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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Published inGenome research Vol. 28; no. 10; pp. 1442 - 1454
Main Authors Savisaar, Rosina, Hurst, Laurence D
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LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 01.10.2018
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Abstract 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.
AbstractList 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.
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.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.
Author Hurst, Laurence D
Savisaar, Rosina
AuthorAffiliation The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
AuthorAffiliation_xml – name: The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
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  givenname: Rosina
  surname: Savisaar
  fullname: Savisaar, Rosina
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Cites_doi 10.1093/molbev/msv234
10.1371/journal.pgen.1003527
10.1093/molbev/msy054
10.1534/genetics.117.300323
10.1093/nar/gks1205
10.1002/art.38952
10.1371/journal.pgen.1004592
10.1038/nrg.2015.3
10.1016/j.cell.2014.01.051
10.1073/pnas.0803230105
10.1534/genetics.116.188102
10.1007/PL00006256
10.1093/gbe/evu210
10.1093/nar/gku1010
10.1093/bioinformatics/btq671
10.1093/molbev/msm104
10.1101/gr.139758.112
10.1101/gr.118638.110
10.1093/bib/bbq072
10.1101/gr.097857.109
10.7554/eLife.02028
10.1002/wrna.1142
10.1261/rna.043893.113
10.1093/molbev/msj035
10.1093/bioinformatics/btq033
10.1371/journal.pgen.1002395
10.1016/j.gene.2004.11.035
10.1186/gb-2013-14-1-r1
10.1073/pnas.0500436102
10.1093/molbev/msh039
10.1093/nar/gkh834
10.1093/bioinformatics/btr330
10.1093/genetics/159.3.1191
10.1093/molbev/msg147
10.1126/science.1243490
10.1016/j.cell.2004.11.010
10.1093/genetics/139.2.1067
10.1371/journal.pgen.1004697
10.1371/journal.pbio.0050014
10.1371/journal.pgen.1000083
10.1371/journal.pone.0018067
10.1073/pnas.1720576115
10.1016/j.jtbi.2005.10.020
10.1126/science.1254806
10.1093/bioinformatics/btp163
10.1534/genetics.107.080663
10.1007/s00239-015-9719-3
10.1093/nar/gnh176
10.1534/genetics.111.128355
10.1093/molbev/msu323
10.1038/nrg2146
10.1109/MCSE.2010.145
10.1073/pnas.87.12.4692
10.1073/pnas.0510638103
10.1093/hmg/ddi350
10.1007/s00239-005-0055-x
10.1016/j.neuron.2016.02.024
10.1016/S0968-0004(00)01549-8
10.1261/rna.2017210
10.1371/journal.pbio.0020268
10.1016/0092-8674(86)90343-0
10.1186/1471-2164-7-67
10.1073/pnas.1101135108
10.1534/genetics.111.131730
10.1534/genetics.116.197145
10.1093/molbev/msu409
10.1016/j.cell.2014.08.011
10.1126/science.1073774
10.1534/genetics.106.057570
10.1007/s00239-005-0273-2
10.1146/annurev-biochem-060614-034316
10.1073/pnas.0502300102
10.1002/humu.23283
10.1007/s00439-017-1798-3
10.1534/genetics.105.047217
10.1073/pnas.0704922104
10.1186/gb-2008-9-2-r29
10.1016/j.semcdb.2014.03.010
10.1093/molbev/msm100
10.1093/nar/gkq009
10.1016/j.molcel.2006.05.008
10.1016/j.bbrc.2004.07.144
10.1093/molbev/msw018
10.1101/gad.7.3.407
10.1101/gad.1195304
10.1186/gb4150
10.1093/molbev/mst019
10.1101/106476
10.1101/gad.286404
10.1038/ng.3837
10.1016/j.cell.2004.12.035
10.1093/molbev/msp219
10.1093/molbev/msv251
10.1101/gr.119628.110
10.1101/gr.070268.107
10.1007/s00239-013-9555-2
10.1093/nar/13.15.5591
10.1534/genetics.112.148023
10.1073/pnas.1833064100
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References 2021111811174778000_28.10.1442.19
2021111811174778000_28.10.1442.18
2021111811174778000_28.10.1442.11
