Detecting functional divergence after gene duplication through evolutionary changes in posttranslational regulatory sequences.

Alex N Nguyen Ba,Jonathan Desmond,Eric L Weiss,Bob Strome,Christian R Landry,Jun Jie Hua,Alan M Moses,Isabelle Gagnon-Arsenault,Yves Van De Peer

doi:10.1371/journal.pcbi.1003977

Alex N Nguyen Ba, Jonathan Desmond + Show 7 more

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https://doi.org/10.1371/journal.pcbi.1003977

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Abstract

Gene duplication is an important evolutionary mechanism that can result in functional divergence in paralogs due to neo-functionalization or sub-functionalization. Consistent with functional divergence after gene duplication, recent studies have shown accelerated evolution in retained paralogs. However, little is known in general about the impact of this accelerated evolution on the molecular functions of retained paralogs. For example, do new functions typically involve changes in enzymatic activities, or changes in protein regulation? Here we study the evolution of posttranslational regulation by examining the evolution of important regulatory sequences (short linear motifs) in retained duplicates created by the whole-genome duplication in budding yeast. To do so, we identified short linear motifs whose evolutionary constraint has relaxed after gene duplication with a likelihood-ratio test that can account for heterogeneity in the evolutionary process by using a non-central chi-squared null distribution. We find that short linear motifs are more likely to show changes in evolutionary constraints in retained duplicates compared to single-copy genes. We examine changes in constraints on known regulatory sequences and show that for the Rck1/Rck2, Fkh1/Fkh2, Ace2/Swi5 paralogs, they are associated with previously characterized differences in posttranslational regulation. Finally, we experimentally confirm our prediction that for the Ace2/Swi5 paralogs, Cbk1 regulated localization was lost along the lineage leading to SWI5 after gene duplication. Our analysis suggests that changes in posttranslational regulation mediated by short regulatory motifs systematically contribute to functional divergence after gene duplication.

Highlights

Gene duplication is thought to be one of the major sources of evolutionary innovation
We develop a statistical framework to identify changes in rate of evolution specific to protein regulatory sequences and identify hundreds of short linear motifs in disordered regions that are likely to have diverged after the wholegenome duplication in budding yeast
Our analysis suggests that changes in short linear motifs in disordered protein regions could be important molecular mechanisms of functional divergence after gene duplication

Summary

Introduction

Gene duplication is thought to be one of the major sources of evolutionary innovation (reviewed in [1]). Studies on genome-wide mRNA expression patterns have established that transcriptional changes are one of the major contributors of functional differences within duplicated genes [12,13,14]. Coding sequences of paralogous genes show increased evolutionary rates after duplication [16,17], consistent with the hypothesis that changes within the amino acid coding sequences are important contributors to functional divergence. Because some functional features in proteins comprise a small number of amino acids, statistical studies comparing evolutionary rates of whole proteins do not provide mechanistic explanations for changes in function [18]. Many proteins contain short linear motifs (SLiMs) such as phosphorylation sites, localization signals and interaction motifs, and these motifs are only 2-15 amino acids long [19]. Recently we [23] and others [24] have shown

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