Genetics of human gene expression: mapping DNA variants that influence gene expression

Abstract

There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis- and trans-acting DNA variants that influence expression levels of human genes. New insights into human gene regulation are emerging from genetic analyses of gene expression in cells at rest and following exposure to stimuli. The integration of these genetic mapping results with data from co-expression networks is leading to a better understanding of how expression levels of individual genes are regulated and how genes interact with each other. These findings are important for basic understanding of gene regulation and of diseases that result from disruption of normal gene regulation.

Figure 1. Inter-individual variation in gene expression levels

Shown are the expression levels of 12 genes in unrelated individuals. Each circle represents the expression level in one individual. The expression levels of two genes, PARK7 and ATP5J2, are less variable than the other 10 genes, even though the 12 genes were measured using the same cells and methods.

Figure 2. Effect of cis- and trans-acting DNA variants on expression levels of genes

Polymorphic forms of regulators that act in cis (a) or in trans (b) to the target genes (also called local and distal regulators, respectively) result in variation in expression levels of the target genes. Cis-acting variants are found close to the target genes and trans-acting variants are located far from the target genes, often on another chromosome. Different allelic forms of the cis- and trans-acting variants have different influence on gene expression. In this example, individuals with the G variant of the cis regulator have a higher expression level of the target gene than individuals with the C variant of the regulator. Similarly, individuals with the A variant of the trans regulator have a higher expression level of the target gene than those with the T variant of the regulator.

Figure 3. The expression level of copine I (CPNE1) is cis regulated

Results from linkage (a) and association (b) studies show that the polymorphic regulator of expression level of CPNE1 is found on chromosome 20, close to the target gene (CPNE1 is located on chromosome 20). A linear regression analysis of the expression level of CPNE1 on the genotypes of the SNP rs3787165 in CPNE1 (c) uncovered marked association between the SNP genotypes and expression levels of CPNE1; TT is associated with higher expression.

Figure 4. The expression level of programmed cell death 10 (PDCD10) is trans regulated

PDCD10 is located on chromosome 3. Linkage results show that regulators of this gene are located on chromosomes 4 and 19.