Simulation of the distribution of spinocerebellar ataxia type 1 in Yakut populations: Model parameters and results of simulation

Koneva, Lada A.; Konev, A V; Кучер, А. Н.

doi:10.1134/s1022795410070148

Cited by 2 publications

(2 citation statements)

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“…Weak selective pressure in the SCA1 cohort indicates that the frequency of a genetic variant may remain unchanged for a long time. Koneva et al [7] developed a simulation model of SCA1 distribution in the Sakha population, predicting that it may take about 1290 years for natural selection to eliminate the mutant ATXN1 chromosomes; this interval could be shortened to 154 years with the introduction of an effective genetic counseling program.…”

Section: Discussionmentioning

confidence: 99%

“…SCA1 prevalence rate in these two regions is the highest in the Sakha (Yakut) Republic [7]. Patients from all affected regions carry an identical haplotype, as determined by typing several intragene variants [8], implying that there has been a single ancestral mutation that occurred no less than 915 years ago and spread through well-documented migrations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia)

Goldfarb¹,

Платонов

2019

Siberian Research

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Over the past several decades, more than 500 cases of Autosomal dominant spinocerebellar ataxia type 1 (SCA1) have been identified in the Republic of Sakha (Yakutia) of North-Eastern Siberia. The disease leads to long-term disability and death, making it a serious public health burden. The prevalence of SCA1 in the indigenous Sakha population has been steadily increasing since the 1970s. It has recently stabilized at a level of 45-53 per 100,000 due to efforts undertaken to limit its further spread. We describe results of a multi-year study of SCA1 in the Sakha population, including molecular genetics, distribution, clinical, electrophysiological and histopathological characteristics. Each studied patient had a mutation in the coding region of the ATXN1 gene on chromosome 6p22.3. The mutation presents as an uncontrolled increase in the number of trinucleotide CAG repeats from normal 25-32 to 39-72 with a loss of a CAT bridge in the middle of the CAG stretch. The number of continuous CAG triplets in the mutant ATXN1 gene correlates with the age of onset and the severity of the disease. The instability of this genomic segment is manifested in meiosis: the number of CAG repeats in a mutant gene increases in transmission from the father by an average of +3.04 repetitions and from the mother by +0.182 repetitions. The total number of repeats transmitted from one generation to another in the Sakha population is on average +1.614, which explains the increase in SCA1 prevalence. Patients from three spatially separate geographic regions of the Republic have the same haplotype, which confirms the origin of the mutation from a common ancestor about 37 generations ago. SCA1 patients in Mongolia, China and the U.S. show a different haplotype. To determine the potential of SCA1 for further spread, the fertility rates of the ATXN1 mutation carriers were evaluated and the Crow selection index calculated. The resulting score of 0.19 indicates that the mutation has little chance of being eliminated from the population without targeted preventive measures.

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Simulation of the distribution of spinocerebellar ataxia type 1 in Yakut populations: Model parameters and results of simulation

Cited by 2 publications

References 6 publications

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

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

Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia)

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