Journal of Molecular Evolution

, Volume 60, Issue 6, pp 748–763 | Cite as

Substantial Regional Variation in Substitution Rates in the Human Genome: Importance of GC Content, Gene Density, and Telomere-Specific Effects

  • Peter F. ArndtEmail author
  • Terence Hwa
  • Dmitri A. Petrov


This study presents the first global, 1-Mbp-level analysis of patterns of nucleotide substitutions along the human lineage. The study is based on the analysis of a large amount of repetitive elements deposited into the human genome since the mammalian radiation, yielding a number of results that would have been difficult to obtain using the more conventional comparative method of analysis. This analysis revealed substantial and consistent variability of rates of substitution, with the variability ranging up to twofold among different regions. The rates of substitutions of C or G nucleotides with A or T nucleotides vary much more sharply than the reverse rates, suggesting that much of that variation is due to differences in mutation rates rather than in the probabilities of fixation of C/G vs. A/T nucleotides across the genome. For all types of substitution we observe substantially more hotspots than coldspots, with hotspots showing substantial clustering over tens of Mbp’s. Our analysis revealed that GC-content of surrounding sequences is the best predictor of the rates of substitution. The pattern of substitution appears very different near telomeres compared to the rest of the genome and cannot be explained by the genome-wide correlations of the substitution rates with GC content or exon density. The telomere pattern of substitution is consistent with natural selection or biased gene conversion acting to increase the GC-content of the sequences that are within 10–15 Mbp away from the telomere.


Genome evolution Nucleotide substitution Genomic isochores Short interspersed elements 



T.H. is supported by the NSF through Grants 0211308, 0216576, and 0225630. D.P. is supported by NSF Grant DEB-0317171, the Terman Award, and the Alfred P. Sloan Fellowship in Computational Molecular Biology. P.A. and D.P. are grateful for the hospitality of the Center for Theoretical Biological Physics at UCSD, where extensive discussions of this research took place.


