Comparison of Mitochondrial Mutation Spectra in Ageing Human Colonic Epithelium and Disease: Absence of Evidence for Purifying Selection in Somatic Mitochondrial DNA Point Mutations

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Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population.

Vyšlo v časopise: Comparison of Mitochondrial Mutation Spectra in Ageing Human Colonic Epithelium and Disease: Absence of Evidence for Purifying Selection in Somatic Mitochondrial DNA Point Mutations. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003082
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003082

Souhrn

Zdroje

1. TroenBR (2003) The biology of aging. Mt Sinai J Med 70: 3–22.

2. KirkwoodTB, MelovS (2011) On the programmed/non-programmed nature of ageing within the life history. Curr Biol 21: R701–707.

3. KirkwoodTB (1977) Evolution of ageing. Nature 270: 301–304.

4. KirkwoodTB (2005) Understanding the odd science of aging. Cell 120: 437–447.

5. LinnaneAW, MarzukiS, OzawaT, TanakaM (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1: 642–645.

6. NassMM (1966) The circularity of mitochondrial DNA. Proc Natl Acad Sci U S A 56: 1215–1222.

7. TaylorRW, TurnbullDM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6: 389–402.

8. OldSL, JohnsonMA (1989) Methods of microphotometric assay of succinate dehydrogenase and cytochrome c oxidase activities for use on human skeletal muscle. Histochem J 21: 545–555.

9. GreavesLC, PrestonSL, TadrousPJ, TaylorRW, BarronMJ, et al. (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A 103: 714–719.

10. TaylorRW, BarronMJ, BorthwickGM, GospelA, ChinneryPF, et al. (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Invest 112: 1351–1360.

11. ShoubridgeEA, WaiT (2007) Mitochondrial DNA and the mammalian oocyte. Curr Top Dev Biol 77: 87–111.

12. ElsonJL, AndrewsRM, ChinneryPF, LightowlersRN, TurnbullDM, et al. (2001) Analysis of European mtDNAs for recombination. Am J Hum Genet 68: 145–153.

13. MullerHJ (1964) The relation of recombination to mutational advance. Mutat Res 106: 2–9.

14. BogenhagenD, ClaytonDA (1977) Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 11: 719–727.

15. RandDM (2008) Mitigating mutational meltdown in mammalian mitochondria. PLoS Biol 6: e35 doi:10.1371/journal.pbio.0060035

16. LeeHC, ChangCM, ChiCW (2010) Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 9Suppl 1: S47–58.

17. CreeLM, SamuelsDC, de Sousa LopesSC, RajasimhaHK, WonnapinijP, et al. (2008) A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40: 249–254.

18. McFarlandR, TaylorRW, TurnbullDM (2007) Mitochondrial disease–its impact, etiology, and pathology. Curr Top Dev Biol 77: 113–155.

19. WaiT, TeoliD, ShoubridgeEA (2008) The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat Genet 40: 1484–1488.

20. ShoubridgeEA, WaiT (2008) Medicine. Sidestepping mutational meltdown. Science 319: 914–915.

21. ElsonJL, TurnbullDM, HowellN (2004) Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Am J Hum Genet 74: 229–238.

22. SunC, KongQP, ZhangYP (2007) The role of climate in human mitochondrial DNA evolution: a reappraisal. Genomics 89: 338–342.

23. StewartJB, FreyerC, ElsonJL, WredenbergA, CansuZ, et al. (2008) Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol 6: e10 doi:10.1371/journal.pbio.0060010.

24. FanW, WaymireKG, NarulaN, LiP, RocherC, et al. (2008) A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319: 958–962.

25. CottrellDA, BlakelyEL, JohnsonMA, IncePG, BorthwickGM, et al. (2001) Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiol Aging 22: 265–272.

26. FellousTG, IslamS, TadrousPJ, EliaG, KocherHM, et al. (2009) Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49: 1655–1663.

27. McDonaldSA, GreavesLC, Gutierrez-GonzalezL, Rodriguez-JustoM, DeheragodaM, et al. (2008) Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134: 500–510.

28. Muller-HockerJ (1989) Cytochrome-c-oxidase deficient cardiomyocytes in the human heart–an age-related phenomenon. A histochemical ultracytochemical study. Am J Pathol 134: 1167–1173.

29. Muller-HockerJ (1990) Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J Neurol Sci 100: 14–21.

30. KujothGC, HionaA, PughTD, SomeyaS, PanzerK, et al. (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481–484.

31. TrifunovicA, WredenbergA, FalkenbergM, SpelbrinkJN, RovioAT, et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.

32. VermulstM, WanagatJ, KujothGC, BielasJH, RabinovitchPS, et al. (2008) DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40: 392–394.

33. BenderA, KrishnanKJ, MorrisCM, TaylorGA, ReeveAK, et al. (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38: 515–517.

34. CortopassiGA, ArnheimN (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18: 6927–6933.

35. CortopassiGA, ShibataD, SoongNW, ArnheimN (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A 89: 7370–7374.

36. KraytsbergY, KudryavtsevaE, McKeeAC, GeulaC, KowallNW, et al. (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38: 518–520.

37. De AlwisN, HudsonG, BurtAD, DayCP, ChinneryPF (2009) Human liver stem cells originate from the canals of Hering. Hepatology 50: 992–993.

38. GreavesLC, BarronMJ, PlusaS, KirkwoodTB, MathersJC, et al. (2010) Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts. Exp Gerontol 45: 573–579.

39. ShinMG, KijigayaS, McCoyJPJr, LevinBC, YoungNS (2004) Marked mitochondrial DNA sequence heterogeneity in single CD34+ cell clones from normal adult bone marrow. Blood 103: 553–561.

