Biased clustered substitutions in the human genome: The footprints of male-driven biased gene conversion
Open accessAbstract
We examined fixed substitutions in the human lineage since divergence from the common ancestor with the chimpanzee, and determined what fraction are AT to GC (weak-to-strong). Substitutions that are densely clustered on the chromosomes show a remarkable excess of weak-to-strong “biased” substitutions. These unexpected biased clustered substitutions (UBCS) are common near the telomeres of all autosomes but not the sex chromosomes. Regions of extreme bias are enriched for genes. Human and chimp orthologous regions show a striking similarity in the shape and magnitude of their respective UBCS maps, suggesting a relatively stable force leads to clustered bias. The strong and stable signal near telomeres may have participated in the evolution of isochores. One exception to the UBCS pattern found in all autosomes is chromosome 2, which shows a UBCS peak midchromosome, mapping to the fusion site of two ancestral chromosomes. This provides evidence that the fusion occurred as recently as 740,000 years ago and no more than ∼3 million years ago. No biased clustering was found in SNPs, suggesting that clusters of biased substitutions are selected from mutations. UBCS is strongly correlated with male (and not female) recombination rates, which explains the lack of UBCS signal on chromosome X. These observations support the hypothesis that biased gene conversion (BGC), specifically in the male germline, played a significant role in the evolution of the human genome.
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The HSA2 fusion formed approximately 0.9 Mya (95% CI 0.4-1.5 Mya), estimated by UBCS analysis comparing chimpanzee and modern human genomes.
“By analyzing the enrichment of these substitutions around the fusion site of HSA2 we estimated its formation time at 0.9 Mya with a 95% confidence interval of 0.4-1.5 Mya.”
From Revised time estimation of the ancestral human chromosome 2 fusion (2022) · cites this paper as [11]
The ‘Dating the fusion of chromosome 2’ section confirms that the authors estimated the fusion date by comparing the human fusion-region UBCS peak with orthologous chimpanzee regions. But ‘Human chromosome 2 fusion retains bias’ reports 0.74 Mya with a 95% confidence interval of 0–2.81 Mya, not 0.9 Mya (0.4–1.5 Mya). (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe ratio of UBCS between the p and q arms of any chromosome is not similar for human and chimpanzee, violating Dreszer et al.'s assumption.
“This assumption is clearly violated in the data and therefore we have devised a different estimation procedure.”
From Revised time estimation of the ancestral human chromosome 2 fusion (2022) · cites this paper as [11]
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
UniProt: the Universal Protein knowledgebase
Apweiler, R. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh131 · Cited by 7,535 · see citing works
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858 · see citing works
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes
Siepel, A., Bejerano, G., Pedersen, J. S., Hinrichs, A. S., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L. W., Richards, S., et al. (2005) · Genome Research · doi:10.1101/gr.3715005 · Cited by 4,408 · cited 1× · see citing works
“methods (Siepel et al. 2005) available in the “conservation” track of the UCSC Genome Browser (hg17).”
MethodSelf-citationA map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms
The International SNP Map Working Group, Laboratories:, C. S. H., Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., National Center for Biotechnology Information:, Marth, G., Sherry, S., et al. (2001) · Nature · doi:10.1038/35057149 · Cited by 2,977 · see citing works
Initial sequence of the chimpanzee genome and comparison with the human genome
The Chimpanzee Sequencing and Analysis Consortium (2005) · Nature · doi:10.1038/nature04072 · Cited by 2,459 · see citing works
The UCSC Genome Browser Database
Karolchik, D. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg129 · Cited by 1,887 · see citing works
A high-resolution recombination map of the human genome
Kong, A., Gudbjartsson, D. F., Sainz, J., Jonsdottir, G. M., Gudjonsson, S. A., Richardsson, B., Sigurdardottir, S. L., Barnard, J., Hallbeck, B., Másson, G., et al. (2002) · Nature Genetics · doi:10.1038/ng917 · Cited by 1,750 · see citing works
Evolutionary and biomedical insights from the rhesus macaque genome.
Gibbs, R. A., Rogers, J., Katze, M. G., Bumgarner, R., Weinstock, G. M., Mardis, E. R., Remington, K. A., Strausberg, R. L., Venter, J. C., Wilson, R. K., et al. (2007) · Science · doi:10.1126/science.1139247 · Cited by 1,403 · see citing works
Self-citationA Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome
Myers, S., Bottolo, L., Freeman, C., McVean, G., & Donnelly, P. (2005) · Science · doi:10.1126/science.1117196 · Cited by 1,134 · see citing works
Benson, D. A. (2004) · Nucleic Acids Research · doi:10.1093/nar/gki063 · Cited by 1,020 · see citing works
An RNA gene expressed during cortical development evolved rapidly in humans
Pollard, K. S., Salama, S. R., Lambert, N., Lambot, M.-A., Coppens, S., Pedersen, J. S., Katzman, S., King, B., Onodera, C., Siepel, A., et al. (2006) · Nature · doi:10.1038/nature05113 · Cited by 1,005 · see citing works
Self-citationDirectional mutation pressure and neutral molecular evolution.
