Negative feedback buffers effects of regulatory variants

Daniel M Bader,Julien Gagneur,Kim Dietrich,Lars M Steinmetz,Gen Lin,Stefan Wilkening,Manu M Tekkedil

doi:10.15252/msb.20145844

Abstract

Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments.

Highlights

Regulatory genetic variants play a major role in phenotypic variation and evolution
Variation in translation efficiency might contribute to buffering but does not appear as an intrinsic mechanism that yields robustness against newly arisen regulatory variants
This study demonstrated for a single gene that negative feedback could act as a buffering mechanism for regulatory variants

Summary

Introduction

Regulatory genetic variants play a major role in phenotypic variation and evolution. Most genetic variants are non-coding and they are the major driver of speciation (King & Wilson, 1975). Two studies have assessed the role of translation in buffering variations in RNA expression (Artieri & Fraser, 2014; McManus et al, 2014). In both studies, allelic differential expression (ADE) was compared to allelic differential translation efficiency estimated from allele-specific ribosome occupancies in a cross of the yeast species S. cerevisiae and S. paradoxus. Muzzey et al (2014) reported a genomewide trend for reinforcing ADE during translation in the yeast C. albicans As these studies used distinct statistical procedures and species, it is hard to compare them and conclude about the generality of these findings. Variation in translation efficiency might contribute to buffering but does not appear as an intrinsic mechanism that yields robustness against newly arisen regulatory variants

Methods

Results

Conclusion