2021111811174778000_28.10.1442.99
2021111811174778000_28.10.1442.10
2021111811174778000_28.10.1442.98
2021111811174778000_28.10.1442.13
2021111811174778000_28.10.1442.12
2021111811174778000_28.10.1442.15
2021111811174778000_28.10.1442.14
2021111811174778000_28.10.1442.17
2021111811174778000_28.10.1442.16
2021111811174778000_28.10.1442.91
2021111811174778000_28.10.1442.93
2021111811174778000_28.10.1442.92
2021111811174778000_28.10.1442.95
2021111811174778000_28.10.1442.94
2021111811174778000_28.10.1442.97
2021111811174778000_28.10.1442.96
2021111811174778000_28.10.1442.1
2021111811174778000_28.10.1442.7
2021111811174778000_28.10.1442.8
2021111811174778000_28.10.1442.5
2021111811174778000_28.10.1442.6
2021111811174778000_28.10.1442.88
2021111811174778000_28.10.1442.9
2021111811174778000_28.10.1442.89
2021111811174778000_28.10.1442.82
2021111811174778000_28.10.1442.81
2021111811174778000_28.10.1442.84
2021111811174778000_28.10.1442.83
2021111811174778000_28.10.1442.86
2021111811174778000_28.10.1442.85
(2021111811174778000_28.10.1442.51) 2017; 38
2021111811174778000_28.10.1442.77
2021111811174778000_28.10.1442.76
2021111811174778000_28.10.1442.79
2021111811174778000_28.10.1442.78
(2021111811174778000_28.10.1442.75) 2017; 136
2021111811174778000_28.10.1442.71
2021111811174778000_28.10.1442.70
2021111811174778000_28.10.1442.73
2021111811174778000_28.10.1442.72
(2021111811174778000_28.10.1442.90) 2001; 159
(2021111811174778000_28.10.1442.74) 2017; 34
(2021111811174778000_28.10.1442.64) 2016; 82
(2021111811174778000_28.10.1442.3) 2015; 67
2021111811174778000_28.10.1442.66
2021111811174778000_28.10.1442.65
2021111811174778000_28.10.1442.67
2021111811174778000_28.10.1442.100
2021111811174778000_28.10.1442.69
2021111811174778000_28.10.1442.101
2021111811174778000_28.10.1442.102
2021111811174778000_28.10.1442.60
(2021111811174778000_28.10.1442.4) 2018; 35
2021111811174778000_28.10.1442.62
2021111811174778000_28.10.1442.61
2021111811174778000_28.10.1442.63
(2021111811174778000_28.10.1442.52) 2006; 172
(2021111811174778000_28.10.1442.80) 2017; 49
2021111811174778000_28.10.1442.55
2021111811174778000_28.10.1442.54
2021111811174778000_28.10.1442.57
2021111811174778000_28.10.1442.56
2021111811174778000_28.10.1442.59
2021111811174778000_28.10.1442.58
2021111811174778000_28.10.1442.50
2021111811174778000_28.10.1442.53
(2021111811174778000_28.10.1442.68) 2013; 76
(2021111811174778000_28.10.1442.87) 2016; 89
2021111811174778000_28.10.1442.44
2021111811174778000_28.10.1442.43
2021111811174778000_28.10.1442.46
2021111811174778000_28.10.1442.45
2021111811174778000_28.10.1442.48
2021111811174778000_28.10.1442.47
2021111811174778000_28.10.1442.49
2021111811174778000_28.10.1442.40
(2021111811174778000_28.10.1442.31) 2016; 2016
2021111811174778000_28.10.1442.42
2021111811174778000_28.10.1442.41
2021111811174778000_28.10.1442.33
2021111811174778000_28.10.1442.32
2021111811174778000_28.10.1442.35
2021111811174778000_28.10.1442.34
2021111811174778000_28.10.1442.37
2021111811174778000_28.10.1442.36
2021111811174778000_28.10.1442.39
2021111811174778000_28.10.1442.38
2021111811174778000_28.10.1442.30
2021111811174778000_28.10.1442.29
2021111811174778000_28.10.1442.22
2021111811174778000_28.10.1442.21
2021111811174778000_28.10.1442.24
2021111811174778000_28.10.1442.23
2021111811174778000_28.10.1442.26
2021111811174778000_28.10.1442.25
2021111811174778000_28.10.1442.28
(2021111811174778000_28.10.1442.2) 1995; 139
2021111811174778000_28.10.1442.20
(2021111811174778000_28.10.1442.27) 2013; 4
References_xml – ident: 2021111811174778000_28.10.1442.1
  doi: 10.1093/molbev/msv234
