Evolutionary Biology

, Volume 34, Issue 3–4, pp 144–151 | Cite as

Understanding Neutral Genomic Molecular Clocks

  • Soojin V. YiEmail author


The molecular clock hypothesis is a central concept in molecular evolution and has inspired much research into why evolutionary rates vary between and within genomes. In the age of modern comparative genomics, understanding the neutral genomic molecular clock occupies a critical place. It has been demonstrated that molecular clocks run differently between closely related species, and generation time is an important determinant of lineage specific molecular clocks. Moreover, it has been repeatedly shown that regional molecular clocks vary even within a genome, which should be taken into account when measuring evolutionary constraint of specific genomic regions. With the availability of a large amount of genomic sequence data, new insights into the patterns and causes of variation in molecular clocks are emerging. In particular, factors such as nucleotide composition, molecular origins of mutations, weak selection and recombination rates are important determinants of neutral genomic molecular clocks.


Molecular clock Generation time effect Regional heterogeneity 


  1. Akashi, H. (1994). Synonymous codon usage in Drosophila melanogaster: Natural selection and translational accuracy. Genetics, 136(3), 927–935.PubMedGoogle Scholar
  2. Akashi, H. (2001). Gene expression and molecular evolution. Current Opinion in Genetics & Development, 11, 660–666.CrossRefGoogle Scholar
  3. Birdsell, J. A. (2002). Integrating genomics, bioinformatics, and classical genetics to study the effects of recombination on genome evolution. Molecular Biology and Evolution, 19, 1181–1197.PubMedGoogle Scholar
  4. Bohossian, H. B., Skaletsky, H., & Page, D. C. (2000). Unexpectedly similar rates of nucleotide substitution found in male and female hominids. Nature, 406, 622–625.PubMedCrossRefGoogle Scholar
  5. Britten, R. J. (1986). Rates of DNA sequence evolution differ between taxonomic groups. Science, 231, 1393–1398.PubMedCrossRefGoogle Scholar
  6. Bromham, L., & Penny, D. (2003). The modern molecular clock. Nature Reviews Genetics, 4, 216–224.PubMedCrossRefGoogle Scholar
  7. Cannarozzi, G., Schneider, A., & Gonnet, G. (2007). A phylogenomic study of human, dog and mouse. PLoS Computational Biology, 3(1), e2.PubMedCrossRefGoogle Scholar
  8. Castresana, J. (2002). Estimation of genetic distances from human and mouse introns. Genome Biology, 3(6), research0028.1–0028.7.CrossRefGoogle Scholar
  9. Chamary, J. V., Parmley, J. L., & Hurst, L. D. (2006). Hearing silence: Non-neutral evolution at synonymous sites in mammals. Nature Reviews Genetics, 7, 98–108.PubMedCrossRefGoogle Scholar
  10. Chang, B. H., Shimmin, L. C., Shyue, S.-K., Hewett-Emmett, D., & Li, W.-H. (1994). Weak male-driven molecular evolution in rodents. Proceedings of the National Academy of Sciences of the United States of America, 91, 827–831.PubMedCrossRefGoogle Scholar
  11. Chen, F. C., & Li, W.-H. (2001). Genomic divergence between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. American Journal of Human Genetics, 68, 444–456.PubMedCrossRefGoogle Scholar
  12. Cheng, J., Kapranov, P., Drenkow, J., Dike, S., Brubaker, S., Patel, S., et al. (2005). Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science, 308(5725), 1149–1154.PubMedCrossRefGoogle Scholar
  13. Chimpanzee Sequencing and Analysis Consortium. (2005). Initial sequence of the chimpanzee genome and comparison with the human genome. Nature, 437, 69–87.CrossRefGoogle Scholar
  14. Dermitzakis, E. T., Reymond, A., Lyle, R., Scamuffa, N., Ucla, C., Deutsch, S., et al. (2002). Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature, 420, 578–582.PubMedCrossRefGoogle Scholar
