Alternative polyadenylation mediates genetic regulation of gene expression

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 tot...

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Bibliographic Details
Published in:eLife 2020-06, Vol.9
Main Authors: Mittleman, Briana E, Pott, Sebastian, Warland, Shane, Zeng, Tony, Mu, Zepeng, Kaur, Mayher, Gilad, Yoav, Li, Yang
Format: Article
Language:English
Subjects:
alternative polyadenylation
apaQTL
Cell Line
DNA methylation
eQTL
Fractionation
Gene expression
Gene Expression Regulation
gene regulation
Genetic diversity
Genetics and Genomics
Genomes
Humans
Lymphoblastoid cell lines
Polyadenylation
Polyadenylation - genetics
Post-transcription
pQTL
Protein expression
Proteins
Quantitative trait loci
RNA polymerase
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.57492