– ident: 2021111811174778000_28.10.1442.44
  doi: 10.1371/journal.pgen.1003527
– volume: 35
  start-page: 1536
  year: 2018
  ident: 2021111811174778000_28.10.1442.4
  article-title: New methods for inferring the distribution of fitness effects for INDELs and SNPs
  publication-title: Mol Biol Evol
  doi: 10.1093/molbev/msy054
– ident: 2021111811174778000_28.10.1442.89
  doi: 10.1534/genetics.117.300323
– ident: 2021111811174778000_28.10.1442.78
  doi: 10.1093/nar/gks1205
– volume: 67
  start-page: 423
  year: 2015
  ident: 2021111811174778000_28.10.1442.3
  article-title: MicroRNA-602 and microRNA-608 regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes
  publication-title: Arthritis Rheumatol
  doi: 10.1002/art.38952
– ident: 2021111811174778000_28.10.1442.5
  doi: 10.1371/journal.pgen.1004592
– ident: 2021111811174778000_28.10.1442.77
  doi: 10.1038/nrg.2015.3
– ident: 2021111811174778000_28.10.1442.85
  doi: 10.1016/j.cell.2014.01.051
– ident: 2021111811174778000_28.10.1442.25
  doi: 10.1073/pnas.0803230105
– ident: 2021111811174778000_28.10.1442.38
  doi: 10.1534/genetics.116.188102
– volume: 2016
  start-page: 1
  year: 2016
  ident: 2021111811174778000_28.10.1442.31
  article-title: Ensembl comparative genomics resources
  publication-title: Database
– ident: 2021111811174778000_28.10.1442.56
  doi: 10.1007/PL00006256
– ident: 2021111811174778000_28.10.1442.7
  doi: 10.1093/gbe/evu210
– ident: 2021111811174778000_28.10.1442.14
  doi: 10.1093/nar/gku1010
– ident: 2021111811174778000_28.10.1442.47
  doi: 10.1093/bioinformatics/btq671
– ident: 2021111811174778000_28.10.1442.58
  doi: 10.1093/molbev/msm104
– ident: 2021111811174778000_28.10.1442.30
  doi: 10.1101/gr.139758.112
– ident: 2021111811174778000_28.10.1442.84
  doi: 10.1101/gr.118638.110
– ident: 2021111811174778000_28.10.1442.32
  doi: 10.1093/bib/bbq072
– ident: 2021111811174778000_28.10.1442.62
  doi: 10.1101/gr.097857.109
– ident: 2021111811174778000_28.10.1442.55
  doi: 10.7554/eLife.02028
– volume: 4
  start-page: 77
  year: 2013
  ident: 2021111811174778000_28.10.1442.27
  article-title: Connections between chromatin signatures and splicing
  publication-title: Wiley Interdiscip Rev RNA
  doi: 10.1002/wrna.1142
– ident: 2021111811174778000_28.10.1442.9
  doi: 10.1261/rna.043893.113
– ident: 2021111811174778000_28.10.1442.59
  doi: 10.1093/molbev/msj035
– ident: 2021111811174778000_28.10.1442.65
  doi: 10.1093/bioinformatics/btq033
– ident: 2021111811174778000_28.10.1442.97
  doi: 10.1371/journal.pgen.1002395
– ident: 2021111811174778000_28.10.1442.43
  doi: 10.1016/j.gene.2004.11.035
– volume: 34
  start-page: 1110
  year: 2017
  ident: 2021111811174778000_28.10.1442.74
  article-title: Both maintenance and avoidance of RNA-binding protein interactions constrain coding sequence evolution
  publication-title: Mol Biol Evol
– ident: 2021111811174778000_28.10.1442.10
  doi: 10.1186/gb-2013-14-1-r1
– ident: 2021111811174778000_28.10.1442.53
  doi: 10.1073/pnas.0500436102
– ident: 2021111811174778000_28.10.1442.79
  doi: 10.1093/molbev/msh039
– ident: 2021111811174778000_28.10.1442.17
  doi: 10.1093/nar/gkh834
– ident: 2021111811174778000_28.10.1442.15
  doi: 10.1093/bioinformatics/btr330
– volume: 159
  start-page: 1191
  year: 2001
  ident: 2021111811174778000_28.10.1442.90
  article-title: Codon usage bias covaries with expression breadth and the rate of synonymous evolution in humans, but this is not evidence for selection
  publication-title: Genetics
  doi: 10.1093/genetics/159.3.1191
– ident: 2021111811174778000_28.10.1442.57
  doi: 10.1093/molbev/msg147
