Advertisement

Current Genetics

, Volume 12, Issue 2, pp 81–90 | Cite as

Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations

  • Douglas C. Wallace
  • Jianhong Ye
  • S. Nicolas Neckelmann
  • Gurparkash Singh
  • Keith A. Webster
  • Barry D. Greenberg
Original Articles

Abstract

We have cloned and sequenced human and bovine cDNAs for the β subunit of the ATP synthase (ATP-synß), a nuclear DNA (nDNA) encoded oxidative phosphorylation (OXPHOS) gene. The two cDNAs were found to share 99% amino acid homology and 94% nucleotide homology. The evolutionary rate of ATPsynß was then compared with that of two mitochondrial DNA (mtDNA) ATP synthase genes (ATPase 6 and 8), seven other mtDNA OXPHOS genes, and a number of nuclear genes. The synonymous substitution rate for ATPsynß proved to be 1.9 × 10−9 substitutions per site per year (substitutions × site−1 × year−1) (SSY). This is less than 1/2 that of the average nDNA gene, 1/12 the rate of ATPase 6 and 8, and 1/17 the rate of the average mtDNA gene. The synonymous and replacement substitution rates were used to calculate a new parameter, the “selective constraint ratio”. This revealed that even the most variable mtDNA protein was more constrained than the average nDNA protein. Thus, the high substitution mutation rate and strong selective constraints of mammalian mtDNA proteins suggest that mtDNA mutations may result in a disproportionately large number of human hereditary diseases of OXPHOS.

