Transcription-associated mutational asymmetry in mammalian evolution
Abstract
Although mutation is commonly thought of as a random process, evolutionary studies show that different types of nucleotide substitution occur with widely varying rates that presumably reflect biases intrinsic to mutation and repair mechanisms. A strand asymmetry, the occurrence of particular substitution types at higher rates than their complementary types, that is associated with DNA replication has been found in bacteria and mitochondria. A strand asymmetry that is associated with transcription and attributable to higher rates of cytosine deamination on the coding strand has been observed in enterobacteria. Here, we describe a qualitatively different transcription-associated strand asymmetry in mammals, which may be a byproduct of transcription-coupled repair in germline cells. This mutational asymmetry has acted over long periods of time to produce a compositional asymmetry, an excess of G+T over A+C on the coding strand, in most genes. The mutational and compositional asymmetries can be used to detect the orientations and approximate extents of transcribed regions.
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Private Asian and African TCC to T SNPs exhibit the strand bias typical of A/C to G/T mutations, with the C to T change usually affecting the antisense strand and the G to A change usually affecting the sense strand.
“Private Asian and African TCC → T SNPs were found to exhibit the strand bias that is typical of A/C → G/T mutations (28), with the C → T change usually affecting the antisense strand and the G → A change usually affecting the sense strand.”
From Evidence for recent, population-specific evolution of the human mutation rate (2015) · cites this paper as [28]
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RNA landscape of evolution for optimal exon and intron discrimination
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“T is more abundant than A, and G is more abundant than C in intronic regions, which is consistent with previous studies (18, 19).”
BackgroundResultMeasurements of spontaneous rates of mutations in the recent past and the near future
Kondrashov, F. A., & Kondrashov, A. S. (2010) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2009.0286 · Cited by 110 · see citing works
Transcription induces strand-specific mutations at the 5′ end of human genesPreprint
Polak, P. P., & Arndt, P. F. (2008) · Genome Research · doi:10.1101/gr.076570.108 · Cited by 107 · see citing works
“The trend of the localized asymmetry that we found is opposite to the one that had been reported by Green et al. (2003). This discrepancy between the results may very well be explained by the fact that, in contrast to the previous study, we surveyed the whole genome and included a broader spectrum of transcripts into…”
BackgroundResultInfluentialNucleotide Frequency Variation Across Human GenesPreprint
Louie, E. (2003) · Genome Research · doi:10.1101/gr.1317703 · Cited by 105 · see citing works
“3 -UTRs contain binding sites for various regulatory proteins, such as the PUF or CPEB binding sites (Grzybowska et al. 2001; Wickens et al. 2002), as well as elements necessary for final processing of pre-mRNA, recognition of the poly(A) site, and the subsequent addition of the poly(A) tail…”
BackgroundComparative analysis of orthologous eukaryotic mRNAs: potential hidden functional signals
Shabalina, S. A. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh313 · Cited by 98 · see citing works
“Recently, signi®cant strand asymmetry, with an excess of G+T over A+C has been reported to exist in most mammalian genes and interpreted as a result of mutational pressure caused by transcription-coupled repair (49).”
BackgroundEöry, L., Halligan, D. L., & Keightley, P. D. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msp219 · Cited by 96 · see citing works
“Our analysis allows for the possibility that transcription-associated processes may affect the mutation rate (Green et al. 2003; Majewski 2003), so different mutation rate estimates are used for the transcribed and the untranscribed portions of the genome, assuming that IGs are not transcribed in the germline.”
BackgroundInfluentialMugal, C. F., & Ellegren, H. (2011) · Genome biology · doi:10.1186/gb-2011-12-6-r58 · Cited by 93 · see citing works
Neutral Mutations and Neutral Substitutions in Bacterial Genomes
Ochman, H. (2003) · Molecular Biology and Evolution · doi:10.1093/molbev/msg229 · Cited by 95 · see citing works
“…a gene has been sequenced in numerous strains or species of known phylogenetic relationships, it is possible to reconstruct the ancestral state by applying a parsimony approach, and to determine the polarity of individual substitutions (Francino et al. 1996; Duret et al. 2002; Green et al. 2003).”
