Revealing the architecture of gene regulation: the promise of eQTL studies

Abstract

Expression quantitative trait loci (eQTL) mapping studies have become a widely used tool for identifying genetic variants that affect gene regulation. In these studies, expression levels are viewed as quantitative traits, and gene expression phenotypes are mapped to particular genomic loci by combining studies of variation in gene expression patterns with genome-wide genotyping. Results from recent eQTL mapping studies have revealed substantial heritable variation in gene expression within and between populations. In many cases, genetic factors that influence gene expression levels can be mapped to proximal (putatively cis) eQTLs and, less often, to distal (putatively trans) eQTLs. Beyond providing great insight into the biology of gene regulation, a combination of eQTL studies with results from traditional linkage or association studies of human disease may help predict a specific regulatory role for polymorphic sites previously associated with disease.

Figure 1

Example of an expression quantitative trait loci (eQTL) for the HLA-C gene in the HapMap European samples (data from Ref. [55]). (a) Plot of •log(P values) for the association between individual single nucleotide polymorphisms (SNPs) and expression of HLA-C. The location of the gene is indicated by the small red bar at the bottom of the figure, and the x-axis measures location relative to the transcription start site (TSS). Each data point is for a single SNP. (b) Individual expression levels of HLA-C, grouped according to the genotype of the most significant SNP in the region (rs2249741; indicated by the red data point in panel (a). Interestingly, one of the SNPs in the signal peak in panel (a) (rs92644942) has also been associated with HIV set point, suggesting that higher expression of HLA-C can help reduce HIV viral load [62].

Figure 2

Breeding designs commonly used in model organism expression quantitative trait loci (eQTL) studies. The original inbred lines are shaded in different colors to track transmission of segments from one pair of homologous chromosomes. However, as inbred lines 1 and 2 undoubtedly are not polymorphic for many alleles, the actual genotypes at many marker loci on the grey and black chromosomes will be the same. (a) F2 design. Two inbred lines are crossed to form a heterozygous but identical F1 generation. These F1 individuals are then crossed to form an F2 generation. (b) Backcross design. Two inbred lines are crossed to form an F1 generation. F1 individuals are then backcrossed to one of the inbred parents to form a B1 generation. (c) Recombinant inbred lines. Inbreeding from the F2 generation on eventually results in near homozygous individuals with a mixture of markers from the original inbred lines. One such line is depicted starting from a brother-sister pair of F2 individuals. Different recombinant lines can be created by crossing different brother-sister pairs.