Sueoka, N. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.8.2653 · Cited by 978 · see citing works
The mosaic genome of warm-blooded vertebrates
Bernardi, G., Olofsson, B., Filipski, J., Zerial, M., Salinas, J., Cuny, G., Meunier-Rotival, M., & Rodier, F. (1985) · Science · doi:10.1126/science.4001930 · Cited by 875 · see citing works
Mutation rates differ among regions of the mammalian genome
Wolfe, K. H., Sharp, P. M., & Li, W. (1989) · Nature · doi:10.1038/337283a0 · Cited by 595 · see citing works
Genetic evidence for complex speciation of humans and chimpanzees
Patterson, N. J., Richter, D. J., Gnerre, S., Lander, E. S., & Reich, D. (2006) · Nature · doi:10.1038/nature04789 · Cited by 582 · see citing works
Isochores and the evolutionary genomics of vertebrates
Bernardi, G. (2000) · Gene · doi:10.1016/s0378-1119(99)00485-0 · Cited by 572 · see citing works
Kim, E., Cho, K.-O., Rothschild, A., & Sheng, M. (1996) · Neuron · doi:10.1016/s0896-6273(00)80284-6 · Cited by 558 · see citing works
Forces shaping the fastest evolving regions in the human genome
Pollard, K. S., Salama, S. R., King, B., Kern, A. D., Dreszer, T., Katzman, S., Siepel, A., Pedersen, J. S., Bejerano, G., Baertsch, R., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020168 · Cited by 511 · see citing works
Self-citationEvolution of synonymous codon usage in metazoans
Duret, L. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00353-2 · Cited by 505 · see citing works
Benson, D. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh045 · Cited by 493 · see citing works
High Guanine and Cytosine Content Increases mRNA Levels in Mammalian Cells
Kudla, G., Lipinski, L., Caffin, F., Helwak, A., & Zylicz, M. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040180 · Cited by 476 · see citing works
Compositional constraints and genome evolution
Bernardi, G., & Bernardi, G. (1986) · Journal of Molecular Evolution · doi:10.1007/bf02099946 · Cited by 462 · see citing works
Chromosomal Speciation and Molecular Divergence--Accelerated Evolution in Rearranged Chromosomes
Navarro, A., & Barton, N. (2003) · Science · doi:10.1126/science.1080600 · Cited by 453 · see citing works
Eyre‐Walker, A., & Hurst, L. D. (2001) · Nature Reviews Genetics · doi:10.1038/35080577 · Cited by 411 · see citing works
Origin of human chromosome 2: an ancestral telomere-telomere fusion.
IJdo, J. W., Baldini, A., Ward, D. C., Reeders, S. T., & Wells, R. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.20.9051 · Cited by 382 · see citing works
Comparison of Fine-Scale Recombination Rates in Humans and Chimpanzees
Winckler, W., Myers, S. R., Richter, D. J., Onofrio, R. C., McDonald, G. J., Bontrop, R. E., McVean, G., Gabriel, S., Reich, D., Donnelly, P., et al. (2005) · Science · doi:10.1126/science.1105322 · Cited by 357 · see citing works
Karolchik, D., Hinrichs, A. S., & Kent, W. J. (2009) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi0104s28 · Cited by 349 · see citing works
Recombination Drives the Evolution of GC-Content in the Human Genome
Meunier, J., & Duret, L. (2004) · Molecular Biology and Evolution · doi:10.1093/molbev/msh070 · Cited by 337 · see citing works
The connection between transcription and genomic instability
Aguilera, A. (2002) · The EMBO Journal · doi:10.1093/emboj/21.3.195 · Cited by 328 · see citing works
Comparison of human genetic and sequence-based physical maps
Yu, A., Zhao, C., Fan, Y., Jang, W., Mungall, A. J. J., Deloukas, P., Olsen, A. S., Doggett, N. A., Ghebranious, N., Broman, K. W., et al. (2001) · Nature · doi:10.1038/35057185 · Cited by 273 · see citing works
Birdsell, J. A. (2002) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a004176 · Cited by 258 · see citing works
Recombination and mammalian genome evolution
Eyre‐Walker, A. (1993) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1993.0071 · Cited by 236 · see citing works
Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot
Jeffreys, A. J., & Neumann, R. (2002) · Nature Genetics · doi:10.1038/ng910 · Cited by 235 · see citing works
Brown, T. C., & Jiricny, J. (1988) · Cell · doi:10.1016/s0092-8674(88)80015-1 · Cited by 230 · see citing works