40. ElsonJL, SwalwellH, BlakelyEL, McFarlandR, TaylorRW, et al. (2009) Pathogenic mitochondrial tRNA mutations–which mutations are inherited and why? Hum Mutat 30: E984–992.

41. LiB, KrishnanVG, MortME, XinF, KamatiKK, et al. (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25: 2744–2750.

42. AndrewsRM, KubackaI, ChinneryPF, LightowlersRN, TurnbullDM, et al. (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23: 147.

43. PereiraL, SoaresP, RadivojacP, LiB, SamuelsDC (2011) Comparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversity. Am J Hum Genet 88: 433–439.

44. ReeveAK, KrishnanKJ, ElsonJL, MorrisCM, BenderA, et al. (2008) Nature of mitochondrial DNA deletions in substantia nigra neurons. Am J Hum Genet 82: 228–235.

45. JenuthJP, PetersonAC, ShoubridgeEA (1997) Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet 16: 93–95.

46. BlackwoodJK, WilliamsonSC, GreavesLC, WilsonL, RigasAC, et al. (2011) In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells. J Pathol 225: 181–188.

47. GaisaNT, GrahamTA, McDonaldSA, Canadillas-LopezS, PoulsomR, et al. (2011) The human urothelium consists of multiple clonal units, each maintained by a stem cell. J Pathol 225: 163–171.

48. Gutierrez-GonzalezL, DeheragodaM, EliaG, LeedhamSJ, ShankarA, et al. (2009) Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations. J Pathol 217: 489–496.

49. FellousTG, McDonaldSA, BurkertJ, HumphriesA, IslamS, et al. (2009) A methodological approach to tracing cell lineage in human epithelial tissues. Stem Cells 27: 1410–1420.

50. FlissMS, UsadelH, CaballeroOL, WuL, ButaMR, et al. (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287: 2017–2019.

51. VermulstM, BielasJH, KujothGC, LadigesWC, RabinovitchPS, et al. (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39: 540–543.

52. HauswirthWW, LaipisPJ (1982) Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc Natl Acad Sci U S A 79: 4686–4690.

53. SuenDF, NarendraDP, TanakaA, ManfrediG, YouleRJ (2010) Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc Natl Acad Sci U S A 107: 11835–11840.

54. GreavesLC, ReeveAK, TaylorRW, TurnbullDM (2012) Mitochondrial DNA and disease. J Pathol 226: 274–286.

55. HinttalaR, SmeetsR, MoilanenJS, UgaldeC, UusimaaJ, et al. (2006) Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency. J Med Genet 43: 881–886.

56. BrunoC, SantorelliFM, AsseretoS, TonoliE, TessaA, et al. (2003) Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene. Muscle Nerve 28: 508–511.

57. RanaM, de CooI, DiazF, SmeetsH, MoraesCT (2000) An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann Neurol 48: 774–781.

58. Acin-PerezR, Fernandez-SilvaP, PeleatoML, Perez-MartosA, EnriquezJA (2008) Respiratory active mitochondrial supercomplexes. Mol Cell 32: 529–539.

59. SchaggerH, PfeifferK (2000) Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO 19: 1777–1783.

60. Hornig-DoHT, TatsutaT, BuckermannA, BustM, KollbergG, et al. (2012) Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly. EMBO J 31: 1293–1307.

61. LarssonNG, ClaytonDA (1995) Molecular genetic aspects of human mitochondrial disorders. 151–178.

62. BrierleyEJ (1997) Mitochonrial damage in human ageing. Reveiws in clinical gerontology 7: 95–105.

63. ElsonJL, SamuelsDC, TurnbullDM, ChinneryPF (2001) Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am J Hum Genet 68: 802–806.

64. KhrapkoK (2011) The timing of mitochondrial DNA mutations in aging. Nat Genet 43: 726–727.

65. YaoYG, BandeltHJ, YoungNS (2007) External contamination in single cell mtDNA analysis. PLoS ONE 2: e681 doi:10.1371/journal.pone.0000681.

66. MitchellAL, ElsonJL, HowellN, TaylorRW, TurnbullDM (2006) Sequence variation in mitochondrial complex I genes: mutation or polymorphism? J Med Genet 43: 175–179.

67. WongLJ (2007) Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve 36: 279–293.

68. AlstonCL, MorakM, ReidC, HargreavesIP, PopeSA, et al. (2010) A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy. Neuromuscul Disord 20: 131–135.

69. DownhamE, WinterthunS, NakkestadHL, HirthA, HalvorsenT, et al. (2008) A novel mitochondrial ND5 (MTND5) gene mutation giving isolated exercise intolerance. Neuromuscul Disord 18: 310–314.

70. MarottaR, ChinJ, KirbyDM, ChiotisM, CookM, et al. (2011) Novel single base pair COX III subunit deletion of mitochondrial DNA associated with rhabdomyolysis. J Clin Neurosci 18: 290–292.

71. FragakiK, ProcaccioV, BannwarthS, SerreV, O'HearnS, et al. (2009) A neonatal polyvisceral failure linked to a de novo homoplasmic mutation in the mitochondrially encoded cytochrome b gene. Mitochondrion 9: 346–352.

72. YarhamJW, Al-DosaryM, BlakelyEL, AlstonCL, TaylorRW, et al. (2011) A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat 32: 1319–1325.

73. MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org (2011) Accessed 2012 May.

74. NgPC, HenikoffS (2001) Predicting deleterious amino acid substitutions. Genome Res 11: 863–874.

75. NgPC, HenikoffS (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: 3812–3814.