  15. Drummond, D. A., Bloom, J. D., Adami, C., Wilke, C. O., & Arnod, F. H. (2005). Why highly expressed proteins evolve slowly. Proceedings of the National Academy of Sciences of the United States of America, 102, 14338–14343.PubMedCrossRefGoogle Scholar
  16. Easteal, S. (1991). The relative ratae of DNA evolution in primates. Molecular Biology and Evolution, 8(1), 115–127.PubMedGoogle Scholar
  17. Ellegren, H., & Fridolfsson, A. K. (1997). Male-driven evolution of DNA sequences in birds. Nature Genetics, 17, 182–184.PubMedCrossRefGoogle Scholar
  18. Filipski, J. (1988). Why the rate of silent codon substitutions is variable within a vertebrate’s genome. Journal of Theoretical Biology, 134(2), 159–164.PubMedCrossRefGoogle Scholar
  19. Fullerton, S. M., Bernardo-Carvalho, A., & Clark, A. G. (2001). Local rates of recombination are positively correlated with GC content in the human genome. Molecular Biology and Evolution, 18(6), 1139–1142.PubMedGoogle Scholar
  20. Galtier, N., Piganeau, G., Mouchiroud, D., & Duret, L. (2001). GC-content evolution in mammalian genomes: The biased gene conversion hypothesis. Genetics, 159, 907–911.PubMedGoogle Scholar
  21. Goodman, M. (1961). The role of immunologic differences in the phyletic development of human behavior. Human Biology, 33, 131–162.Google Scholar
  22. Goodman, M. (1962). Evolution of the immunologic species specificity of human serum proteins. Human Biology, 34, 104–150.Google Scholar
  23. Gu, X., & Li, W.-H. (1992). Higher rates of amino acid substitution in rodents than in humans. Molecular Phylogenetics and Evolution, 1(3), 211–214.PubMedCrossRefGoogle Scholar
  24. Hellmann, I., Ebersberger, I., Ptak, S. E., Paabo, S., & Przeworski, M. (2003). A neutral explanation for the correlation of diversity with recombination rates in humans. American Journal of Human Genetics, 72(6), 1527–1535.PubMedCrossRefGoogle Scholar
  25. Huang, S.-W., Friedman, R., Yu, N., Yu, A., & Li, W.-H. (2005). How strong is the mutagenicity of recombination in mammals? Molecular Biology and Evolution, 22(3), 426–431.PubMedCrossRefGoogle Scholar
  26. Huttley, G. A., Wakefield, M. J., & Easteal, S. (2007). Rates of genome evolution and branching order from whole genome analysis. Molecular Biology and Evolution, 24, 1772–1730.CrossRefGoogle Scholar
  27. Jeffreys, A. J., Holloway, J. K., Kauppi, L., May, C. A., Neumann, R., Timothy Slingsby, M., et al. (2004). Meiotic recombination hot spots and human DNA diversity. Philosophical Transactions of the Royal Society London, B., 359, 141–152.CrossRefGoogle Scholar
  28. Jeffreys, A. J., Kauppi, L., & Neumann, R. (2001). Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nature Genetics, 29, 217–222.PubMedCrossRefGoogle Scholar
  29. Jensen-Seaman, M. I., Furey, T. S., Payseur, B. A., Lu, Y., Roskin, K. M., Chen, C.-F., et al. (2004). Comparative recombination rates in the rat, mouse, and human genomes. Genome Research, 14(4), 528–538.PubMedCrossRefGoogle Scholar
  30. Jones, P. A., & Takai, D. (2001). The role of DNA methylation in mammalian epigenetics. Science, 293, 1068–1070.PubMedCrossRefGoogle Scholar
  31. Keightley, P. D., Lercher, M. J., & Eyre-Walker, A. (2005). Evidence for widespread degradation of gene control regions in hominoid genomes. PLoS Biology, 3, e42.PubMedCrossRefGoogle Scholar
  32. Kim, S.-H., Elango, N., Warden, C. W., Vigoda, E., & Yi, S. (2006). Heterogenous genomic molecular clocks in primates. PLoS Genetics, 2, e163.PubMedCrossRefGoogle Scholar
  33. Kimura, M. (1983). The neutral theory of molecular evolution. Cambridge, UK: Cambridge University Press.Google Scholar
