Cargando…
Exonic splice regulation imposes strong selection at synonymous sites
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...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169883/ https://www.ncbi.nlm.nih.gov/pubmed/30143596 http://dx.doi.org/10.1101/gr.233999.117 |
_version_ | 1783360576816152576 |
---|---|
author | Savisaar, Rosina Hurst, Laurence D. |
author_facet | Savisaar, Rosina Hurst, Laurence D. |
author_sort | Savisaar, Rosina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6169883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-61698832018-10-12 Exonic splice regulation imposes strong selection at synonymous sites Savisaar, Rosina Hurst, Laurence D. Genome Res Research 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. Cold Spring Harbor Laboratory Press 2018-10 /pmc/articles/PMC6169883/ /pubmed/30143596 http://dx.doi.org/10.1101/gr.233999.117 Text en © 2018 Savisaar and Hurst; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Savisaar, Rosina Hurst, Laurence D. Exonic splice regulation imposes strong selection at synonymous sites |
title | Exonic splice regulation imposes strong selection at synonymous sites |
title_full | Exonic splice regulation imposes strong selection at synonymous sites |
title_fullStr | Exonic splice regulation imposes strong selection at synonymous sites |
title_full_unstemmed | Exonic splice regulation imposes strong selection at synonymous sites |
title_short | Exonic splice regulation imposes strong selection at synonymous sites |
title_sort | exonic splice regulation imposes strong selection at synonymous sites |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169883/ https://www.ncbi.nlm.nih.gov/pubmed/30143596 http://dx.doi.org/10.1101/gr.233999.117 |
work_keys_str_mv | AT savisaarrosina exonicspliceregulationimposesstrongselectionatsynonymoussites AT hurstlaurenced exonicspliceregulationimposesstrongselectionatsynonymoussites |