MethodChamary, J., & Hurst, L. D. (2004) · Molecular Biology and Evolution · doi:10.1093/molbev/msh087 · Cited by 94 · see citing works
“These discrepancies cannot be the result of transcription-coupled processes (Green et al. 2003; Majewski 2003), nor to biased gene conversion (Galtier et al. 2001), both of which should affect introns and flanking exons equally.”
BackgroundManrubia, S., Cuesta, J. A., Aguirre, J., Ahnert, S. E., Altenberg, L., Cano, A. V., Catalán, P., Diaz-Uriarte, R., Elena, S. F., García-Martín, J. A., et al. (2021) · Physics of Life Reviews · doi:10.1016/j.plrev.2021.03.004 · Cited by 88 · see citing works
Transcription-coupled and splicing-coupled strand asymmetries in eukaryotic genomes
Touchon, M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh823 · Cited by 85 · see citing works
“First, in a comparative study of mammalian orthologous regions, asymmetries of nucleotide substitution rates were evidenced in transcribed regions (25).”
GC-compositional strand bias around transcription start sites in plants and fungi
Fujimori, S., Washio, T., & Tomita, M. (2005) · BMC Genomics · doi:10.1186/1471-2164-6-26 · Cited by 83 · see citing works
“Also, mammalian and enterobacterial genomes have been reported to show a strand bias associated with transcribed regions [6-8].”
Dependence of Mutational Asymmetry on Gene-Expression Levels in the Human Genome
Majewski, J. (2003) · The American Journal of Human Genetics · doi:10.1086/378134 · Cited by 82 · see citing works
“I used the HuGE Index Database (Haverty et al. 2002) to categorize genes by tissue specificity and expression levels.”
MethodDifferences in the rare variant spectrum among human populations
Mathieson, I., & Reich, D. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006581 · Cited by 82 · see citing works
Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease
Gratten, J., Visscher, P. M., Mowry, B. J., & Wray, N. R. (2013) · Nature Genetics · doi:10.1038/ng.2555 · Cited by 77 · see citing works
Mutation patterns in cancer genomes
Rubin, A. F., & Green, P. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912499106 · Cited by 80 · see citing works
Self-citationNo Evidence for Tissue-Specific Adaptation of Synonymous Codon Usage in Humans
Sémon, M., Lobry, J. R., & Duret, L. (2005) · Molecular Biology and Evolution · doi:10.1093/molbev/msj053 · Cited by 80 · see citing works
Comprehensive analysis of the base composition around the transcription start site in Metazoa
Aerts, S., Thijs, G., Dąbrowski, M., Moreau, Y., & Moor, B. D. (2004) · BMC Genomics · doi:10.1186/1471-2164-5-34 · Cited by 77 · see citing works
Patterns of Synonymous Codon Usage in Drosophila melanogaster Genes With Sex-Biased Expression
Hambuch, T. M., & Parsch, J. (2005) · Genetics · doi:10.1534/genetics.104.038109 · Cited by 76 · see citing works
Margulies, E. H., Program‡, N. C. S., Maduro, V. V. B., Thomas, P. J., Tomkins, J., Amemiya, C. T., Luo, M., & Green, E. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408539102 · Cited by 76 · see citing works
Self-citationOverlapping codes within protein-coding sequencesPreprint
Itzkovitz, S., Hodis, E., & Segal, E. (2010) · Genome Research · doi:10.1101/gr.105072.110 · Cited by 75 · see citing works
Transcription‐coupled TA and GC strand asymmetries in the human genome
Touchon, M., Nicolay, S., Arnéodo, A., d’Aubenton-Carafa, Y., & Thermes, C. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01306-1 · Cited by 72 · see citing works
Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans
Harpak, A., Bhaskar, A., & Pritchard, J. K. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006489 · Cited by 75 · see citing works
Replication-Associated Mutational Asymmetry in the Human Genome
Chen, C.-L., Duquenne, L., Audit, B., Guilbaud, G., Rappailles, A., Baker, A., Huvet, M., d’Aubenton-Carafa, Y., Hyrien, O., Arnéodo, A., et al. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr056 · Cited by 69 · see citing works
“The substitution rate asymmetries measured in intronic regions change their sign with the direction of transcription as shown previously (Green et al. 2003; Polak and Arndt 2009), but surprisingly their values also depend on their position on one side or the other of the S-jumps (e.”
