Journal of Molecular Evolution

, Volume 63, Issue 3, pp 375–392 | Cite as

The Relationship Between the Rate of Molecular Evolution and the Rate of Genome Rearrangement in Animal Mitochondrial Genomes



Evolution of mitochondrial genes is far from clock-like. The substitution rate varies considerably between species, and there are many species that have a significantly increased rate with respect to their close relatives. There is also considerable variation among species in the rate of gene order rearrangement. Using a set of 55 complete arthropod mitochondrial genomes, we estimate the evolutionary distance from the common ancestor to each species using protein sequences, tRNA sequences, and breakpoint distances (a measure of the degree of genome rearrangement). All these distance measures are correlated. We use relative rate tests to compare pairs of related species in several animal phyla. In the majority of cases, the species with the more highly rearranged genome also has a significantly higher rate of sequence evolution. Species with higher amino acid substitution rates in mitochondria also have more variable amino acid composition in response to mutation pressure. We discuss the possible causes of variation in rates of sequence evolution and gene rearrangement among species and the possible reasons for the observed correlation between the two rates.


Mitochondrial genome Genome rearrangement Molecular clock Relative rate test Phylogenetics of arthropods 



This work has been supported by Canada Research Chairs, NSERC (Canada), and BBSRC (UK).


  1. Adachi J, Hasegawa M (1996) A model of amino acid substitution in proteins encoded by mitochondrial DNA. J Mol Evol 42:459–468PubMedCrossRefGoogle Scholar
  2. Bielawski JP, Gold JR (2002) Mutation patterns of mitochondrial H- and L-strand DNA in closely related cyprinid fishes. Genetics 161:1589–1597PubMedGoogle Scholar
  3. Blanchette M, Kunisawa T, Sankoff D (1999) Gene order breakpoint evidence in animal mitochondrial phylogeny. J Mol Evol 49:193–203PubMedCrossRefGoogle Scholar
  4. Bogenhagen DF, Clayton DA (2003) The mitochondrial DNA replication bubble has not burst. Trends Biochem Sci 28:357–360PubMedCrossRefGoogle Scholar
  5. Bowmaker M, Yang MY, Yasukawa T, Reyes A, Jacobs HT, Huberman JA, Holt IJ (2003) Mammalian mitochondrial DNA replicates bidirectionally from an initiation zone. J Biol Chem 278:50961–50960PubMedCrossRefGoogle Scholar
  6. Boore JL (2000) The duplication/random loss model for gene rearrangement exemplified by mitochondrial genomes of deuterostome animals. In: Sankoff D, Nadeau JH (eds) Comparative genomics. Kluwer Academic, Dordrecht, pp 133–147Google Scholar
  7. Boore JL, Staton JL (2002) The mitochondrial genome of the Sipunculid Phascolopsis gouldii supports its association with Annelida rather than Mollusca. Mol Biol Evol 19:127–137PubMedGoogle Scholar
  8. Boore JL, Lavrov DV, Brown WM (1998) Gene translocation links insects and crustaceans. Nature 392:667–668PubMedCrossRefGoogle Scholar
  9. Bourque G, Pevzner PA (2002) Genome-scale evolution: reconstructing gene orders in ancestral species. Genome Res 12:26–36PubMedGoogle Scholar
  10. Castro LR, Dowton M (2005) The position of the Hymenoptera within the Holometabola is inferred from the mitochondrial genome of Perga condei (Hymenoptera:Symphyta:Pergidae). Mol Phylogenet Evol 34:469–470PubMedCrossRefGoogle Scholar
  11. Cosner ME, Jansen RK, Moret BME, Raubeson LA, Wang LS, Wanrnow T, Wyman S (2000) An empirical comparison of phylogenetic methods on chloroplast gene order data in Campanulaceae. In: Sankoff D, Nadeau JH (eds) Comparative genomics. Kluwer Academic, Dordrecht, pp 99–121Google Scholar
  12. Del Bo R, Bordoni A, Sciacco M, Di Fonzo A, Galbiati S, Crimi M, Bresolin N, Comi GP (2003) Remarkable infidelity of polymerase gamma A associated with mutations in POLG1 exonuclease domain. Neurology 61:903–908PubMedGoogle Scholar
