A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/268363 |
Resumo: | Background: 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 increases in the expanded repeats, 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. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: 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. Results: 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. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 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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Sena, Lucas Schenatto deLemes, Renan BarbosaFurtado, Gabriel VasataPereira, Maria Luiza SaraivaJardim, Laura Bannach2023-12-13T03:25:55Z20231664-8021http://hdl.handle.net/10183/268363001189575Background: 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 increases in the expanded repeats, 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. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: 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. Results: 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. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.application/pdfengFrontiers in genetics. Lausanne. Vol. 14 (Nov. 2023), 1296614, 13 p.Doenças cerebelaresGenesAlelosDoença de Machado-JosephAtaxias espinocerebelaresAllele dynamicsMachado-Joseph diseaseMathematical modelPolyglutamine diseasesSpinocerebellar ataxia type 2Spinocerebellar ataxia type 3Selective forcesA model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypesEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001189575.pdf.txt001189575.pdf.txtExtracted Texttext/plain71469http://www.lume.ufrgs.br/bitstream/10183/268363/2/001189575.pdf.txta8dfe1e8d1424ebd27d5aa6ef0e47de4MD52ORIGINAL001189575.pdfTexto completo (inglês)application/pdf1018981http://www.lume.ufrgs.br/bitstream/10183/268363/1/001189575.pdfda90d8246f0d85a1e0efe0760ce0fa73MD5110183/2683632023-12-14 04:24:12.548792oai:www.lume.ufrgs.br:10183/268363Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-12-14T06:24:12Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
title |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
spellingShingle |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes Sena, Lucas Schenatto de Doenças cerebelares Genes Alelos Doença de Machado-Joseph Ataxias espinocerebelares Allele dynamics Machado-Joseph disease Mathematical model Polyglutamine diseases Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 Selective forces |
title_short |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
title_full |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
title_fullStr |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
title_full_unstemmed |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
title_sort |
A model for the dynamics of expanded CAG repeat alleles : ATXN2 and ATXN3 as prototypes |
author |
Sena, Lucas Schenatto de |
author_facet |
Sena, Lucas Schenatto de Lemes, Renan Barbosa Furtado, Gabriel Vasata Pereira, Maria Luiza Saraiva Jardim, Laura Bannach |
author_role |
author |
author2 |
Lemes, Renan Barbosa Furtado, Gabriel Vasata Pereira, Maria Luiza Saraiva Jardim, Laura Bannach |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
Sena, Lucas Schenatto de Lemes, Renan Barbosa Furtado, Gabriel Vasata Pereira, Maria Luiza Saraiva Jardim, Laura Bannach |
dc.subject.por.fl_str_mv |
Doenças cerebelares Genes Alelos Doença de Machado-Joseph Ataxias espinocerebelares |
topic |
Doenças cerebelares Genes Alelos Doença de Machado-Joseph Ataxias espinocerebelares Allele dynamics Machado-Joseph disease Mathematical model Polyglutamine diseases Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 Selective forces |
dc.subject.eng.fl_str_mv |
Allele dynamics Machado-Joseph disease Mathematical model Polyglutamine diseases Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 Selective forces |
description |
Background: 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 increases in the expanded repeats, 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. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: 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. Results: 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. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-12-13T03:25:55Z |
dc.date.issued.fl_str_mv |
2023 |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
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http://hdl.handle.net/10183/268363 |
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1664-8021 |
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001189575 |
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http://hdl.handle.net/10183/268363 |
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dc.relation.ispartof.pt_BR.fl_str_mv |
Frontiers in genetics. Lausanne. Vol. 14 (Nov. 2023), 1296614, 13 p. |
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