Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.
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.
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Fedor A
FA
Platonov
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
Kathrin
K
Tyryshkin
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Dmitriy G
DG
Tikhonov
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Tatyana S
TS
Neustroyeva
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Tatyana M
TM
Sivtseva
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Natalya V
NV
Yakovleva
Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk, 677010, The Russian Federation.
Valerian P
VP
Nikolaev
Center for Integrated Medical Research, Academy of Medical Sciences, Yakutsk, 677010, The Russian Federation.
Oksana G
OG
Sidorova
Center for Integrated Medical Research, Academy of Medical Sciences, Yakutsk, 677010, The Russian Federation.
Sardana K
SK
Kononova
National Institute of Neurological Disorder and Stoke, NIH, Bethesda, MD, 20892, USA. GoldfarbL@ninds.nih.gov.
Lev G
LG
Goldfarb
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
Neil M
NM
Renwick
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000067696:Ataxin-1 / Q000235:genetics*; D001723:Birth Rate; D015331:Cohort Studies; D005260:Female; D056084:Genetic Fitness; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012641:Selection, Genetic; D012800:Siberia / Q000453:epidemiology; D020754:Spinocerebellar Ataxias / Q000453:epidemiology* / Q000235:genetics*
C000593749:ATXN1 protein, human; D000067696:Ataxin-1
ATXN1 gene; Crow’s index; Genetic fitness; Northeast Siberia; Sakha (Yakut) population; Spinocerebellar ataxia type 1