Skip to main content
PMC home page
Genetics logoLink to Genetics
. 1983 Feb;103(2):287–312. doi: 10.1093/genetics/103.2.287

Human Mitochondrial DNA Variation and Evolution: Analysis of Nucleotide Sequences from Seven Individuals

Charles F Aquadro 1,2, Barry D Greenberg 1,2
PMCID: PMC1219980  PMID: 6299878

Abstract

We have analyzed nucleotide sequence variation in an approximately 900-base pair region of the human mitochondrial DNA molecule encompassing the heavy strand origin of replication and the D-loop. Our analysis has focused on nucleotide sequences available from seven humans. Average nucleotide diversity among the sequences is 1.7%, several-fold higher than estimates from restriction endonuclease site variation in mtDNA from these individuals and previously reported for other humans. This disparity is consistent with the rapidly evolving nature of this noncoding region. However, several instances of convergent or parallel gain and loss of restriction sites due to multiple substitutions were observed. In addition, other results suggest that restriction site (as well as pairwise sequence) comparisons may underestimate the total number of substitutions that have occurred since the divergence of two mtDNA sequences from a common ancestral sequence, even at low levels of divergence. This emphasizes the importance of recognizing the large standard errors associated with estimates of sequence variability, particularly when constructing phylogenies among closely related sequences. Analysis of the observed number and direction of substitutions revealed several significant biases, most notably a strand dependence of substitution type and a 32-fold bias favoring transitions over transversions. The results also revealed a significantly nonrandom distribution of nucleotide substitutions and sequence length variation. Significantly more multiple substitutions were observed than expected for these closely related sequences under the assumption of uniform rates of substitution. The bias for transitions has resulted in predominantly convergent or parallel changes among the observed multiple substitutions. There is no convincing evidence that recombination has contributed to the mtDNA sequence diversity we have observed.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson S., de Bruijn M. H., Coulson A. R., Eperon I. C., Sanger F., Young I. G. Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome. J Mol Biol. 1982 Apr 25;156(4):683–717. doi: 10.1016/0022-2836(82)90137-1. [DOI] [PubMed] [Google Scholar]
  2. Avise J. C., Giblin-Davidson C., Laerm J., Patton J. C., Lansman R. A. Mitochondrial DNA clones and matriarchal phylogeny within and among geographic populations of the pocket gopher, Geomys pinetis. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6694–6698. doi: 10.1073/pnas.76.12.6694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown G. G., Simpson M. V. Novel features of animal mtDNA evolution as shown by sequences of two rat cytochrome oxidase subunit II genes. Proc Natl Acad Sci U S A. 1982 May;79(10):3246–3250. doi: 10.1073/pnas.79.10.3246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown W. M. Mechanisms of evolution in animal mitochondrial DNA. Ann N Y Acad Sci. 1981;361:119–134. doi: 10.1111/j.1749-6632.1981.tb46515.x. [DOI] [PubMed] [Google Scholar]
  5. Brown W. M. Polymorphism in mitochondrial DNA of humans as revealed by restriction endonuclease analysis. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3605–3609. doi: 10.1073/pnas.77.6.3605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Denaro M., Blanc H., Johnson M. J., Chen K. H., Wilmsen E., Cavalli-Sforza L. L., Wallace D. C. Ethnic variation in Hpa 1 endonuclease cleavage patterns of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5768–5772. doi: 10.1073/pnas.78.9.5768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Engels W. R. Estimating genetic divergence and genetic variability with restriction endonucleases. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6329–6333. doi: 10.1073/pnas.78.10.6329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ewens W. J., Spielman R. S., Harris H. Estimation of genetic variation at the DNA level from restriction endonuclease data. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3748–3750. doi: 10.1073/pnas.78.6.3748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fitch W. M. Estimating the total number of nucleotide substitutions since the common ancestor of a pair of homologous genes: comparison of several methods and three beta hemoglobin messenger RNA's. J Mol Evol. 1980 Dec;16(3-4):153–209. doi: 10.1007/BF01804976. [DOI] [PubMed] [Google Scholar]
  10. Fitch W. M., Markowitz E. An improved method for determining codon variability in a gene and its application to the rate of fixation of mutations in evolution. Biochem Genet. 1970 Oct;4(5):579–593. doi: 10.1007/BF00486096. [DOI] [PubMed] [Google Scholar]
