Abstract
Little is known about co-transcriptional or post-transcriptional regulatory mechanisms linking noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3' Seq to study the impact of genetic variation on alternative polyadenylation (APA) in the nuclear and total mRNA fractions of 52 HapMap Yoruba human lymphoblastoid cell lines. We mapped 602 APA quantitative trait loci (apaQTLs) at 10% FDR, of which 152 were nuclear specific. Effect sizes at intronic apaQTLs are negatively correlated with eQTL effect sizes. These observations suggest genetic variants can decrease mRNA expression levels by increasing usage of intronic PAS. We also identified 24 apaQTLs associated with protein levels, but not mRNA expression. Finally, we found that 19% of apaQTLs can be associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression, protein expression, and disease risk, and reveals uncharted modes of genetic regulation.
Highlights
Most genetic variants associated with complex traits are noncoding, suggesting that inter-individual variation in gene regulation plays a dominant role in determining phenotypic outcome
We found that the ratio of the number of nuclear 3’ RNA-seq (3’ Seq) read count to total mRNA 3’ Seq read count is positively correlated with two different measures of mRNA decay (Supplementary file 1), supporting our expectation that 3’ Seq applied to the nuclear mRNA fraction captured RNA transcripts at an earlier stage of RNA processing
We focused on the set of 602 apaQTLs that we identified in the nuclear mRNA fraction, representing genetic variants that impact polyadenylation sites (PAS) choice
Summary
Most genetic variants associated with complex traits are noncoding, suggesting that inter-individual variation in gene regulation plays a dominant role in determining phenotypic outcome. Battle and colleagues found that about half of the cis-pQTLs they identified in human LCLs (146 out of 278, 52%) did not appear to impact gene expression levels in the same lymphoblastoid cell lines (LCLs) (Battle et al, 2015) These findings indicate that there may be unknown or understudied regulatory mechanisms that link genetic variation to complex traits, and that these mechanisms are independent of changes in the amplitude of mRNA expression levels. A third of all eQTLs identified in human LCLs are not associated with variation in chromatin as measured using assays for chromatin accessibility or for modification levels of several histone marks (Li et al, 2016) These observations raise the possibility that understudied regulatory mechanisms mediate the effect of a substantial number of genetic variants on gene expression level. The online version of this article includes the following figure supplement(s) for figure 1:
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