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Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = −0.81); most patients with low-medium (39–55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39–55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow’s index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone.

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Acknowledgments

The study was funded in part by the Ministry of Education and Science of the Russian Federation through individual or group projects: PFA—project 1742, TDG, NTS, YNV, and NVP—project 18.1742.2014/K and KSK—project 6.656.2014/K. KT was supported by the Department of Pathology and Molecular Medicine, Queen’s University. GLG was funded in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke. NR was funded through a SEAMO New Clinician-Scientist Investigator Award and the Queen’s University Principal’s Development Fund. The authors wish to thank Dr. A.L. Suhomâsova for helpful advice.

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Authors and Affiliations

  1. Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation

    Fedor A. Platonov, Dmitriy G. Tikhonov, Tatyana S. Neustroyeva, Tatyana M. Sivtseva, Natalya V. Yakovleva & Valerian P. Nikolaev

  2. Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, K7L 3N6, Canada

    Kathrin Tyryshkin & Neil M. Renwick

  3. Center for Integrated Medical Research, Academy of Medical Sciences, Yakutsk, 677010, The Russian Federation

    Oksana G. Sidorova & Sardana K. Kononova

  4. National Institute of Neurological Disorder and Stoke, NIH, Bethesda, MD, 20892, USA

    Lev G. Goldfarb

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  1. Fedor A. Platonov
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  2. Kathrin Tyryshkin
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  3. Dmitriy G. Tikhonov
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  6. Natalya V. Yakovleva
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  7. Valerian P. Nikolaev
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  8. Oksana G. Sidorova
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  9. Sardana K. Kononova
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  10. Lev G. Goldfarb
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Correspondence to Lev G. Goldfarb.

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The authors declare that they have no conflict of interest.

Human and animal rights and informed consent

We complied with the ethical principles regarding research involving human subjects set forth in the Belmont Report and the Declaration of Helsinki, and informed consent has been obtained from each study participant.

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Platonov, F.A., Tyryshkin, K., Tikhonov, D.G. et al. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1. Neurogenetics 17, 179–185 (2016). https://doi.org/10.1007/s10048-016-0481-5

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  • DOI: https://doi.org/10.1007/s10048-016-0481-5

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