  34. Kohne, C. (1970). Evolution of higher-organism DNA. Quarterly Reviews of Biophysics, 3, 327–375.PubMedCrossRefGoogle Scholar
  35. Kondrashov, F. A., Ogurtsov, A. Y., & Kondrashov, A. S. (2006). Selection in favor of nucleotides G and C diversifies evolution rates and levels of polymorphism at mammalian synonymous sites. Journal of Theoretical Biology, 240, 616–626.PubMedCrossRefGoogle Scholar
  36. Kong, A., Gudbhartsson, D. F., Sainz, J., Jonsdottir, G. M., Gudjonsson, S. A., Richardsson, B., et al. (2002). A high-resolution recombination map of the human genome. Nature Genetics, 31, 241–247.PubMedGoogle Scholar
  37. Kumar, S. (2005). Molecular clocks: Four decades of evolution. Nature Reviews Genetics, 6, 654–662.PubMedCrossRefGoogle Scholar
  38. Kumar, S., & Subramanian, S. (2002). Mutation rates in mammalian genomes. Proceedings of the National Academy of Sciences of the United States of America, 99(2), 803–808.PubMedCrossRefGoogle Scholar
  39. Laird, C. D., McConaughy, B. L., & McCarthy, B. J. (1969). Rate of fixation of nucleotide substitutions in evolution. Nature, 224, 149–154.PubMedCrossRefGoogle Scholar
  40. Lercher, M. J., & Hurst, L. D. (2002). Human SNP variability and mutation rate are higher in regions of high recombination. Trends in Genetics, 18(7), 337–340.PubMedCrossRefGoogle Scholar
  41. Li, W.-H. (1997). Molecular evolution. Sunderland, MA: Sinauer.Google Scholar
  42. Li, E. (2002). Chromatin modification and epigenetic reprogramming in mammalian development. Nature Reviews Genetics, 3, 662–673.PubMedCrossRefGoogle Scholar
  43. Li, W.-H., Ellsworth, D. L., Krushkal, J., Chang, B. H.-J., & Hewett-Emmett, D. (1996). Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis. Molecular Phylogenetics and Evolution, 5(1), 182–187.PubMedCrossRefGoogle Scholar
  44. Li, W.-H., Tanimura, M., & Sharp, P. M. (1987). An evaluation of the molecular clock hypothesis using mammalian DNA sequences. Journal of Molecular Evolution, 25, 330–342.PubMedCrossRefGoogle Scholar
  45. Li, W.-H., Yi, S., & Makova, K. (2002). Male-driven evolution. Current Opinion in Genetics & Development, 12(6), 650–656.CrossRefGoogle Scholar
  46. Makova, K. D., & Li, W.-H. (2002). Strong male-driven evolution of DNA sequences in humans and apes. Nature, 416, 624–626.PubMedCrossRefGoogle Scholar
  47. Margoliash, E. (1963). Primary structure and evolution of cytochrome C. Proceedings of the National Academy of Sciences of the United States of America, 50, 672–679.PubMedCrossRefGoogle Scholar
  48. McVean, G. A. T., Myers, S. R., Hunt, S., Deloukas, P., Bentley, D. R., & Donnelly, P. (2004). The fine-scale structure of recombination rate variation in the human genome. Science, 304, 581–584.PubMedCrossRefGoogle Scholar
  49. Meunier, J., & Duret, L. (2004). Recombination drives the evolution of GC-content in the human genome. Molecular Biology and Evolution, 21(6), 984–990.PubMedCrossRefGoogle Scholar
  50. Montoya-Burgos, J. I., Boursot, P., & Galtier, N. (2003). Recombination explains isochores in mammalian genomes. Trends in Genetics, 19, 128–130.PubMedCrossRefGoogle Scholar
  51. Murphy, W. J., Eizirik, E., O’Brien, S. J., Madsen, O., Scally, M., Douady, C. J., et al. (2001). Resoluion of the early placental mammal radiation using Bayesian phylogenetics. Science, 294, 2348–2351.PubMedCrossRefGoogle Scholar
  52. Myers, S., Bottolo, L., Frreeman, C., McVean, G., & Donnelly, P. (2005). A fine-scale map of recombination rates and hotspots across the human genome. Science, 310(Oct. 14), 321–324.PubMedCrossRefGoogle Scholar
  53. Nachman, M. W., & Crowell, S. L. (2000). Estimate of the mutation rate per nucleotide in humans. Genetics, 156(1), 297–304.PubMedGoogle Scholar
