Exonic splice regulation imposes strong selection at synonymous sites

Rosina Savisaar, Laurence Hurst

Research output: Contribution to journalArticlepeer-review

30 Citations (SciVal)


What proportion of 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 swaths 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 ESEs. The analyses converged to suggest that ∼15%-20% of fourfold degenerate sites are part of functional ESEs. Most of these sites are under 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.

Original languageEnglish
Pages (from-to)1442-1454
Number of pages13
JournalGenome Research
Issue number10
Early online date24 Aug 2018
Publication statusPublished - 1 Oct 2018

Bibliographical note

© 2018 Savisaar and Hurst; Published by Cold Spring Harbor Laboratory Press.


  • Enhancer Elements, Genetic
  • Evolution, Molecular
  • Exons
  • Gene Expression Regulation
  • Humans
  • Polymorphism, Genetic
  • RNA Splice Sites
  • RNA Splicing
  • RNA, Messenger/genetics
  • Selection, Genetic
  • Silent Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


Dive into the research topics of 'Exonic splice regulation imposes strong selection at synonymous sites'. Together they form a unique fingerprint.

Cite this