Abstract
Variation in gene expression is heritable and has been mapped to the genome in humans and model organisms as expression quantitative trait loci (eQTLs). We applied integrated genome-wide expression profiling and linkage analysis to the regulation of gene expression in fat, kidney, adrenal, and heart tissues using the BXH/HXB panel of rat recombinant inbred strains. Here, we report the influence of heritability and allelic effect of the quantitative trait locus on detection of cis- and trans-acting eQTLs and discuss how these factors operate in a tissue-specific context. We identified several hundred major eQTLs in each tissue and found that cis-acting eQTLs are highly heritable and easier to detect than trans-eQTLs. The proportion of heritable expression traits was similar in all tissues; however, heritability alone was not a reliable predictor of whether an eQTL will be detected. We empirically show how the use of heritability as a filter reduces the ability to discover trans-eQTLs, particularly for eQTLs with small effects. Only 3% of cis- and trans-eQTLs exhibited large allelic effects, explaining more than 40% of the phenotypic variance, suggestive of a highly polygenic control of gene expression. Power calculations indicated that, across tissues, minor differences in genetic effects are expected to have a significant impact on detection of trans-eQTLs. Trans-eQTLs generally show smaller effects than cis-eQTLs and have a higher false discovery rate, particularly in more heterogeneous tissues, suggesting that small biological variability, likely relating to tissue composition, may influence detection of trans-eQTLs in this system. We delineate the effects of genetic architecture on variation in gene expression and show the sensitivity of this experimental design to tissue sampling variability in large-scale eQTL studies.
Highlights
Quantitative variation in gene expression levels acts as an intermediate phenotype situated between genomic DNA sequence variation and more complex cellular, organ, or whole body phenotypes
Heritability of Gene Expression in recombinant inbred (RI) Strains Gene expression profiles and trait heritability (h2trait) across 30 RI strains were investigated in fat, kidney, adrenal, and left ventricle (LV) tissue for each transcript considered in this study
We investigated the overall sensitivity of the genetical genomics approach to discriminate between cis and trans regulation within and between tissues
Summary
Quantitative variation in gene expression levels acts as an intermediate phenotype situated between genomic DNA sequence variation and more complex cellular, organ, or whole body phenotypes. Gene expression can be mapped to the genome using standard linkage methods, allowing identification of expression quantitative trait loci (eQTLs), which represent genomic regions for the genetic control of gene expression [6]. This approach has been termed genetical genomics [7,8], and recent technological and methodological advances have made its large-scale application feasible at the level of the genome. By combining the genomic position of the gene encoding each transcript and the position of its eQTL, it is possible to discriminate between cis- and trans-regulatory control elements of gene expression for thousands of genes across the genome
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