Key words

ATP synthase β Selective constraint mtDNA Evolution 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson S, Bankier AT, Barrell BG, de Bruijn MHL, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJH, Staden R, Young IG (1981) Nature 290:457–465Google Scholar
  2. Anderson S, de Bruijn MHL, Coulson AR, Eperon IC, Sanger F, Young IG (1982) J Mol Biol 156:683–717Google Scholar
  3. Aquadro CF, Greenberg BD (1983) Genetics 103:287–312Google Scholar
  4. Aviv H, Leder P (1972) Proc Natl Acad Sci USA 69:1408–1412Google Scholar
  5. Bibb MJ, Van Etten RA, Wright CT, Walberg MW, Clayton DA (1981) Cell 26:167–180Google Scholar
  6. Boutry M, Vassarotti A, Ghislain M, Douglas M, Goffeau A (1984) J Biol Chem 259:2840–2844Google Scholar
  7. Brown WM, George M Jr, Wilson AC (1979) Proc Natl Acad Sci USA 76:1967–1971Google Scholar
  8. Brown WM, Prager EM, Wang A, Wilson AC (1982) J Mol Evol 18:225–239Google Scholar
  9. Brown GG, Simpson MV (1982) Proc Natl Acad Sci USA 79:3246–3250Google Scholar
  10. Case JT, Wallace DC (1981) Somatic Cell Mol Genet 7:103–108Google Scholar
  11. Dale RMK, McClure BA, Houchins JP (1985) Plasmid 13:31–40Google Scholar
  12. Feinberg AP, Vogelstein B (1983) Anal Biochem 132:6–13Google Scholar
  13. Feinberg AP, Vogelstein B (1984) Anal Biochem 137:266–267Google Scholar
  14. Fitzgerald M, Shenk T (1981) Cell 24:251–260Google Scholar
  15. Gay NJ, Walker JE (1985) EMBO J 4:3519–3524Google Scholar
  16. Giles RE, Blanc H, Cann HM, Wallace DC (1980) Proc Natl Acad Sci USA 77:6715–6719Google Scholar
  17. Gojobori T, Ishii K, Nei M (1982) J Mol Evol 18:414–423Google Scholar
  18. Greenberg BD, Newbold JE, Sugino A (1983) Gene 21:33–49Google Scholar
  19. Hasegawa M, Kishino H, Yano T-A (1985) J Mol Evol 22:160174Google Scholar
  20. Hixon JE, Brown WM (1986) Mol Biol Evol 3:1–18Google Scholar
  21. Howley PM, Israel MA, Law M-F, Martin MA (1979) J Biol Chem 254:4876–4883Google Scholar
  22. Huynh TV, Young RA, Davis RW (1985) Constructing and screening cDNA libraries in λgt10 and λgt11. In: Glover DM (ed) DNA cloning, vol I, a practical approach. IRL Press, Washington DC, pp 49–78Google Scholar
  23. Jarausch J, Kadenbach B (1982) Hoppe-Seyler's Z Physiol Chem 363:1133–1140Google Scholar
  24. Kimura M (1981) Proc Natl Acad Sci USA 78:454–458Google Scholar
  25. Lanave C, Preparata G, Saccone C, Serio G (1984) J Mol Evol 20:86–93Google Scholar
  26. Lanave C, Preparata G, Saccone C (1985) J Mol Evol 21:346–350Google Scholar
  27. Li W-H, Luo C-C, Wu C-I (1985) Evolution of DNA sequences. In: MacIntyre RJ (ed) Molecular evolutionary genetics. Plenum, New York, pp 1–94Google Scholar
  28. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular Cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkGoogle Scholar
  29. Merle P, Kadenbach B (1982) Eur J Biochem 125:239–244Google Scholar
  30. Merril CR, Harrington MG (1985) Trends Genet 1:140–144Google Scholar
  31. Messing J, Vieira J (1982) Gene 19:269–276Google Scholar
  32. Miyata T, Hayashida H, Kikuno R, Hasegawa M, Kobayashi M, Koike K (1982) J Mol Evol 19:28–35Google Scholar
  33. Novotny EJ Jr, Singh G, Wallace DC, Dorfman LJ, Louis A, Sogg RL, Steinman L (1986) Neurology 36:1053–1060Google Scholar
  34. Oliver NA, Wallace DC (1982) Mol Cell Biol 2:30–41Google Scholar
  35. Ohta S, Kagawa Y (1986) J Biochem (Tokyo) 99:135–141Google Scholar
  36. Pepe G, Holtrop M, Gadaleta G, Kroon AM, Cantatore P, Gallerani R, de Benedetto C, Quagliariello C, Sbisa E, Saccone C (1983) Biochem Int 6:553–563Google Scholar
  37. Proudfoot NJ, Brownlee GG (1974) Nature 252:359–362Google Scholar
  38. Proudfoot NJ, Brownlee GG (1976) Nature 263:211–214Google Scholar
  39. Queen C, Korn LJ (1984) Nucleic Acids Res 12:581–599Google Scholar
  40. Rosing HS, Hopkins LC, Wallace DC, Epstein CM, Weidenheim K (1985) Ann Neurol 17:228–237Google Scholar
  41. Runswick MJ, Walker JE (1983) J Biol Chem 258:3081–3089Google Scholar
  42. Rupert CS, Harm W (1966) Reactivation after Photobiological Damage. In: Augenstein LG, Mason R, Zelle M (eds) Advances in radiation biology, vol II. Academic, New York, pp 1–81Google Scholar
  43. Sanger F, Coulson AR, Barrell BG, Smith AJH, Roe BA (1980) J Mol Biol 143:161–178Google Scholar
  44. Sanger F, Nicklen S, Coulson AR (1977) Proc Natl Acad Sci USA 74:5463–5467Google Scholar
  45. Schultheiss H-P, Klingenberg M (1984) Eur J Biochem 143:599–605Google Scholar
  46. Schultheiss H-P, Klingenberg M (1985) Arch Biochem Biophys 239:273–279Google Scholar
  47. Southern EM (1975) J Mol Biol 98:503–517Google Scholar
  48. Takeda M, Vassarotti A, Douglas MG (1985) J Biol Chem 260:15458–15465Google Scholar
  49. Tajima F, Nei M (1984) Mol Biol Evol 1:269–285Google Scholar
  50. Ullrich A, Shine J, Chirgwin J, Pictet R, Tischer E, Rutter WJ, Goodman HM (1977) Science 196:1313–1319Google Scholar
  51. Wallace DC (1987) In: McKusick V (ed) Experimental mammalian genetics: a perspective. March of Dimes, New York (in press)Google Scholar
  52. Wallace DC (1987) Maternal genes: Mitochondrial Diseases. In: McKusick V (ed) Experimental mammalian genetics: a perspective. March of Dimes, New York (in press)Google Scholar
  53. Wallace DC, Singh G, Hopkins LC, Novotny EJ Jr (1985) Maternally inherited diseases of man. In: Quagliarello E, Slater EC, Palmieri F, Saccone C, Kroon AM (eds) Achievements and perspectives of mitochondrial research, vol II: biogenesis. Elsevier, New York, pp 427–436Google Scholar
  54. Woo SLC (1979) Methods Enzymol 68:389–395Google Scholar
  55. Yang J, Ye J, Wallace DC (1984) Nucleic Acids Res 12:837–843Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • Douglas C. Wallace
    • 1
  • Jianhong Ye
    • 1
  • S. Nicolas Neckelmann
    • 1
  • Gurparkash Singh
    • 1
  • Keith A. Webster
    • 2
  • Barry D. Greenberg
    • 3
  1. 1.Departments of Biochemistry, Pediatrics and Anthropology, Woodruff Memorial BuildingEmory University Medical SchoolAtlantaUSA
  2. 2.Department of MedicineStanford University Medical Center and Veterans Administration Medical CenterPalo AltoUSA
  3. 3.California Biotechnology, Inc.Mountain ViewUSA

Personalised recommendations