  1. Arndt PF (2004) Identification and measurement of neighbor dependent nucleotide substitution process. Lecture Notes in Informatics P-53 (2004) 227–234; accepted for publication in Bioinformatics (2005). Google Scholar
  2. Arndt, PF, Burge, CB, Hwa, T 2003aDNA sequence evolution with neighbor-dependent mutationJ Comput Biol10313322CrossRefGoogle Scholar
  3. Arndt, PF, Petrov, DA, Hwa, T 2003bDistinct changes of genomic biases in nucleotide substitution at the time of mammalian radiationMol Biol Evol2618871896CrossRefGoogle Scholar
  4. Bernardi, G 2000Isochores and the evolutionary genomics of vertebratesGene241317CrossRefPubMedGoogle Scholar
  5. Box, MJ 1966A comparison of several current optimization methods and use of transformations in constrained problemsCompute J96777Google Scholar
  6. Britten, RJ, Baron, WF, Stout, DB, Davidson, EH 1988Sources and evolution of human Alu repeated sequencesProc Natl Acad Sci USA8547704774PubMedGoogle Scholar
  7. Caspersson, T, Castleman, KR, Lomakka, G, Modest, EJ, Moller, A, Nathan, R, Wall, RJ, Zech, L 1971Automatic karyotyping of quinacrine mustard stained human chromosomesExp Cell Res67233235CrossRefPubMedGoogle Scholar
  8. Cheung, VG, Nowak, N, Jang, W,  et al. 2001Integration of cytogenetic landmarks into the draft sequence of the human genomeNature409953988CrossRefPubMedGoogle Scholar
  9. Coulondre, C, Miller, JH, Farabaugh, PJ, Gilbert, W 1978Molecular basis of base substitution hotspots in Escherichia coliNature274775780PubMedGoogle Scholar
  10. Duret, L, Galtier, N 2000The covariation between TpA deficiency, CpG deficiency, and G+C content of human isochores is due to a mathematical artifactMol Biol Evol1716201625PubMedGoogle Scholar
  11. Duret, L, Semon, M, Piganeau, G, Mouchiroud, D, Galtier, N 2002Vanishing GC-rich isochores in mammalian genomesGenetics16218371847PubMedGoogle Scholar
  12. Ellegren, H, Smith, NG, Webster, MT 2003Mutation rate variation in the mammalian genomeCurr Opin Genet Dev13562568CrossRefPubMedGoogle Scholar
  13. Eyre-Walker, A, Hurst, LD 2001The evolution of isochoresNature Rev Genet2549555CrossRefGoogle Scholar
  14. Filipski, J, Thiery, JP, Bernard, G 1973An analysis of the bovine genome by Cs2SO4-Ag density gradient centrifugationJ Mol Biol80177197CrossRefPubMedGoogle Scholar
  15. Fryxell, KJ, Zuckerkandl, E 2000Cytosine deamination plays a primary role in the evolution of mammalian isochoresMol Biol Evol1713711383PubMedGoogle Scholar
  16. Furey, TS, Haussler, D 2003Integration of the cytogenetic map with the draft human genome sequenceHum Mol Genet1210371044CrossRefPubMedGoogle Scholar
  17. Hardison, RC, Roskin, KM, Yang, S,  et al. 2003Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolutionGenome Res131326CrossRefPubMedGoogle Scholar
  18. Hess, ST, Blake, JD, Blake, RD 1994Wide variations in neighbor-dependent substitution ratesJ Mol Biol23610221033CrossRefPubMedGoogle Scholar
  19. Hubbard, T, Barker, D, Birney, E,  et al. 2002The Ensembl genome database projectNucleic Acids Res303841CrossRefPubMedGoogle Scholar
  20. Jurka, J 2000Repbase update: a database and an electronic journal of repetitive elementsTrends Genet16418420PubMedGoogle Scholar
  21. Jurka, J, Smith, T 1988A fundamental division in the Alu family of repeated sequencesProc Natl Acad Sci USA8547754778PubMedGoogle Scholar
  22. Kapitonov, V, Jurka, J 1996The age of Alu subfamiliesJ Mol Evol425965PubMedGoogle Scholar
  23. Kong, A, Gudbjartsson, DF, Sainz, J,  et al. 2002A high-resolution recombination map of the human genomeNature Genet31241247PubMedGoogle Scholar
  24. Kritzer, HM 1980comparing partial order correlations from contingency table dataSociol Methods Res8420433Google Scholar
  25. Kumar, S, Subramanian, S 2002Mutation rates in mammalian genomesProc Natl Acad Sci USA99803808CrossRefPubMedGoogle Scholar
  26. Lander, ES, Linton, LM, Birren, B,  et al. 2001Initial sequencing and analysis of the human genomeNature409860921CrossRefPubMedGoogle Scholar
  27. Lerche, MJ, Urrutia, AO, Pavlicek, A, Hurst, LD 2003A unification of mosaic structures in the human genomeHum Mol Genet1224112415CrossRefPubMedGoogle Scholar
  28. Lercher, MJ, Chamary, JV, Hurst, LD 2004Genomic regionally in rate of evolution is not explained by clustering of genes of comparable expression profileGenome Res1410021013CrossRefPubMedGoogle Scholar
  29. Meunier, J, Duret, L 2004Recombination drives the evolution of GC-content in the human genomeMol Biol Evol21984990CrossRefPubMedGoogle Scholar
  30. Mouchiroud, D, D’Onofrio, G, Aissani, B, Macaya, G, Gautier, C, Bernardi, G 1991The distribution of genes in the human genomeGene100181187CrossRefPubMedGoogle Scholar
  31. Press, WH, Teukolsky, SA, Vetterling, WT, Flannery, BP 1992Numerical recipes in C. The art of scientific computingCambridge University PressCambridgeGoogle Scholar
  32. Rabinowicz, PD, Palmer, LE, May, BP, Hemann, MT, Lowe, SW, McCombie, WR, Martienssen, RA 2003Genes and transposons are differentially methylated in plants, but not in mammalsGenome Res1326582664CrossRefPubMedGoogle Scholar
  33. Razin, A, Riggs, AD 1980DNA methylation and gene functionScience210604610PubMedGoogle Scholar
  34. Saccone, S, De Sario, A, Wiegant, J, Raap, AK, Delia Valle, G, Bernard, G 1993Correlations between isochores and chromosomal bands in the human genomeProc Natl Acad Sci USA901192911933PubMedGoogle Scholar
  35. Smith, NG, Webster, MT, Ellegren, H 2002Deterministic mutation rate variation in the human genomeGenome Res1213501356CrossRefPubMedGoogle Scholar
  36. Subramanian, S, Kumar, S 2003Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomesGenome Res13838844CrossRefPubMedGoogle Scholar
  37. Waterston, RH, Lindblad-Toh, K, Birney, E,  et al. 2002Initial sequencing and comparative analysis of the mouse genomeNature420520562CrossRefPubMedGoogle Scholar
  38. Yoder, JA, Walsh, CP, Bestor, TH 1997Cytosine methylation and the ecology of intragenomic parasitesTrends Genet13335340PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Peter F. Arndt
    • 1
    Email author
  • Terence Hwa
    • 2
  • Dmitri A. Petrov
    • 3
  1. 1.Max Planck Institute for Molecular GeneticsBerlinGermany
  2. 2.Department of Physics and Center for Theoretical Biological PhysicsUC San DiegoLa JollaUSA
  3. 3.Department of Biological SciencesStanford UniversityStanfordUSA

Personalised recommendations