genetic variation and its influence on gene expression within and between all major tissues in the human body. The GTEx project was proposed in 2008 with the lofty goals of establishing a resource database and associated tissue biobank to study the relationship between genetic variation and gene expression in all major human tissues across 1000 individuals. This nearly decade long effort now brings the largest multi-tissue research study using postmortem donors, which entailed overcoming many challenges including developing protocols to obtain high quality biospecimens as well as establishing a framework for the ethical, legal and social issues surrounding postmortem donation.
In this second phase of the project, GTEx profiles genetic variation, gene expression, histological and clinical data for 449 human donors across 44 tissues. The authors use the GTEx data to analyze the influence of genetic variation on gene expression within and between tissues and individuals. These studies have helped to crack the regulatory code of our genome, demonstrating that the expression of nearly all genes are regulated by genetic variation, most of which is located close to the affected gene.
GTEx Resources
The GTEx Portal https://www.gtexportal.org
NIH news release: NIH completes atlas of human DNA differences that influence gene expression
GTEx Pilot Phase publications
The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
The GTEx Consortium. Science. 8 May 2015: Vol 348 no. 6235 pp 648-660. DOI: 10.1126/science.
The paper presents an analysis of RNA seq data from 1641 samples across 43 tissues and 175 individuals to provide an understanding of the cellular and biological consequences of genetic variation and the heterogeneity of its effects across diverse human tissues. The paper catalogs thousands of tissue-specific and shared regulatory eQTL variants, describes complex cross-tissue and individual networks, and identifies signals from GWAS studies explained by eQTLs.
The human transcriptome across tissues and individuals
Melé et al. Science. 8 May 2015: Vol 348 no. 6235 pp 660-665. DOI: 10.1126/science.aaa0355.
The paper used RNA sequence data generated by the GTEx project to investigate the patterns of transcriptome variation across individuals and tissues. Gene expression varied much more across tissues than individuals, but genes exhibiting relatively high inter-individual variation in expression include candidates for diseases associated with sex, ethnicity, and age.
Effect of predicted protein-truncating genetic variants on the human transcriptome
Rivas et al. Science. 8 May 2015: Vol 348 no. 6235 pp 666-669. DOI: 10.1126/science.1261877.
This study examines the impact of variants, that have a high probability of causing proteins to be missing or incomplete (Protein-truncating variants), on gene expression levels. Tissue-specific and positional effects on nonsense-mediated transcript decay were quantified and the paper presents an improved predictive model for this decay. The results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
The landscape of genomic imprinting across diverse adult human tissues
Baran et al. Genome Research. 8 May 2015. DOI: 10.1101/gr.192278.115
This study uses allele-specific expression in the GTEx pilot data to detect parental expression by genomic imprinting and characterize the imprinting map across a diverse set of human tissues.
Sharing and specificity of co-expression networks across 35 human tissues
Pierson et al. PLOS Computational Biology. 11(5):e1004220. DOI:10.137 1/journal.pcbi.1004220 8 May 2015.
Co-expression networks provide insight into gene function, and are widely used in interpreting disease-associated genes and loci. This paper presents tissue-specific co-expression networks learned using expression data for 35 human tissues from the GTEx project, enabling a refined understanding of tissue-specificity of gene function and regulation. The study describes a novel method for jointly learning a set of related networks, improving accuracy and utility of the resulting networks.
Assessing allele-specific expression across multiple tissues from RNA-seq read data. Pirinen et al. Bioinformatics. DOI: 10.1093/bioinformatics/btv074
The paper presents a statistical method to compare different patterns of allele specific expression across tissues and to classify genetic variants according to their impact on the tissue-wide expression profile. The study adopts a Bayesian model comparison framework to allow a simultaneous comparison between several cross-tissue models for the observed data.
A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Carithers et al. Biopreservation and Biobanking. October 2015, 13(5): 311-319. doi:10.1089/bio.2015.0032.
The paper describes how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project.
RNA-SeQC: RNA-seq metrics for quality control and process optimization DeLuca DS, Levin JZ, Sivachenko A, Fennell T, Nazaire MD, Williams C, Reich M, Winckler W, Getz G. Bioinformatics. 2012 Jun 1;28(11):1530-2. doi: 10.1093/bioinformatics/bts196. Epub 2012 Apr 25.