Ozawa, T. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni032 · Cited by 224 · see citing works
Li, W. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00354-4 · Cited by 224 · see citing works
Cytosine Deamination Plays a Primary Role in the Evolution of Mammalian Isochores
Fryxell, K. J., & Zuckerkandl, E. (2000) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a026420 · Cited by 214 · see citing works
Matthes, H. W. D., Boschert, U., Amlaiky, N., Grailhe, R., Plassat, J., Muscatelli, F., Mattéi, M., & Hen, R. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13615-8 · Cited by 210 · see citing works
Holt, W. V., & Look, K. J. W. V. (2004) · Reproduction · doi:10.1530/rep.1.00134 · Cited by 200 · see citing works
Vanishing GC-Rich Isochores in Mammalian Genomes
Duret, L., Sémon, M., Piganeau, G., Mouchiroud, D., & Galtier, N. (2002) · Genetics · doi:10.1093/genetics/162.4.1837 · Cited by 199 · see citing works
Briggs, S. D., & Strahl, B. D. (2002) · Nature Genetics · doi:10.1038/ng0302-241 · Cited by 198 · see citing works
Evolution of a finite population under gene conversion.
Nagylaki, T. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.20.6278 · Cited by 197 · see citing works
Maki, H. (2002) · Annual Review of Genetics · doi:10.1146/annurev.genet.36.042602.094806 · Cited by 191 · see citing works
Eyre‐Walker, A. (1999) · Genetics · doi:10.1093/genetics/152.2.675 · Cited by 191 · see citing works
How much do we know about spontaneous human mutation rates?
Crow, J. F. (1993) · Environmental and Molecular Mutagenesis · doi:10.1002/em.2850210205 · Cited by 150 · see citing works
Low Levels of Nucleotide Diversity in Mammalian Y Chromosomes
Hellborg, L. (2003) · Molecular Biology and Evolution · doi:10.1093/molbev/msh008 · Cited by 141 · see citing works
Webb, J. C., Patel, D. D., Jones, M. D., Knight, B. L., & Soutar, A. K. (1994) · Human Molecular Genetics · doi:10.1093/hmg/3.4.531 · Cited by 133 · see citing works
Neutral theory of molecular evolution
Takahata, N. (1996) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(96)80034-7 · Cited by 132 · see citing works
A unification of mosaic structures in the human genome
Lercher, M. J., Urrutia, A. O., Pavlı́ček, A., et al. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg251 · Cited by 131 · see citing works
Isochores and tissue-specificity
Vinogradov, A. E. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg699 · Cited by 111 · see citing works
A new perspective on isochore evolution
Duret, L., Eyre‐Walker, A., & Galtier, N. (2006) · Gene · doi:10.1016/j.gene.2006.04.030 · Cited by 100 · see citing works
Lercher, M. J., Williams, E. J. B., & Hurst, L. D. (2001) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a003744 · Cited by 97 · see citing works
Transcription Stimulates Homologous Recombination in Mammalian Cells
Nickoloff, J. A., & Reynolds, R. J. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.9.4837 · Cited by 96 · see citing works
Recombination between DNA repeats in yeast hpr1Δ cells is linked to transcription elongation
Prado, F., Piruat, J. I., & Aguilera, A. (1997) · The EMBO Journal · doi:10.1093/emboj/16.10.2826 · Cited by 94 · see citing works
Reduced X-Linked Diversity in Derived Populations of House Mice
Baines, J. F., & Harr, B. (2007) · Genetics · doi:10.1534/genetics.106.069419 · Cited by 89 · see citing works
Modeling dependencies in pre-mRNA splicing signals
Burge, C. B. (1998) · New comprehensive biochemistry · doi:10.1016/s0167-7306(08)60465-2 · Cited by 86 · see citing works
The scale of mutational variation in the murid genomePreprint
Gaffney, D. J., & Keightley, P. D. (2005) · Genome Research · doi:10.1101/gr.3895005 · Cited by 84 · see citing works
Substitution Rates in the X- and Y-Linked Genes of the Plants, Silene latifolia and S. dioica
Filatov, D. A., & Charlesworth, D. (2002) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a004147 · Cited by 80 · see citing works
Compositional Evolution of Noncoding DNA in the Human and Chimpanzee Genomes
Webster, M. T. (2003) · Molecular Biology and Evolution · doi:10.1093/molbev/msg037 · Cited by 79 · see citing works
Belle, E. M. S., Duret, L., Galtier, N., & Eyre‐Walker, A. (2004) · Journal of Molecular Evolution · doi:10.1007/s00239-004-2587-x · Cited by 72 · see citing works
