Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Genetic Basis for Variation in Transcript Abundance


Science 8 May 2015: Vol. 348 no. 6235 pp. 640-641

GTEx detects genetic effects

Greg Gibson

School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA


One of the lessons from the past several years of genomic analysis is that well-conceived, ambitious, and thoughtfully analyzed genetic studies carried out by large consortia can advance the field in giant leaps.

GTEx is an effort coordinated by the U.S. National Human Genome Research Institute to understand the genetic basis for variation among individuals in transcript abundance across many tissues. Hitherto, our knowledge of the genetics of gene expression in humans has derived mostly from studies of blood, lymphoblast cell lines, and isolated studies of accessible tissues such as fat or skin. The plan for GTEx is to associate whole-genome sequence variation with RNA sequencing data for more than 50 tissue types from almost 1000 next-of-kin consented postmortem donors. This knowledge will provide direct evidence addressing the function of the many thousands of disease-associated variants supplied by genome-wide association studies (GWAS) and will illuminate mechanisms of variation for disease risk among healthy people. The pilot phase results are based on data from the first 237 donors, of whom around 100 have RNA samples analyzed in 9 tissues, with data from smaller subsets of donors available for 33 other tissues.

Researchers report on the effect that protein-truncating variants have on human transcription, generating a quantitative model of how nonsense-mediated decay (the elimination of transcripts that contain a premature stop codon) varies across tissues and may be genetically regulated.

Common regulatory polymorphisms (expression quantitative trait loci, or cis-eQTLs) located within a few hundred kilobases of a gene significantly influence the expression of at least half of all genes in one tissue or another.

The largest eQTL effects can be detected with sample sizes of as few as 100 individuals. It is to be expected that rare variants also contribute to disease, although their discovery is in its infancy. Epigenetic influences such as chromatin modification and microRNA regulation certainly also explain substantial amounts of the variance. A critical feature of transcriptional variation is the very high degree of co-regulation, sometimes of thousands of genes. This can be attributed to the collective effects of trans-acting regulatory factors (transcription factors, hormones, environmental agents) as well as variation in the abundance of cell types within tissues.

One of the big surprises reported is the discovery of module QTLs (modQTLs), which are regulatory variants that influence the co-regulation of gene expression. The idea is that most genes are organized into expression modules. Even though they are located on different chromosomes, they tend to be have similar expression levels. Often, many genes in a module share a function such as controlling the cell division cycle. The reported analysis finds 117 modules of between 25 and 414 transcripts each.

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