Pervasive allele-specific regulation on RNA decay in hybrid mice.

Wei Sun,Yuhui Hu,Bernhard Schaefke,Qingsong Gao,Wei Chen

doi:10.26508/lsa.201800052

Abstract

Cellular RNA abundance is determined by both RNA transcription and decay. Therefore, change in RNA abundance, which can drive phenotypic diversity between different species, could arise from genetic variants affecting either process. However, previous studies in the evolution of RNA expression have been largely focused on transcription. Here, to globally investigate the effects of cis-regulatory divergence on RNA decay in mammals for the first time, we quantified allele-specific differences in RNA decay rates (ASD) in an F1 hybrid mouse. Out of 8,815 genes with sufficient data, we identified 621 genes exhibiting significant cis-divergence. Systematic analysis of these genes revealed that the genetic variants affecting microRNA binding and RNA secondary structures contribute to the observed divergences. Finally, we demonstrated that although the divergences in RNA abundance were predominantly determined by allelic differences in RNA transcription, most genes with significant ASD did not exhibit significant difference in RNA abundance. For these genes, the apparently compensatory effect between the allelic differences in RNA transcription and ASD suggests that changes in RNA decay could serve as important means to stabilize RNA abundances during mammalian evolution.

Highlights

Eukaryotic gene expression is regulated at multiple steps, and the balance between two opposing biological processes, RNA transcription and its decay, determines the cellular abundance of RNA transcripts (Garneau et al, 2007; Dolken et al, 2008; Schwanhausser et al, 2011; Rabani et al, 2011, 2014)
Via investigating the role of allele-specific differences in RNA decay rates (ASD) in the allele-specific RNA abundances (ASA), we demonstrated that on one hand, the observed ASA divergences were predominantly determined by the allelic differences in RNA transcription (AST) and on the other hand, most (>80%) of the genes with significant ASD did not exhibit significant ASA, indicating the pervasive compensatory effects between AST and ASD existing in mammalian evolution and suggesting that changes in RNA decay rates could serve as important means to stabilize RNA abundances during evolution
To investigate the allelic divergence of RNA decay rates in a mammalian system, we measured the ASD in a fibroblast cell line derived from an F1 hybrid mouse between the BL6 and SPRET strains

Summary

Introduction

Eukaryotic gene expression is regulated at multiple steps, and the balance between two opposing biological processes, RNA transcription and its decay, determines the cellular abundance of RNA transcripts (Garneau et al, 2007; Dolken et al, 2008; Schwanhausser et al, 2011; Rabani et al, 2011, 2014). Changes in RNA expression constitute one of the major forces driving both phenotypic diversity among individuals within the same species (Albert & Kruglyak, 2015) and evolutionary divergence between different species (Necsulea & Kaessmann, 2014) Such changes could arise from genetic variants affecting either transcription or decay. The Gilad and Pritchard labs analyzed the individual-specific mRNA decay rates of more than 16,000 genes in 70 Yoruba HapMap lymphoblastoid cell lines and identified 31 genes with significant cis-RNA decay quantitative trait loci (rdQTLs) at a false discovery rate (FDR) of 15% (Pai et al, 2012) To increase their detection power, they focused on single-nucleotide polymorphisms (SNPs) already identified as steady-state expression QTLs (eQTLs) (Pai et al, 2012). Among the joint QTLs, whereas in 55% cases, the alleles with higher steady-state level decay slower, the remaining 45% showed the opposite pattern of allelic bias between the steady-state expression and RNA decay

Methods

Results

Conclusion