Mother’s curse neutralizes natural selection against a human genetic disease over three centuries

Abstract

According to evolutionary theory, mitochondria could be poisoned gifts that mothers transmit to their sons. This is because mutations harmful to males are expected to accumulate in the mitochondrial genome, the so-called ‘mother’s curse’. However, the contribution of the mother’s curse to the mutation load in nature remains largely unknown and hard to predict, because compensatory mechanisms could impede the spread of deleterious mitochondria. Here we provide evidence for the mother’s curse in action over 290 years in a human population. We studied a mutation causing Leber’s hereditary optical neuropathy, a disease with male-biased prevalence and which has long been suspected to be maintained in populations by the mother’s curse. Male carriers showed a low fitness relative to non-carriers and to females, mostly explained by their high rate of infant mortality. Despite poor male fitness, selection analysis predicted a slight (albeit non-significant) increase in frequency, which sharply contrasts with the 35.5% per-generation decrease predicted if mitochondrial DNA transmission had been through males instead of females. Our results are therefore even suggestive of positive selection through the female line that may exacerbate effects of the mother’s curse. This study supports a contribution of the mother’s curse to the reduction of male lifespan, uncovering a large fitness effect associated with a single mitochondrial variant.

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Fig. 1: Fitness components in 97 individuals carrying the T14484C mitochondrial variant in the French-Canadian population of Québec between 1670 and 1750.
Fig. 2: Sex ratio of married individuals in French-Canadian lineages between 1670 and 1960.
Fig. 3: Change in the frequency of the LHON causing T14484C variant between 1670 and 1775 (RPQA data) and between 1670 and 1960 (BALSAC data).

References

  1. 1.

    White, D. J., Wolff, J. N., Pierson, M. & Gemmell, N. J. Revealing the hidden complexities of mtDNA inheritance. Mol. Ecol. 17, 4925–4942 (2008).

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Frank, S. A. & Hurst, L. D. Mitochondria and male disease. Nature 383, 224 (1996).

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Murlas Cosmides, L. & Tooby, J. Cytoplasmic inheritance and intragenomic conflict. J. Theor. Biol. 89, 83–129 (1981).

    Article  Google Scholar 

  4. 4.

    Wolff, J. N. & Gemmell, N. J. Mitochondria, maternal inheritance, and asymmetric fitness: why males die younger. BioEssays 35, 93–99 (2013).

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Ruiz-Pesini, E. et al. Human mtDNA haplogroups associated with high or reduced spermatozoa motility. Am. J. Hum. Genet. 67, 682–696 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Holyoake, A. J. et al. High incidence of single nucleotide substitutions in the mitochondrial genome is associated with poor semen parameters in men. Int. J. Androl. 24, 175–182 (2001).

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Gemmell, N. J., Metcalf, V. J. & Allendorf, F. W. Mother’s curse: the effect of mtDNA on individual fitness and population viability. Trends Ecol. Evol. 19, 238–244 (2004).

    Article  PubMed  Google Scholar 

  8. 8.

    Hedrick, P. W. Reversing mother’s curse revisited. Evolution 66, 612–616 (2012).

    Article  PubMed  Google Scholar 

  9. 9.

    Wade, M. J. & Brandvain, Y. Reversing mother’s curse: selection on male mitochondrial fitness effects. Evolution 63, 1084–1089 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kuijper, B., Lane, N. & Pomiankowski, A. Can paternal leakage maintain sexually antagonistic polymorphism in the cytoplasm? J. Evol. Biol. 28, 468–480 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Beekman, M., Dowling, D. K. & Aanen, D. K. The costs of being male: are there sex-specific effects of uniparental mitochondrial inheritance? Phil. Trans R. Soc. B 369, 20130440 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Dordevic, M. et al. Sex-specific mitonuclear epistasis and the evolution of mitochondrial bioenergetics, ageing, and life history in seed beetles. Evolution 71, 274–288 (2017).