  11. Gojobori T., Li W. H., Graur D. Patterns of nucleotide substitution in pseudogenes and functional genes. J Mol Evol. 1982;18(5):360–369. doi: 10.1007/BF01733904. [DOI] [PubMed] [Google Scholar]
  12. Hauswirth W. W., Laipis P. J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4686–4690. doi: 10.1073/pnas.79.15.4686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hayashi J. I., Yonekawa H., Gotoh O., Tagashira Y., Moriwaki K., Yosida T. H. Evolutionary aspects of variant types of rat mitochondrial DNA'S. Biochim Biophys Acta. 1979 Sep 27;564(2):202–211. doi: 10.1016/0005-2787(79)90219-3. [DOI] [PubMed] [Google Scholar]
  14. Holmquist R., Pearl D. Theoretical foundations for quantitative paleogenetics. Part III: The molecular divergence of nucleic acids and proteins for the case of genetic events of unequal probability. J Mol Evol. 1980 Dec;16(3-4):211–267. doi: 10.1007/BF01804977. [DOI] [PubMed] [Google Scholar]
  15. Jakovcic S., Casey J., Rabinowitz M. Sequence homology between mitochondrial DNAs of different eukaryotes. Biochemistry. 1975 May 20;14(10):2043–2050. doi: 10.1021/bi00681a002. [DOI] [PubMed] [Google Scholar]
  16. Kaplan N., Risko K. A method for estimating rates of nucleotide substitution using DNA sequence data. Theor Popul Biol. 1982 Jun;21(3):318–328. doi: 10.1016/0040-5809(82)90021-1. [DOI] [PubMed] [Google Scholar]
  17. Kaplan N., Risko K. A method for estimating rates of nucleotide substitution using DNA sequence data. Theor Popul Biol. 1982 Jun;21(3):318–328. doi: 10.1016/0040-5809(82)90021-1. [DOI] [PubMed] [Google Scholar]
  18. Kaplan N., Risko K. An improved method for estimating sequence divergence of DNA using restriction endonuclease mappings. J Mol Evol. 1981;17(3):156–162. doi: 10.1007/BF01733909. [DOI] [PubMed] [Google Scholar]
  19. Kimura M. Estimation of evolutionary distances between homologous nucleotide sequences. Proc Natl Acad Sci U S A. 1981 Jan;78(1):454–458. doi: 10.1073/pnas.78.1.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miyata T., Yasunaga T., Nishida T. Nucleotide sequence divergence and functional constraint in mRNA evolution. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7328–7332. doi: 10.1073/pnas.77.12.7328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nei M., Li W. H. Mathematical model for studying genetic variation in terms of restriction endonucleases. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5269–5273. doi: 10.1073/pnas.76.10.5269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ojala D., Crews S., Montoya J., Gelfand R., Attardi G. A small polyadenylated RNA (7 S RNA), containing a putative ribosome attachment site, maps near the origin of human mitochondrial DNA replication. J Mol Biol. 1981 Aug 5;150(2):303–314. doi: 10.1016/0022-2836(81)90454-x. [DOI] [PubMed] [Google Scholar]
  23. Potter S. S., Newbold J. E., Hutchison C. A., 3rd, Edgell M. H. Specific cleavage analysis of mammalian mitochondrial DNA. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4496–4500. doi: 10.1073/pnas.72.11.4496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shah D. M., Langley C. H. Inter- and intraspecific variation in restriction maps of Drosophila mitochondrial DNAs. Nature. 1979 Oct 25;281(5733):696–699. doi: 10.1038/281696a0. [DOI] [PubMed] [Google Scholar]
  25. Sheppard H. W., Gutman G. A. Allelic forms of rat kappa chain genes: evidence for strong selection at the level of nucleotide sequence. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7064–7068. doi: 10.1073/pnas.78.11.7064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tajima F., Nei M. Biases of the estimates of DNA divergence obtained by the restriction enzyme technique. J Mol Evol. 1982;18(2):115–120. doi: 10.1007/BF01810830. [DOI] [PubMed] [Google Scholar]
  27. Topal M. D., Fresco J. R. Complementary base pairing and the origin of substitution mutations. Nature. 1976 Sep 23;263(5575):285–289. doi: 10.1038/263285a0. [DOI] [PubMed] [Google Scholar]
  28. Upholt W. B., Dawid I. B. Mapping of mitochondrial DNA of individual sheep and goats: rapid evolution in the D loop region. Cell. 1977 Jul;11(3):571–583. doi: 10.1016/0092-8674(77)90075-7. [DOI] [PubMed] [Google Scholar]
  29. Walberg M. W., Clayton D. A. Sequence and properties of the human KB cell and mouse L cell D-loop regions of mitochondrial DNA. Nucleic Acids Res. 1981 Oct 24;9(20):5411–5421. doi: 10.1093/nar/9.20.5411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. van Ooyen A., van den Berg J., Mantei N., Weissmann C. Comparison of total sequence of a cloned rabbit beta-globin gene and its flanking regions with a homologous mouse sequence. Science. 1979 Oct 19;206(4416):337–344. doi: 10.1126/science.482942. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES