Exonic splice regulation imposes strong selection at synonymous sites

Rosina Savisaar, Laurence Hurst

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

What proportion of our coding sequence nucleotides have roles in splicing and how strong is the selection that maintains them? Despite a large body of research into exonic splice regulatory signals, these questions have not been answered. This is because, to our knowledge, previous investigations have not explicitly disentangled the frequency of splice regulatory elements from the strength of the evolutionary constraint under which they evolve. Current data are consistent both with a scenario of weak and diffuse constraint, enveloping large swathes of sequence, as well as with well-defined pockets of strong purifying selection. In the former case, natural selection on exonic splice enhancers (ESEs) might primarily act as a slight modifier of codon usage bias. In the latter, mutations that disrupt ESEs are likely to have large fitness and, potentially, clinical effects. To distinguish between these scenarios, we used several different methods to determine the distribution of selection coefficients for new mutations within
exonic splice enhancers. The analyses converged to suggest that roughly 15-20% of fourfold degenerate sites are part of functional exonic splice enhancers. Most of these sites are under strikingly strong evolutionary constraint. Therefore, exonic splice regulation does not simply impose a weak bias that gently nudges coding sequence evolution in a particular direction. Rather, the selection to preserve these motifs is a strong force that severely constrains the evolution of a substantial proportion of coding nucleotides. Thus synonymous mutations that disrupt ESEs should be considered as a potentially common cause of single-locus genetic disorders.
LanguageEnglish
JournalGenome Research
Early online date24 Aug 2018
DOIs
StatusE-pub ahead of print - 24 Aug 2018

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Mutation
Inborn Genetic Diseases
Genetic Selection
Codon
Nucleotides
Research
Direction compound
Silent Mutation

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Exonic splice regulation imposes strong selection at synonymous sites. / Savisaar, Rosina; Hurst, Laurence.

In: Genome Research, 24.08.2018.

Research output: Contribution to journalArticle

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abstract = "What proportion of our coding sequence nucleotides have roles in splicing and how strong is the selection that maintains them? Despite a large body of research into exonic splice regulatory signals, these questions have not been answered. This is because, to our knowledge, previous investigations have not explicitly disentangled the frequency of splice regulatory elements from the strength of the evolutionary constraint under which they evolve. Current data are consistent both with a scenario of weak and diffuse constraint, enveloping large swathes of sequence, as well as with well-defined pockets of strong purifying selection. In the former case, natural selection on exonic splice enhancers (ESEs) might primarily act as a slight modifier of codon usage bias. In the latter, mutations that disrupt ESEs are likely to have large fitness and, potentially, clinical effects. To distinguish between these scenarios, we used several different methods to determine the distribution of selection coefficients for new mutations within exonic splice enhancers. The analyses converged to suggest that roughly 15-20{\%} of fourfold degenerate sites are part of functional exonic splice enhancers. Most of these sites are under strikingly strong evolutionary constraint. Therefore, exonic splice regulation does not simply impose a weak bias that gently nudges coding sequence evolution in a particular direction. Rather, the selection to preserve these motifs is a strong force that severely constrains the evolution of a substantial proportion of coding nucleotides. Thus synonymous mutations that disrupt ESEs should be considered as a potentially common cause of single-locus genetic disorders.",
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