The Contribution of RNA Decay Quantitative Trait Loci to Inter-Individual Variation in Steady-State Gene Expression Levels

Recent gene expression QTL (eQTL) mapping studies have provided considerable insight into the genetic basis for inter-individual regulatory variation. However, a limitation of all eQTL studies to date, which have used measurements of steady-state gene expression levels, is the inability to directly distinguish between variation in transcription and decay rates. To address this gap, we performed a genome-wide study of variation in gene-specific mRNA decay rates across individuals. Using a time-course study design, we estimated mRNA decay rates for over 16,000 genes in 70 Yoruban HapMap lymphoblastoid cell lines (LCLs), for which extensive genotyping data are available. Considering mRNA decay rates across genes, we found that: (i) as expected, highly expressed genes are generally associated with lower mRNA decay rates, (ii) genes with rapid mRNA decay rates are enriched with putative binding sites for miRNA and RNA binding proteins, and (iii) genes with similar functional roles tend to exhibit correlated rates of mRNA decay. Focusing on variation in mRNA decay across individuals, we estimate that steady-state expression levels are significantly correlated with variation in decay rates in 10% of genes. Somewhat counter-intuitively, for about half of these genes, higher expression is associated with faster decay rates, possibly due to a coupling of mRNA decay with transcriptional processes in genes involved in rapid cellular responses. Finally, we used these data to map genetic variation that is specifically associated with variation in mRNA decay rates across individuals. We found 195 such loci, which we named RNA decay quantitative trait loci (“rdQTLs”). All the observed rdQTLs are located near the regulated genes and therefore are assumed to act in cis. By analyzing our data within the context of known steady-state eQTLs, we estimate that a substantial fraction of eQTLs are associated with inter-individual variation in mRNA decay rates.
Author Summary Recent studies of functional genetic variation in humans have identified numerous loci that are associated with variation in gene expression levels, called expression quantitative trait loci (eQTLs). The mechanisms by which these loci affect gene expression, however, are still largely unknown. Specifically, since most studies rely on measures of steady-state gene expression levels, they are unable to distinguish between the relative influences of either transcriptional- or decay-related processes. To address this gap, we examined the specific impact of mRNA decay processes on steady-state gene expression levels for over 16,000 genes in human lymphoblastoid cell lines. By characterizing decay rates in 70 individuals, we show that steady-state expression levels are significantly influenced by variation in decay rates for 10% of genes. Yet, for roughly half of these genes, we find that individuals with higher expression levels also have faster decay rates. This pattern points to a non-simple mechanistic interplay between transcriptional and decay processes, especially for genes involved in rapid cellular responses. Finally, we identify 195 genetic variants that are significantly associated with both gene expression variation and variation in mRNA decay rates. Using these data, we estimate that that a substantial fraction of eQTLs are associated with inter-individual variation in mRNA decay rates.