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Wade, M. J. Paradox of mother’s curse and the maternally provisioned offspring microbiome. Cold Spring Harb. Perspect. Biol. 6, a017541 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Wade, M. J. & Drown, D. M. Nuclear–mitochondrial epistasis: a gene’s eye view of genomic conflict. Ecol. Evol. 6, 6460–6472 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ross, J. M., Coppotelli, G., Hoffer, B. J. & Olson, L. Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci. Rep. 4, 6569 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Latorre-Pellicer, A. et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Camus, M. F., Clancy, D. J. & Dowling, D. K. Mitochondria, maternal inheritance, and male aging. Curr. Biol. 22, 1717–1721 (2012).

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Smith, S., Turbill, C. & Suchentrunk, F. Introducing mother’s curse: low male fertility associated with an imported mtDNA haplotype in a captive colony of brown hares. Mol. Ecol. 19, 36–43 (2010).

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Innocenti, P., Morrow, E. H. & Dowling, D. K. Experimental evidence supports a sex-specific selective sieve in mitochondrial genome evolution. Science 332, 845–848 (2011).

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Maklakov, A. A. & Lummaa, V. Evolution of sex differences in lifespan and aging: causes and constraints. BioEssays 35, 717–724 (2013).

    Article  PubMed  Google Scholar 

  21. 21.

    Wallace, D. C. A mitochondrial bioenergetic etiology of disease. J. Clin. Invest. 123, 1405–1412 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Reinhardt, K., Dowling, D. K. & Morrow, E. H. Mitochondrial replacement, evolution, and the clinic. Science 341, 1345–1346 (2013).

    Article  PubMed  Google Scholar 

  23. 23.

    Tonska, K., Kodron, A. & Bartnik, E. Genotype–phenotype correlations in Leber hereditary optic neuropathy. Biochim. Biophys. Acta 1797, 1119–1123 (2010).

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Piotrowska, A., Korwin, M., Bartnik, E. & Tonska, K. Leber hereditary optic neuropathy: historical report in comparison with the current knowledge. Gene 555, 41–49 (2015).

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Macmillan, C. et al. Pedigree analysis of French Canadian families with T14484C Leber’s hereditary optic neuropathy. Neurology 50, 417–422 (1998).

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Man, P. Y. W., Turnbull, D. M. & Chinnery, P. F. Leber hereditary optic neuropathy. J. Med. Genet. 39, 162–169 (2002).

    Article  PubMed Central  Google Scholar 

  27. 27.

    Mackey, D. A. Three subgroups of patients from the United Kingdom with Leber hereditary optic neuropathy. Eye 8, 431–436 (1994).

    Article  PubMed  Google Scholar 

  28. 28.

    Barboni, P. et al. Leber’s hereditary optic neuropathy with childhood onset. Invest. Ophth. Vis. Sci. 47, 5303–5309 (2006).

    Article  Google Scholar 

  29. 29.

    Chinnery, P. F. et al. The challenges of mitochondrial replacement. PLoS Genet. 10, e1004315 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Landry, Y. Les Filles du Roi au XVIIe Siècle: Orphelines en France, Pionnières au Canada [The Filles du Roi in the 17th Century: Orphans in France, Pionneers in Canada] (Leméac, 1992).

  31. 31.

    Laberge, A.-M. et al. A “Fille du Roy” introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians. Am. J. Hum. Genet. 77, 313–317 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Desjardins, B. Le Registre de la population du Québec ancien [The Early Québec Population Register]. Ann. Démogr. Hist. (Paris) 2, 215–226 (1998).

    Google Scholar 

  33. 33.

    Moorad, J. A. Individual fitness and phenotypic selection in age-structured populations with constant growth rates. Ecology 95, 1087–1095 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Landry, Y., Gadoury, L. & Charbonneau, H. Démographie différentielle en Nouvelle-France : villes et campagnes [Differential demography in New France: cities and countryside]. Rev. Hist. Am. Fr. 38, 357–378 (1985).

    PubMed  Google Scholar 

  35. 35.

    Amorevieta-Gentil, M. Les Niveaux et les Facteurs Déterminants de la Mortalité Infantile en Nouvelle-France et au Début du Régime Anglais. [Levels and determinants of infant mortality in New France and at the onset of the English Regime.] PhD thesis, Université de Montréal, (2010).

