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

Nguyen Ba AN, Strome B, Hua JJ, Desmond J, Gagnon-Arsenault I, Weiss EL, Landry CR, Moses AM - PLoS Comput. Biol. (2014)

Bottom Line: 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.Our analysis suggests that changes in posttranslational regulation mediated by short regulatory motifs systematically contribute to functional divergence after gene duplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, Canada; Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada.

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 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.

Show MeSH
Regulatory turnover after gene duplication.A-B) The proportion of motifs with changes in constraints at a 5% false-discovery rate is significantly larger than in genes with retained duplicates (B) than in single-copy genes (A). Error bars represent the 95% confidence interval of the estimated proportion (binomial distribution). Bolded clades are clades with significant changes in constraints. α is the rate of evolution.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4256066&req=5

pcbi-1003977-g002: Regulatory turnover after gene duplication.A-B) The proportion of motifs with changes in constraints at a 5% false-discovery rate is significantly larger than in genes with retained duplicates (B) than in single-copy genes (A). Error bars represent the 95% confidence interval of the estimated proportion (binomial distribution). Bolded clades are clades with significant changes in constraints. α is the rate of evolution.

Mentions: Having confirmed that our approach to detect type I functional divergence could be applied on short linear motifs, we then analyzed our set of protein alignments. After correction for multiple testing, we identified 159 short linear motifs with significantly different rates of evolution after gene duplication at a false discovery rate of 5% (see Methods, S1 Table). This corresponds to 1.2% of the motifs identified in single-copy genes (67/5825 significant motifs, Fig. 2A) and 9.8% of the identified motifs in retained duplicates (92/942 significant motifs, Fig. 2B). Because motifs in retained duplicates are tested twice (once per branch), changes in constraints are approximately 4.5 times more frequent in retained duplicates versus single-copy proteins (5.26% vs 1.15% of LRTs, p-value <10-20, Fisher's exact test).


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

Nguyen Ba AN, Strome B, Hua JJ, Desmond J, Gagnon-Arsenault I, Weiss EL, Landry CR, Moses AM - PLoS Comput. Biol. (2014)

Regulatory turnover after gene duplication.A-B) The proportion of motifs with changes in constraints at a 5% false-discovery rate is significantly larger than in genes with retained duplicates (B) than in single-copy genes (A). Error bars represent the 95% confidence interval of the estimated proportion (binomial distribution). Bolded clades are clades with significant changes in constraints. α is the rate of evolution.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256066&req=5

pcbi-1003977-g002: Regulatory turnover after gene duplication.A-B) The proportion of motifs with changes in constraints at a 5% false-discovery rate is significantly larger than in genes with retained duplicates (B) than in single-copy genes (A). Error bars represent the 95% confidence interval of the estimated proportion (binomial distribution). Bolded clades are clades with significant changes in constraints. α is the rate of evolution.
Mentions: Having confirmed that our approach to detect type I functional divergence could be applied on short linear motifs, we then analyzed our set of protein alignments. After correction for multiple testing, we identified 159 short linear motifs with significantly different rates of evolution after gene duplication at a false discovery rate of 5% (see Methods, S1 Table). This corresponds to 1.2% of the motifs identified in single-copy genes (67/5825 significant motifs, Fig. 2A) and 9.8% of the identified motifs in retained duplicates (92/942 significant motifs, Fig. 2B). Because motifs in retained duplicates are tested twice (once per branch), changes in constraints are approximately 4.5 times more frequent in retained duplicates versus single-copy proteins (5.26% vs 1.15% of LRTs, p-value <10-20, Fisher's exact test).

Bottom Line: 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.Our analysis suggests that changes in posttranslational regulation mediated by short regulatory motifs systematically contribute to functional divergence after gene duplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, Canada; Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada.

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 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.

Show MeSH