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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...

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Autores principales: Savisaar, Rosina, Hurst, Laurence D.
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
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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.
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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
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