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

Платонов, Федор Алексеевич; Tyryshkin, Kathrin; Тихонов, Дмитрий; Neustroyeva, Tatyana S.; Sivtseva, Tatyana M.; Yakovleva, N.V.; Nikolaev, Valerian P.; Sidorova, Oksana G.; Кононова, С.К.; Goldfarb, Lev G.; Renwick, Neil

doi:10.1007/s10048-016-0481-5

Cited by 14 publications

(8 citation statements)

References 20 publications

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“…A large variance exists in the number of individuals with ADCAs that are confirmed to be SCA1. The prevalence ranges from no cases reported in a study among Korean patients [ 51 ] to essentially 100% of all patients in an Eastern Siberian study, where SCA1 was the only type of ADCA identified in the ethnic Sakha population [ 52 ].…”

Section: Sca1mentioning

confidence: 99%

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Buijsen¹,

Toonen²,

et al. 2019

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Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.

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Section: Sca1mentioning

confidence: 99%

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Buijsen¹,

Toonen²,

et al. 2019

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“…Prevalence of SCA3/MJD in the Azores archipelago increased between 1981 and 2015 (de Araújo et al 2016) [50]. Similarly, prevalence of SCA1 in the Sakha (Yakut) people of Eastern Siberia increased between 1994 and 2013 (Platonov et al 2016) [51].…”

Section: Discussionmentioning

confidence: 99%

A model for the dynamics of expanded CAG repeat alleles:ATXN2andATXN3as prototypes

Sena,

Lemes,

Furtado

et al. 2023

Preprint

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Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to new expansions, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Here, we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of ade novoexpansion last. A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Therefore, the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and thede novoSCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.

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“…Studies on the fitness of polyQs have shown mixed results. Fitness in SCA1 was estimated to be increased 69 or unchanged 70 while increased fitness was reported in SCA3/MJD 71 and in SCA2 16 . Studies on HD have described increased fitness 69 in one study and unchanged fitness in another, 72 but the latter was performed prior to HD gene discovery.…”

Section: Discussionmentioning

confidence: 99%

Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta‐analysis

et al. 2021

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Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta‐analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22‐repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.

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

Cited by 14 publications

References 20 publications

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

A model for the dynamics of expanded CAG repeat alleles:ATXN2andATXN3as prototypes

Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta‐analysis

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