  13. Delsuc F, Phillips MJ, Penny D. (2003) Comment on “Hexapod Origins: Monophyletic or Paraphyletic?” Science 301:1482dCrossRefGoogle Scholar
  14. Dowton M (2004) Assessing the relative rate of (mitochondrial) genomic change. Genetics 167:1027–1030PubMedCrossRefGoogle Scholar
  15. Dowton M, Campbell NJH (2001) Intramitochondrial recombination—Is it why some mitochondrial genes sleep around. Trends Ecol Evol 16:269–271PubMedCrossRefGoogle Scholar
  16. Dowton M, Castro LR, Campbell SL, Bargon SD, Austin AD (2003) Frequent mitochondrial gene rearrangements at the hymenopteran nad3−nad5 junction. J Mol Evol 56:517–526PubMedCrossRefGoogle Scholar
  17. Faith JJ, Pollock DD (2003) Likelihood analysis of asymmetrical mutation bias gradients in vertebrate mitochondrial genomes. Genetics 165:735–745PubMedGoogle Scholar
  18. Fernandez-Silva P, Enriquez JA, Montoya J (2003) Replication and transcription of mammalian mitochondrial DNA. Exp Physiol 88:41–56PubMedCrossRefGoogle Scholar
  19. Gillooly JF, Allen AP, West GB, Brown JH (2005) The rate of DNA evolution: effects of body size and temperature on the molecular clock. Proc Natl Acad Sci USA 102:140–145PubMedCrossRefGoogle Scholar
  20. Giribet G, Edgecombe GD, Wheeler WC (2001) Arthropod phylogeny based on eight molecular loci and morphology. Nature 413:157–161PubMedCrossRefGoogle Scholar
  21. Halanych KM (2004) The new view of animal phylogeny. Annu Rev Ecol Evol Syst 35:229–256CrossRefGoogle Scholar
  22. Higgs PG, Jameson D, Jow H, Rattray M (2003) The evolution of tRNA-Leucine genes in animal mitochondrial genomes. J Mol Evol 57:435–445PubMedCrossRefGoogle Scholar
  23. Jameson D, Gibson AP, Hudelot C, Higgs PG (2003) OGRe: a relational database for comparative analysis of mitochondrial genomes. Nucleic Acids Res 31:202–206PubMedCrossRefGoogle Scholar
  24. Kaguni LS (2004) DNA polymerase γ, the mitochondrial replicase. Annu Rev Biochem 73:293–320PubMedCrossRefGoogle Scholar
  25. Kajander OA, Rovio AT, Majamaa K, Poulton J, Spelbrink JN, Holt IJ, Karhunen PJ, Jacobs HT (2000) Human mtDNA sublimons resemble rearranged mitochondrial genomes found in pathological states. Hum Mol Genet 9:2821–2835PubMedCrossRefGoogle Scholar
  26. Knudsen B, Kohn AB, Nahir B, McFadden CS, Moroz LL (2006) Complete DNA sequence of the mitochondrial genome of the sea-slug, Aplysia californica:Conservation of the gene order in Euthyneura. Mol Phylogenet Evol 38:459–460PubMedCrossRefGoogle Scholar
  27. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M (2004) Reconstruction of a minimal mtDNA replisome in vitro. EMBO J 23:2423–2420CrossRefGoogle Scholar
  28. Krishnan NM, Seligmann H, Raina SZ, Pollock DD (2004) Detecting gradients of asymmetry in site-specific substitutions in mitochondrial genomes. DNA Cell Biol 23:707–714PubMedCrossRefGoogle Scholar
  29. Larget B, Simon DL, Kadane JB (2002) Bayesian phylogenetic inference from animal mitochondrial genome arrangements. J Roy Stat Soc B 64:681–693CrossRefGoogle Scholar
  30. Lavrov DV, Boore JL, Brown WM (2002) Complete mtDNA sequences of two millipedes suggest a new model for mitochondrial gene rearrangements: duplication and non-random loss. Mol Biol Evol 19:163–160Google Scholar
  31. Lavrov DV, Brown WM, Boore JL (2004) Phylogenetic position of the Pentastomida and (pan) crustacean relationships. Proc Roy Soc Lond B 271:537–544CrossRefGoogle Scholar
  32. Li WH (1993) So what about the molecular clock hypothesis? Curr Opin Genet Dev 3:896–901PubMedCrossRefGoogle Scholar
  33. Lunt DH, Hyman BC (1997) Animal mitochondrial DNA recombination. Nature 387:247PubMedCrossRefGoogle Scholar
  34. Mallatt JM, Garey JR, Shultz JW (2004) Ecdysozoan phylogeny and Bayesian inference: first use of nearly complete 28S and 18S rRNA gene sequences to classify the arthropods and their kin. Mol Phylogenet Evol 31:178–191PubMedCrossRefGoogle Scholar