Male-Driven Biased Gene Conversion Governs the Evolution of Base Composition in Human Alu Repeats
Webster, M. T., Smith, N. G. C., Hultin‐Rosenberg, L., et al. (2005) · Molecular Biology and Evolution · doi:10.1093/molbev/msi136 · Cited by 69 · see citing works
The Evolution of Isochores: Evidence From SNP Frequency Distributions
Lercher, M. J., Smith, N. G. C., Eyre‐Walker, A., & Hurst, L. D. (2002) · Genetics · doi:10.1093/genetics/162.4.1805 · Cited by 65 · see citing works
Wei, M.-H., Karavanova, I. D., Ivanov, S. V., Popescu, N. C., Keck, C. L., Pack, S., Eisen, J. A., & Lerman, M. I. (1998) · Human Genetics · doi:10.1007/s004390050829 · Cited by 63 · see citing works
Persistence and Loss of Meiotic Recombination Hotspots
Pineda‐Krch, M., & Redfield, R. J. (2005) · Genetics · doi:10.1534/genetics.104.034363 · Cited by 61 · see citing works
Goetting‐Minesky, M. P., & Makova, K. D. (2006) · Journal of Molecular Evolution · doi:10.1007/s00239-005-0308-8 · Cited by 55 · see citing works
Fixation 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
Transcription Stimulates Homologous Recombination in Mammalian Cells
Nickoloff, J. A., & Reynolds, R. J. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.9.4837-4845.1990 · Cited by 35 · see citing works
Bell, S. J., Chow, Y.-L., Ho, J. Y. K., et al. (1998) · Gene · doi:10.1016/s0378-1119(98)00333-3 · Cited by 28 · see citing works
Dipeptidyl Peptidase IV Gene Family
Chen, T., Ajami, K., McCaughan, G. W., et al. (2005) · Kluwer Academic Publishers eBooks · doi:10.1007/0-306-47920-6_10 · Cited by 27 · see citing works
The role of CSMD1 in head and neck carcinogenesis
Scholnick, S. B., & Richter, T. M. (2003) · Genes Chromosomes and Cancer · doi:10.1002/gcc.10279 · Cited by 21 · see citing works
Schmegner, C., Hoegel, J. J., Vogel, W., et al. (2006) · Genetics · doi:10.1534/genetics.106.064386 · Cited by 12 · see citing works
Lipatov, M., Arndt, P. F., Hwa, T., et al. (2005) · Journal of Molecular Evolution · doi:10.1007/s00239-005-0207-z · Cited by 11 · see citing works
Isochores Exhibit Evidence of Genes Interacting With the Large-Scale Genomic Environment
Press, W. H., & Robins, H. S. (2006) · Genetics · doi:10.1534/genetics.105.054445 · Cited by 8 · see citing works
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Research works printed but not linked: 2
- [18]18. Dreszer, T. 2006. "Biased clustered substitutions in the human genome: Sex, gambling and non-Darwinian evolution." M.S. thesis, University of California, Santa Cruz. http://www.soe.ucsc.edu/ research/compbio/ubcs/Thesis.pdf
- [51]51. National Center for Biotechnology Information. 2002. NCBI handbook. National Library of Medicine (U.S.), National Center for Biotechnology Information, Bethesda, MD. http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?db=Books.
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Influential
- Authors
- Dreszer, T. R., Wall, G. D., Haussler, D., & Pollard, K. S.
- Affiliations
- University of California, Santa Cruz (US)
- University of California, Davis (US)
- Howard Hughes Medical Institute (US)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-09-04
- Volume
- 17
- Issue
- 10
- Pages
- 1420-1430
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC1987345
- OpenAlex
- W2143699138
- Cited by
- 112
- References
- 75
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 15 · 2020: 4 · 2019: 3 · 2018: 4 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 8
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genome Research (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- biased gene conversion, human-chimpanzee divergence, telomeres, isochores, recombination rate, male germline, sex chromosomes, orthologous regions, karyotype evolution, human genome evolution
- MeSH terms
- Animals, Pan troglodytes, Chromosomes, Human, Pair 2, Female, Gene Conversion, Humans, Male, Models, Genetic, Recombination, Genetic, Sex Characteristics, Species Specificity, Time Factors, Genome, Human, Telomere, Evolution, Molecular, Polymorphism, Single Nucleotide, Chromosomes, Human, X, Chromosomes, Human, Y, Gene Fusion
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