  54. Patterson, N., Richter, D. J., Gnerre, S., Lander, E. S., & Reich, D. (2006). Genetic evidence for complex speciation of humans and chimpanzees. Nature, 441, 1103–1108.PubMedCrossRefGoogle Scholar
  55. Perry, J., & Ashworth, A. (1999). Evolutionary rate of a gene affected by chromosomal position. Current Biology, 9, 987–989.PubMedCrossRefGoogle Scholar
  56. Pollard, K. S., Salama, S. R., Lambert, N., Lambot, M.-A., Coppens, S., Pedersen, J. S., et al. (2006). An RNA gene expressed during cortical development evolved rapidly in humans. Nature, 443, 167–172.PubMedCrossRefGoogle Scholar
  57. Ptak, S. E., Hinds, D. A., Koehler, K., Nickel, B., Patil, N., Ballinger, D. G., et al. (2005). Fine-scale recombination patterns differ between chimpanzees and humans. Nature Genetics, 37(4), 429–434.PubMedCrossRefGoogle Scholar
  58. Rogers, J., Mahaney, M. C., et al. (2000). A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms. Genomics, 67, 237–247.PubMedCrossRefGoogle Scholar
  59. Sarich, V. M., & Wilson, A. C. (1967). Immunological tie scale for hominid evolution. Science, 158, 1200–1203.PubMedCrossRefGoogle Scholar
  60. Semon, M., & Duret, L. (2004). Evidence that functional transcription units cover at least half of the human genome. Trends in Genetics, 20, 229–232.PubMedCrossRefGoogle Scholar
  61. Shimmin, L. C., Chang, B. H., & Li, W.-H. (1993). Male-driven evolution of DNA sequences. Nature, 362, 745–747.PubMedCrossRefGoogle Scholar
  62. Steiper, M. E., & Young, N. M. (2006). Primate molecular divergence dates. Molecular Phylogenetics and Evolution, 41, 384–394.PubMedCrossRefGoogle Scholar
  63. Steiper, M. E., Young, N. M., & Sukrarna, T. Y. (2004). Genomic data support the hominoid slowdown and an early Oligocene estimate for the hominoid-cercopithecoid divergence. Proceedings of the National Academy of Sciences of the United States of America, 101, 17021–17026.PubMedCrossRefGoogle Scholar
  64. Subramanian, S., & Kumar, S. (2003). Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes. Genome Research, 13, 838–844.PubMedCrossRefGoogle Scholar
  65. Winckler, W., Myers, S. R., Richter, D. J., Onofrio, R. C., McDonald, G. J., Bontrop, R. E., et al. (2005). Comparison of fine-scale recombination rates in humans and chimpanzees. Science, 308(5718), 107–111.PubMedCrossRefGoogle Scholar
  66. Wolfe, K. H., Sharp, P. M., & Li, W.-H. (1989). Mutation rates differ among regions of the mammalian genome. Nature, 337, 283–285.PubMedCrossRefGoogle Scholar
  67. Wu, C.-I., & Li, W.-H. (1985). Evidence for higher rates of nucleotide substitution in rodents than in man. Proceedings of the National Academy of Sciences of the United States of America, 82, 1741–1745.PubMedCrossRefGoogle Scholar
  68. Yi, S., Ellsworth, D. L., & Li, W.-H. (2002). Slow molecular clocks in Old World monkeys, apes, and humans. Molecular Biology and Evolution, 19(12), 2191–2198.PubMedGoogle Scholar
  69. Yi, S., & Li, W.-H. (2005). Molecular evolution of recombination hotspots and highly recombining pseudoautosomal regions in hominoids. Molecular Biology and Evolution, 22, 1223–1230.PubMedCrossRefGoogle Scholar
  70. Yi, S., Summers, T. J., Pearson, N. M., & Li, W.-H. (2004). Recombination has little effect on the rate of sequence divergence in pseudoausotomal boundary 1 among humans and great apes. Genome Research, 14, 37–43.PubMedCrossRefGoogle Scholar
  71. Zuckerkandl, E., & Pauling, L. B. (1962). Molecular disease, evolution, and genetic heterogeneity. In M. Kasha & B. Pullman (Eds.), Horizons in biochemistry (pp. 189–225). New York: Academic Press.Google Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.School of BiologyGeorgia Institute of TechnologyAtlantaUSA

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