  35. Martin AP, Palumbi SR (1993) Body size, metabolic rate, generation time, and the molecular clock. Proc Natl Acad Sci USA 90:4087–4091PubMedCrossRefGoogle Scholar
  36. Mooers AO, Harvey PH (1994) Metabolic rate, generation time, and the rate of molecular evolution in birds. Mol Phylogenet Evol 3:344–350PubMedCrossRefGoogle Scholar
  37. Moret BME, Siepel AC, Tang J, Liu T (2002) Inversion medians outperform breakpoint medians in phylogeny reconstruction from gene order data. Lect Notes Comp Sci 2452:521–536CrossRefGoogle Scholar
  38. Morrison CL, Harvey AW, Lavery S, Tieu K, Huang Y, Cunningham CW (2002) Mitochondrial gene rearrangements confirm the parallel evolution of the crab-like form. Proc R Soc Lond B 269:345–350CrossRefGoogle Scholar
  39. Mueller RL, Boore JL (2005) Molecular mechanisms of extensive mitochondrial gene rearrangement in plethodontid salamanders. Mol Biol Evol 22:2104–2112PubMedCrossRefGoogle Scholar
  40. Nardi F, Spinsanti G, Boore JL, Carapelli A, Dallai R, Frati F (2003) Hexapod origins: Monophyletic or paraphyletic? Science 299:1887–1880 (see also Science 301:1482e)PubMedCrossRefGoogle Scholar
  41. Notredame C, Higgins DG, Heringa J (2000) T–Coffee: a novel method for fast and accurate multiple sequence alignment. J Mol Biol 302:205–217PubMedCrossRefGoogle Scholar
  42. Ojala D, Montoya A, Attardi G (1981) tRNA punctuation model of RNA processing in human mitochondria. Nature 290:470–474PubMedCrossRefGoogle Scholar
  43. Pisani D (2004) Identifying and removing fast-evolving sites using compatibility analysis: an example from the Arthropoda. Syst Biol 53:978–980PubMedCrossRefGoogle Scholar
  44. Posada D, Crandall KA (2001) Selecting the best-fit model of nucleotide substitution. Syst Biol 50:580–601PubMedCrossRefGoogle Scholar
  45. Raina SZ, Faith JJ, Dusotell TR, Seligmann H, Stewart CB, Pollock DD. (2005) Evolution of base-substitution gradients in primate mitochondrial genomes. Genome Res 15:665–673PubMedCrossRefGoogle Scholar
  46. Regier JC, Shultz JW (1997) Molecular phylogeny of the major arthorpod groups indicates polyphyly of the crustaceans and a new hypothesis for the origin of hexapods. Mol Biol Evol 14:909–913Google Scholar
  47. Regier JC, Shultz JW, Kambic RE (2005) Pancrustacean phylogeny:hexapods are terrestrial crustaceans and maxillopods are not monophyletic. Proc Roy Soc Lond B 272:395–401CrossRefGoogle Scholar
  48. Reyes A, Gissi C, Pesole G, Saccone C (1998) Asymmetrical directional mutation pressure in the mitochondrial genome of mammals. Mol Biol Evol 15:957–966PubMedGoogle Scholar
  49. Richter S (2002) The Tetraconata concept: hexapod-crustacean relationships and the phylogeny of Crustacea. Organisms Diversity Evol 2:217–237CrossRefGoogle Scholar
  50. Samuels DC, Schon EA, Chinnery PF (2004) Two direct repeats cause most human mtDNA deletions. Trends Genet 20:393–398PubMedCrossRefGoogle Scholar
  51. Sankoff D, Deneault M, Bryant D, Lemieux C, Turmel M (2000a) Chloroplast gene order and the divergence of plants and algae, from the normalized number of induced breakpoints. In: Sankoff D, Nadeau JH (eds) Comparative genomics. Kluwer Academic, Dordrecht, pp 89–98Google Scholar
  52. Sankoff D, Bryant D, Deneault M, Lang BF, Burger G (2000b) Early eukaryote evolution based on mitochondrial gene order breakpoints. J Comp Biol 7:521–535CrossRefGoogle Scholar
  53. Scouras A, Smith MJ (2001) A novel gene order in the crinoid echinoderm Florometra serratissima. Mol Biol Evol 18:61–73PubMedGoogle Scholar
  54. Segawa RD, Aotsuka T (2005) The mitochondrial genome of the Japanese freshwater crab, Geothelphusa (Crustacea:Brachyura):evidence for its evolution via gene duplication. Gene 355:28–30PubMedCrossRefGoogle Scholar
