Biology subjects

Warland, S.

Publications and source records attributed to Warland, S..

2 recordsLinked to original sources

bioRxiv2020

Divergence in alternative polyadenylation contributes to gene regulatory differences between humans and chimpanzees

Comparative functional genomic studies have shown that differences in gene expression between species can often be explained by corresponding inter-species differences in genetic and epigenetic regulatory mechanisms. In the quest to understand gene regulatory evolution in primates, the role of co-transcriptional regulatory mechanisms, such as alternative polyadenylation (APA), have so far received little attention. To begin addressing this gap, we studied APA in lymphoblastoid cell lines from six humans and six chimpanzees, and estimated usage for 44,432 polyadenylation sites (PAS) in 9,518 genes in both species. While APA is largely conserved in humans and chimpanzees, we identified 1,705 genes with significantly different PAS usage (FDR of 0.05) between the two species. We found that genes with divergent APA patterns are enriched among differentially expressed genes, as well as among genes that show differences in protein translation between species. In particular, differences in APA between humans and chimpanzees can explain a subset of observed inter-species protein expression differences that do not display corresponding differences at the transcript level. Finally, we focused on genes that have a dominant PAS, namely a PAS that is used more often than all others. Dominant PAS are highly conserved, and inter-species differences in dominant PAS are particularly enriched for genes that also show expression differences between the species. This study establishes APA as another key mechanism underlying the genetic regulation of transcript and protein expression levels in primates.

genomics↗

bioRxiv2019

Alternative polyadenylation mediates genetic regulation of gene expression

With the exception of mRNA splicing, little is known about co-transcriptional or post-transcriptional regulatory mechanisms that link noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3 Seq to characterize alternative polyadenylation (APA) in the nuclear and total RNA fractions of 52 HapMap Yoruba lymphoblastoid cell lines, which we have studied extensively in the past. We identified thousands of polyadenylation sites that are differentially detected in nuclear mRNA and whole cell mRNA, and found that APA is an important mediator of genetic effects on gene regulation and complex traits. Specifically, we mapped 602 apaQTLs at 10% FDR, of which 152 were found only in the nuclear fraction. Nuclear-specific apaQTLs are highly enriched in introns and are also often associated with changes in steady-state expression levels, suggesting a widespread mechanism whereby genetic variants decrease mRNA expression levels by increasing usage of intronic PAS. We identified 24 apaQTLs associated with protein expression levels, but not mRNA expression, and found that eQTLs that are not associated with chromatin QTLs are enriched in apaQTLs. These findings support multiple independent pathways through which genetic effects on APA can impact gene regulation. Finally, we found that 19% of apaQTLs were also previously associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression levels, protein expression levels, and disease risk, and reveals uncharted modes of genetic regulation.

genomics↗