  36. 36.

    Gagnon, A. & Mazan, R. Does exposure to infectious diseases in infancy affect old-age mortality? Evidence from a pre-industrial population. Soc. Sci. Med. 68, 1609–1616 (2009).

    Article  PubMed  Google Scholar 

  37. 37.

    Davenport, R., Schwarz, L. & Boulton, J. The decline of adult smallpox in eighteenth-century London. Econ. Hist. Rev. 64, 1289–1314 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Unckless, R. L. & Herren, J. K. Population genetics of sexually antagonistic mitochondrial mutants under inbreeding. J. Theor. Biol. 260, 132–136 (2009).

    Article  PubMed  Google Scholar 

  39. 39.

    Bower, S. P., Hawley, I. & Mackey, D. A. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. Lancet 339, 1427–1428 (1992).

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    La Russa, A. et al. Leber’s hereditary optic neuropathy associated with a multiple-sclerosis-like picture in a man. Mult. Scler. J. 17, 763–766 (2011).

    Article  Google Scholar 

  41. 41.

    Gropman, A. et al. Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. Am. J. Med. Genet. 124A, 377–382 (2004).

    Article  PubMed  Google Scholar 

  42. 42.

    Nikoskelainen, E. K. et al. Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J. Neurol. Neurosurg. Psychiatry 59, 160–164 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Wallace, D. C. A new manifestation of Leber’s disease and a new explanation for the agency responsible for its unusual pattern of inheritance. Brain 93, 121–132 (1970).

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Fruhman, G. et al. Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation. Mol. Genet. Metab. 103, 153–160 (2011).

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Chinnery, P. F., Andrews, R. M., Turnbull, D. M. & Howell, N. Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am. J. Med. Genet. 98, 235–243 (2001).

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Yen, M.-Y., Wang, A.-G. & Wei, Y.-H. Leber’s hereditary optic neuropathy: a multifactorial disease. Prog. Retin. Eye Res. 25, 381–396 (2006).

    Article  PubMed  Google Scholar 

  47. 47.

    Man, P. Y. W. et al. Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees. J. Med. Genet. 41, e41 (2004).

    Article  PubMed Central  Google Scholar 

  48. 48.

    Hamzelou, J. World’s first baby born with new “3 parent” technique, https://www.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique (2016).

  49. 49.

    Moorad, J. A. A demographic transition altered the strength of selection for fitness and age-specific survival and fertility in a 19th century American population. Evolution 67, 1622–1634 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Heyer, E. et al. Phylogenetic and familial estimates of mitochondrial substitution rates: study of control region mutations in deep-rooting pedigrees. Am. J. Hum. Genet. 69, 1113–1126 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. 51.

    Moreau, C. et al. When genetics and genealogies tell different stories—maternal lineages in Gaspesia. Ann. Hum. Genet. 75, 247–254 (2011).

    PubMed  Google Scholar 

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Acknowledgements

We thank S. Gravel, L. Barreiro, A. Hodgkinson, J. Moorad, D. H. Nussey and D. Réale for their useful comments that helped improve the manuscript; H. Vézina, M. Jomphe and B. Desjardins for their support in working with the BALSAC register and the RPQA. This study was funded by the Fonds de recherche du Québec—Santé, through the Québec Network of Applied Genetic Medicine (D.L.) and a Natural Sciences and Engineering Research Council of Canada Discovery grant (E.M.).

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D.L., E.M. and C.M. designed the study, C.M. performed the analyses, E.M. wrote the paper; B.B., A.A.C. and A.G. brought their expertise, respectively, in genetic medicine, evolution and ageing, and demography; all authors discussed the results and commented on the manuscript.

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Correspondence to Emmanuel Milot.

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Milot, E., Moreau, C., Gagnon, A. et al. Mother’s curse neutralizes natural selection against a human genetic disease over three centuries. Nat Ecol Evol 1, 1400–1406 (2017). https://doi.org/10.1038/s41559-017-0276-6

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