  55. Serb JM, Lydeard C (2003) Complete mtDNA sequence of the North American freshwater mussel Lampsilis ornata (Unionidae): an examination of the evolution and phylogenetic utility of mitochondrial genome organization in Bivalvia (Mollusca). Mol Biol Evol 20:1854–1866PubMedCrossRefGoogle Scholar
  56. Shadel GS, Clayton DA (1997) Mitochondrial DNA maintenance in verebrates. Annu Rev Biochem 66:409–435PubMedCrossRefGoogle Scholar
  57. Shao R, Dowton M, Murrell A, Barker SC (2003) Rates of genome rearrangement and nucleotide substitution are correlated in the mitochondrial genomes of insects. Mol Biol Evol 20:1612–1610PubMedCrossRefGoogle Scholar
  58. Shultz JW, Regier JC (2000) Phylogenetic analysis of arthropods using two nuclear protein-encoding genes supports a crustacean + hexapod clade. Proc R Soc Lond B 267:1011–1010CrossRefGoogle Scholar
  59. Spears T, Abele LG (2000) Branchiopod monophyly and interordinal phylogeny inferred from 18S ribosomal DNA. J Crust Biol 20:1–24CrossRefGoogle Scholar
  60. Spelbrink JN, Toivinen JM, Hakkaart GAJ, Kurkela JM, Cooper HM, Lehtinen SK, Lecrenier N, Back JP, Speijer D, Foury F, Jacobs HT (2000) In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem 275:24818–24828PubMedCrossRefGoogle Scholar
  61. Stanton DJ, Daehler LL, Moritz CC, Brown WM (1994) Sequences with potential to form stem-and-loop structures are associated with coding region duplications in animal mitochondrial DNA. Genetics 137:233–241PubMedGoogle Scholar
  62. Tajima F (1993) Simple methods for testing the molecular evolutionary clock hypothesis. Genetics 135:599–607PubMedGoogle Scholar
  63. Tao N, Richardson R, Bruno W, Kuiken C (2005) FindModel;–db/findmodel/findmodel.html
  64. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL X windows interface:flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882PubMedCrossRefGoogle Scholar
  65. Tracy RL, Stern DB (1995) Mitochondrial transcription initiation: promoter structures and RNA polymerases. Curr Genet 28:205–216PubMedCrossRefGoogle Scholar
  66. Urbina D, Tang B, Higgs PG (2006) The response of amino acid frequencies to directional mutational pressure in mitochondrial genome sequences is related to the physical properties of the amino acids and to the structure of the genetic code. J Mol Evol 62:340–361PubMedCrossRefGoogle Scholar
  67. Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genet 28:211–212PubMedCrossRefGoogle Scholar
  68. Wanrooij S, Luoma P, Van Goethem G, Van Broeckhoven C, Suomalainen A, Spelbrink JN (2004) Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res 32:3053–3064PubMedCrossRefGoogle Scholar
  69. Wheeler WC, Whiting M, Wheeler QD, Carpenter JM (2001) The phylogeny of the extant hexapod orders. Cladistics 17:113–160 (see also erratum in Cladistics 17:403)CrossRefGoogle Scholar
  70. Wilson K, Cahill V, Ballment E, Benzie J (2000) The complete sequence of the mitochondrial genome of the crustacean Penaeus monodon: Are malacostracan crustaceans more closely related to insects than to branchiopods? Mol Biol Evol 17:863–874PubMedGoogle Scholar
  71. Yang MY, Bowmaker M, Reyes A, Vergani L, Angeli P, Gringeri E, Jacobs HT, Holt IJ (2002) Biased incorporation of ribonucleotides on the mitochondrial L-strand accounts for apparent strand-asymmetric DNA replication. Cell 111:495–505PubMedCrossRefGoogle Scholar
  72. Yang Z (2002) Phylogenetic Analysis Using Maximum Likelihood (PAML), version 314;
  73. Zeviani M, Spinazzola A, Carelli V (2003) Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 13:262–270PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Wei Xu
    • 1
  • Daniel Jameson
    • 2
  • Bin Tang
    • 3
  • Paul G. Higgs
    • 1
  1. 1.Department of Physics and AstronomyMcMaster UniversityHamiltonCanada
  2. 2.Faculty of Life SciencesUniversity of ManchesterManchesterUK
  3. 3.Division of Genomics and ProteomicsOntario Cancer Institute, University of TorontoTorontoCanada

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