BackgroundMethodResultInfluentialThe mutational spectrum of non-CpG DNA varies with CpG contentPreprint
Walser, J., & Furano, A. V. (2010) · Genome Research · doi:10.1101/gr.103283.109 · Cited by 71 · see citing works
Baker, A., Audit, B., Chen, C.-L., Moindrot, B., Leleu, A., Guilbaud, G., Rappailles, A., Vaillant, C., Goldar, A., Mongélard, F., et al. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002443 · Cited by 67 · see citing works
Transcription-Induced Mutational Strand Bias and Its Effect on Substitution Rates in Human Genes
Mugal, C. F., von Grünberg, H. H., & Peifer, M. (2008) · Molecular Biology and Evolution · doi:10.1093/molbev/msn245 · Cited by 66 · see citing works
“Finally, we show that in addition to transcription also the replication process biases the substitution rates in genes.”
BackgroundMethodResultInfluentialPopulation sequencing data reveal a compendium of mutational processes in the human germ line
Seplyarskiy, V. B., Soldatov, R., Koch, E. M., McGinty, R. J., Goldmann, J. M., Hernandez, R. D., Barnes, K. C., Correa, A., Burchard, E. G., Ellinor, P. T., et al. (2021) · Science · doi:10.1126/science.aba7408 · Cited by 65 · see citing works
“In line with previous studies, we defined clustered de novo mutations as pairs of mutations observed in the same individual at distances less than 20,000 nucleotides (13, 14).”
DNA Replication and Strand Asymmetry in Prokaryotic and Mitochondrial Genomes
Xia, X. (2012) · Current Genomics · doi:10.2174/138920212799034776 · Cited by 62 · see citing works
“1) whose flanking sequences change direction in GC skew [2, 10-14] or in the components of the Z-curve [11, 15-17].”
BackgroundThe Mutational Profile of the Yeast Genome Is Shaped by Replication
Agier, N., & Fischer, G. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr280 · Cited by 61 · see citing works
Human Genome Replication Proceeds through Four Chromatin States
Julienne, H., Zoufir, A., Audit, B., & Arnéodo, A. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003233 · Cited by 60 · see citing works
Transcription-Associated Genome Instability
Gaillard, H., Herrera‐Moyano, E., & Aguilera, A. (2013) · Chemical Reviews · doi:10.1021/cr400017y · Cited by 59 · see citing works
Marín, A., & Xia, X. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2008.04.004 · Cited by 60 · see citing works
“The strand compositional asymmetry is strong enough to identify the location of the bacterial origin of replication whose flanking sequences change direction in GC skew (Frank and Lobry, 2000; Green et al., 2003; Lobry, 1996; Worning et al., 2006; Zhang and Li, 2003; Zhang and Zhang, 2003).”
BackgroundKondrashov, F. A., Ogurtsov, A. Y., & Kondrashov, A. S. (2005) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2005.10.020 · Cited by 55 · see citing works
“The exon–intron contrasts also argue against transcription- coupled repair bias (Green et al., 2003; Majewski, 2003) as a cause of patterns reported here.”
BackgroundCharacterizing the strand-specific distribution of non-CpG methylation in human pluripotent cells
Guo, W., Chung, W.-Y., Qian, M., Pellegrini, M. A., & Zhang, M. Q. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1306 · Cited by 59 · see citing works
Seplyarskiy, V. B., Koch, E. M., Lee, D. J., Lichtman, J. S., Luan, H. H., & Sunyaev, S. R. (2023) · Nature Genetics · doi:10.1038/s41588-023-01562-0 · Cited by 51 · see citing works
“Site-specific mutation rate estimates are a necessary input to genetic methods with applications ranging from rare disease gene mapping 17–19 to estimation of selective constraint 7,20,21 , while many others are sensitive to mutation rate variation.”