– ident: 2021111811174778000_28.10.1442.82
  doi: 10.1126/science.1243490
– ident: 2021111811174778000_28.10.1442.93
  doi: 10.1016/j.cell.2004.11.010
– volume: 139
  start-page: 1067
  year: 1995
  ident: 2021111811174778000_28.10.1442.2
  article-title: Inferring weak selection from patterns of polymorphism and divergence at “silent” sites in Drosophila DNA
  publication-title: Genetics
  doi: 10.1093/genetics/139.2.1067
– ident: 2021111811174778000_28.10.1442.67
  doi: 10.1371/journal.pgen.1004697
– ident: 2021111811174778000_28.10.1442.60
  doi: 10.1371/journal.pbio.0050014
– ident: 2021111811174778000_28.10.1442.8
  doi: 10.1371/journal.pgen.1000083
– ident: 2021111811174778000_28.10.1442.24
  doi: 10.1371/journal.pone.0018067
– ident: 2021111811174778000_28.10.1442.71
  doi: 10.1073/pnas.1720576115
– ident: 2021111811174778000_28.10.1442.40
  doi: 10.1016/j.jtbi.2005.10.020
– ident: 2021111811174778000_28.10.1442.100
  doi: 10.1126/science.1254806
– ident: 2021111811174778000_28.10.1442.12
  doi: 10.1093/bioinformatics/btp163
– ident: 2021111811174778000_28.10.1442.36
  doi: 10.1534/genetics.107.080663
– volume: 82
  start-page: 51
  year: 2016
  ident: 2021111811174778000_28.10.1442.64
  article-title: Are synonymous sites in primates and rodents functionally constrained?
  publication-title: J Mol Evol
  doi: 10.1007/s00239-015-9719-3
– ident: 2021111811174778000_28.10.1442.23
  doi: 10.1093/nar/gnh176
– ident: 2021111811174778000_28.10.1442.37
  doi: 10.1534/genetics.111.128355
– ident: 2021111811174778000_28.10.1442.50
  doi: 10.1093/molbev/msu323
– ident: 2021111811174778000_28.10.1442.19
  doi: 10.1038/nrg2146
– ident: 2021111811174778000_28.10.1442.66
– ident: 2021111811174778000_28.10.1442.91
  doi: 10.1109/MCSE.2010.145
– ident: 2021111811174778000_28.10.1442.86
  doi: 10.1073/pnas.87.12.4692
– ident: 2021111811174778000_28.10.1442.13
  doi: 10.1073/pnas.0510638103
– ident: 2021111811174778000_28.10.1442.101
  doi: 10.1093/hmg/ddi350
– ident: 2021111811174778000_28.10.1442.11
  doi: 10.1007/s00239-005-0055-x
– volume: 89
  start-page: 940
  year: 2016
  ident: 2021111811174778000_28.10.1442.87
  article-title: De novo synonymous mutations in regulatory elements contribute to the genetic etiology of autism and schizophrenia
  publication-title: Neuron
  doi: 10.1016/j.neuron.2016.02.024
– ident: 2021111811174778000_28.10.1442.6
  doi: 10.1016/S0968-0004(00)01549-8
– ident: 2021111811174778000_28.10.1442.48
  doi: 10.1261/rna.2017210
– ident: 2021111811174778000_28.10.1442.22
  doi: 10.1371/journal.pbio.0020268
– ident: 2021111811174778000_28.10.1442.69
  doi: 10.1016/0092-8674(86)90343-0
– ident: 2021111811174778000_28.10.1442.41
  doi: 10.1186/1471-2164-7-67
– ident: 2021111811174778000_28.10.1442.49
  doi: 10.1073/pnas.1101135108
– ident: 2021111811174778000_28.10.1442.76
  doi: 10.1534/genetics.111.131730
– ident: 2021111811174778000_28.10.1442.39
  doi: 10.1534/genetics.116.197145
– ident: 2021111811174778000_28.10.1442.99
  doi: 10.1093/molbev/msu409
– ident: 2021111811174778000_28.10.1442.26
  doi: 10.1016/j.cell.2014.08.011
– ident: 2021111811174778000_28.10.1442.21
  doi: 10.1126/science.1073774
– ident: 2021111811174778000_28.10.1442.20
  doi: 10.1534/genetics.106.057570
– ident: 2021111811174778000_28.10.1442.33
  doi: 10.1007/s00239-005-0273-2
– ident: 2021111811174778000_28.10.1442.45
  doi: 10.1146/annurev-biochem-060614-034316
– ident: 2021111811174778000_28.10.1442.96
  doi: 10.1073/pnas.0502300102
– volume: 38
  start-page: 1336
  year: 2017
  ident: 2021111811174778000_28.10.1442.51
