Global properties and functional complexity of human gene regulatory variation

Abstract

Identification and functional interpretation of gene regulatory variants is a major focus of modern genomics. The application of genetic mapping to molecular and cellular traits has enabled the detection of regulatory variation on genome-wide scales and revealed an enormous diversity of regulatory architecture in humans and other species. In this review I summarise the insights gained and questions raised by a decade of genetic mapping of gene expression variation. I discuss recent extensions of this approach using alternative molecular phenotypes that have revealed some of the biological mechanisms that drive gene expression variation between individuals. Finally, I highlight outstanding problems and future directions for development.

Figure 1. Three examples of alternative biological routes to gene expression variation identified using alternative molecular phenotypes from the recent literature.

(A) A joint DNase-sensitivity/eQTL in the gene SLFN5 from . The left-hand panel shows the landscape of open chromatin in a region ∼10 kb upstream of the gene TSS across 70 individuals grouped according to genotype at SNP rs11080327. The SNP is located in an interferon stimulated response element (inset), a TFBS that binds a range of related immune response TFs. The right-hand panel shows RNA-seq read depth across the transcript region, with the gene annotation from ENSEMBL underneath. This plot has been shortened slightly from the original for formatting reasons. Adapted with permission from . (B) A splice variant that alters both the expression level and relative isoform abundance in the gene MRPL43 from . The top panel shows RNA-seq read depth in two individuals that are homozygous or heterozygous for a SNP (rs2863095) immediately downstream of a splice donor site in exon 3. Below are shown the transcript annotations inferred from RNA-seq. The pie chart shows the relative isoform abundance usage in the two individuals, while the height of the pie chart reflects overall gene expression, summed over all transcripts. The star shows the location of the splice polymorphism in the transcript. Adapted with permission from . (C) An example of a SNP (rs10954213) that alters 3′ polyadenylation site usage in IRF5 from . Shown is the transcript annotation with the two alternative polyadenylation sites used, and the 3′ paired end RNA-seq data from six individuals with read pairs from each genotype colored dark red, blue, or green and the intervening sequence fragment colored pale red, blue, or green. Adapted with permission from .