BackgroundTransfer RNA genes experience exceptionally elevated mutation rates
Thornlow, B. P., Hough, J., Roger, J. M., Gong, H. Z., Lowe, T. M., & Corbett-Detig, R. B. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801240115 · Cited by 56 · see citing works
Causes and evolutionary consequences of primordial germ-cell specification mode in metazoans
Whittle, C. A., & Extavour, C. G. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610600114 · Cited by 54 · see citing works
New insights into the interplay between codon bias determinants in plants
Camiolo, S., Melito, S., & Porceddu, A. (2015) · DNA Research · doi:10.1093/dnares/dsv027 · Cited by 54 · see citing works
“The positive association between the RSCU value and expression level of codons ending inT is reminiscent of transcription-associatedmutational bias (TAMB), a well-known repair system that increases bias towards G|T rather thanC|A in the pre-mRNA sequence.(34) For this reason, we repeated our analysis by constructing a…”
MethodNikolaou, C. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki988 · Cited by 54 · see citing works
“Recently, transcription coupled asymmetry of nucleotide transition rates was also reported in mammalian genomes (14,15).”
BackgroundMethodFixation biases affecting human SNPs
Webster, M. T., & Smith, N. G. C. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.01.005 · Cited by 53 · see citing works
The Variation of Base Composition in Plant Genomes
Šmarda, P., & Bureš, P. (2012) · Springer eBooks · doi:10.1007/978-3-7091-1130-7_14 · Cited by 54 · see citing works
The Relationship between DNA Replication and Human Genome Organization
Necşulea, A., Guillet, C., Cadoret, J., Prioleau, M., & Duret, L. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msn303 · Cited by 50 · see citing works
Mutational pattern and frequency of induced nucleotide changes in mouse ENU mutagenesis
Takahasi, K. R., Sakuraba, Y., & Gondo, Y. (2007) · BMC Molecular Biology · doi:10.1186/1471-2199-8-52 · Cited by 49 · see citing works
Codon usage trend in mitochondrial CYB gene.
Uddin, A., & Chakraborty, S. (2016) · Gene · doi:10.1016/j.gene.2016.04.005 · Cited by 44 · see citing works
Estimates of the Effect of Natural Selection on Protein-Coding Content
Yap, V. B., Lindsay, H. A., Easteal, S., & Huttley, G. A. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msp232 · Cited by 47 · see citing works
“We chose primate introns as they experience the same mutagenic environment as their flanking exons (Green et al. 2003; Duret et al. 2006; Elango et al. 2008), they are not affected by selection for protein-coding content, and they are mostly nonfunctional (Siepel et al.”
BackgroundDeb, B., Uddin, A., & Chakraborty, S. (2021) · Archives of Virology · doi:10.1007/s00705-020-04890-2 · Cited by 47 · see citing works
- Authors
- Program, N. C. S., Green, P., Ewing, B., Miller, W., Thomas, P. J., & Green, E. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Pennsylvania State University (US)
- National Institutes of Health (US)
- Corresponding author
- Green, Phil
- ORCID
- Green, Eric D.
- Venue
- Nature Genetics
- Published
- 2003-03-03
- Volume
- 33
- Issue
- 4
- Pages
- 514-517
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2087627409
- Cited by
- 285
- References
- 29
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 16 · 2015: 15 · 2014: 13 · 2013: 18 · 2012: 18
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- strand asymmetry, cytosine deamination, transcription-coupled repair, germ cells, compositional asymmetry, GC content, DNA replication, mammalian evolution, nucleotide substitution rates
- MeSH terms
- Animals, Chromosomes, Human, Pair 22, DNA Mutational Analysis, Biological Evolution, Humans, Models, Genetic, Papio, RNA, Messenger, Transcription, Genetic, Sequence Analysis, DNA, CpG Islands, Cell Lineage, Databases as Topic
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