Mutational bias and the protein code shape the evolution of splicing enhancers

Stephen Rong,Christy L Rhine,William G Fairbrother,Jing Wang,Luke Buerer,Kamil J Cygan

doi:10.1038/s41467-020-16673-z

Stephen Rong, Christy L Rhine + Show 4 more

Open Access

https://doi.org/10.1038/s41467-020-16673-z

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Journal: Nature Communications	Publication Date: Jun 5, 2020
Citations: 17	License type: open-access

Affiliation: Brown University, Providence College

Abstract

Exonic splicing enhancers (ESEs) are enriched in exons relative to introns and bind splicing activators. This study considers a fundamental question of co-evolution: How did ESE motifs become enriched in exons prior to the evolution of ESE recognition? We hypothesize that the high exon to intron motif ratios necessary for ESE function were created by mutational bias coupled with purifying selection on the protein code. These two forces retain certain coding motifs in exons while passively depleting them from introns. Through the use of simulations, genomic analyses, and high throughput splicing assays, we confirm the key predictions of this hypothesis, including an overlap between protein and splicing information in ESEs. We discuss the implications of mutational bias as an evolutionary driver in other cis-regulatory systems.

Highlights

Exonic splicing enhancers (ESEs) are enriched in exons relative to introns and bind splicing activators
Simulations were used to test the hypothesis that mutational bias in conjunction with purifying selection on the protein code could create motifs that were precursors to ESEs
Substitutions were drawn in proportion to recently published estimated relative mutation (ERM) rates based on heptamer contexts[32]

Summary

Introduction

Exonic splicing enhancers (ESEs) are enriched in exons relative to introns and bind splicing activators. We hypothesize that the high exon to intron motif ratios necessary for ESE function were created by mutational bias coupled with purifying selection on the protein code. These two forces retain certain coding motifs in exons while passively depleting them from introns. This study investigates how exonic splicing enhancers (ESE) became enriched in exons relative to introns prior to their recognition by splicing activators. ESEs are often recognized by SR proteins, a family of splicing factors that typically act as activators when bound in exonic sequence and repressors when bound in the intron[15]. More sophisticated models leveraging large variant datasets have recently been used to estimate the relative mutation rate of nucleotides based on different k-mer sequence contexts[32,33]

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