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

Nature Ecology & Evolution volume 1, pages 1400–1406 (2017)Cite this article

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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.

In most species maternal inheritance of mitochondrial DNA (mtDNA) is the norm1. This implies that natural selection should not restrict the transmission of mtDNA mutations that reduce the fitness of males, but are neutral or advantageous in females2, leading to intersexual intragenomic conflicts3. In principle, deleterious mutations could accumulate in the mitochondrial genome at high cost to males, limiting their fecundity, health and lifespan4,5,6. This selective sieve, known as the mother’s curse7 could be a widespread phenomenon shaping male life history and fitness, whenever selection acting on mtDNA genes is asymmetric between the sexes4.

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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).

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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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Author notes

  1. Emmanuel Milot and Claudia Moreau contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Biochemistry and Physics, and Forensic Research Group, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, G9A 5H7, Canada

    Emmanuel Milot

  2. CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, H3T 1C5, Canada

    Claudia Moreau & Damian Labuda

  3. Department of Demography & Institut de Recherche en Santé Publique, Université de Montréal, Montréal, Québec, H3T 1N8, Canada

    Alain Gagnon

  4. PRIMUS Research Group, Department of Family Medicine, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada

    Alan A. Cohen

  5. Departments of Neurology and Neurosurgery and Human Genetics, McGill University, Montreal Neurological Institute, Montréal, Québec, H3A 2B4, Canada

    Bernard Brais

  6. Department of Pediatrics, Université de Montréal, Montréal, Québec, H3T 1C5, Canada

    Damian Labuda

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Contributions

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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