  article-title: Investigating DNA-, RNA-, and protein-based features as a means to discriminate pathogenic synonymous variants
  publication-title: Hum Mutat
  doi: 10.1002/humu.23283
– volume: 136
  start-page: 1059
  year: 2017
  ident: 2021111811174778000_28.10.1442.75
  article-title: Estimating the prevalence of functional exonic splice regulatory information
  publication-title: Hum Genet
  doi: 10.1007/s00439-017-1798-3
– volume: 172
  start-page: 1079
  year: 2006
  ident: 2021111811174778000_28.10.1442.52
  article-title: Estimating selection on nonsynonymous mutations
  publication-title: Genetics
  doi: 10.1534/genetics.105.047217
– ident: 2021111811174778000_28.10.1442.88
  doi: 10.1073/pnas.0704922104
– ident: 2021111811174778000_28.10.1442.94
  doi: 10.1186/gb-2008-9-2-r29
– ident: 2021111811174778000_28.10.1442.16
  doi: 10.1016/j.semcdb.2014.03.010
– ident: 2021111811174778000_28.10.1442.70
  doi: 10.1093/molbev/msm100
– ident: 2021111811174778000_28.10.1442.92
  doi: 10.1093/nar/gkq009
– ident: 2021111811174778000_28.10.1442.28
  doi: 10.1016/j.molcel.2006.05.008
– ident: 2021111811174778000_28.10.1442.63
  doi: 10.1016/j.bbrc.2004.07.144
– ident: 2021111811174778000_28.10.1442.73
  doi: 10.1093/molbev/msw018
– ident: 2021111811174778000_28.10.1442.95
  doi: 10.1101/gad.7.3.407
– ident: 2021111811174778000_28.10.1442.102
  doi: 10.1101/gad.1195304
– ident: 2021111811174778000_28.10.1442.83
  doi: 10.1186/gb4150
– ident: 2021111811174778000_28.10.1442.29
  doi: 10.1093/molbev/mst019
– ident: 2021111811174778000_28.10.1442.54
  doi: 10.1101/106476
– ident: 2021111811174778000_28.10.1442.72
  doi: 10.1101/gad.286404
– volume: 49
  start-page: 848
  year: 2017
  ident: 2021111811174778000_28.10.1442.80
  article-title: Pathogenic variants that alter protein code often disrupt splicing
  publication-title: Nat Genet
  doi: 10.1038/ng.3837
– ident: 2021111811174778000_28.10.1442.46
  doi: 10.1016/j.cell.2004.12.035
– ident: 2021111811174778000_28.10.1442.18
  doi: 10.1093/molbev/msp219
– ident: 2021111811174778000_28.10.1442.98
  doi: 10.1093/molbev/msv251
– ident: 2021111811174778000_28.10.1442.35
  doi: 10.1101/gr.119628.110
– ident: 2021111811174778000_28.10.1442.34
  doi: 10.1101/gr.070268.107
– volume: 76
  start-page: 228
  year: 2013
  ident: 2021111811174778000_28.10.1442.68
  article-title: Testing for natural selection in human exonic splicing regulators associated with evolutionary rate shifts
  publication-title: J Mol Evol
  doi: 10.1007/s00239-013-9555-2
– ident: 2021111811174778000_28.10.1442.81
  doi: 10.1093/nar/13.15.5591
– ident: 2021111811174778000_28.10.1442.42
  doi: 10.1534/genetics.112.148023
– ident: 2021111811174778000_28.10.1442.61
  doi: 10.1073/pnas.1833064100
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Snippet 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...
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SubjectTerms Enhancer Elements, Genetic
Enhancers
Evolution
Evolution, Molecular
Exons
Gene Expression Regulation
Genetic disorders
Humans
Mutation
Natural selection
Nucleotide sequence
Polymorphism, Genetic
Regulation
Regulatory sequences
RNA Splice Sites
RNA Splicing
RNA, Messenger - genetics
RNA, Messenger - metabolism
Selection, Genetic
Silent Mutation
Splicing
Title Exonic splice regulation imposes strong selection at synonymous sites
URI https://www.ncbi.nlm.nih.gov/pubmed/30143596
https://www.proquest.com/docview/2136899544
https://www.proquest.com/docview/2093397796
https://pubmed.ncbi.nlm.nih.gov/PMC6169883
Volume 28
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