Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.16/2627 |
Resumo: | The polymorphic trinucleotide repetitive region in the FMR1 gene 5'UTR contains AGG interspersions, particularly in normal-sized alleles (CGG < 45). In this range repetitive stretches are typically interrupted once or twice, although alleles without or with three or more AGG interspersions can also be observed. AGG interspersions together with the total length of the repetitive region confer stability and hinder expansion to pathogenic ranges: either premutation (55 < CGG < 200) or full mutation (CGG > 200). The AGG interspersions have long been identified as one of the most important features of FMR1 repeat stability, being particularly important to determine expansion risk estimates in female premutation carriers. We sought to compute the combined AGG interspersion numbers and patterns, aiming to define FMR1 repetitive tract complexity combinations. A mathematical model, the first to compute this cumulative effect, was developed and validated using data from 131 young and healthy females. Plotting of their allelic complexity enabled the identification of two statistically distinct groups - equivalent and dissimilar allelic combinations. The outcome, a numerical parameter designated allelic score, depicts the repeat substructure of each allele, measuring the allelic complexity of the FMR1 gene including the AGGs burden, thus allowing new behavioral scrutiny of normal-sized alleles in females. |
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Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele CombinationsAGG interspersion patternCGG repeatsFMR1 geneallelic scoremodeling allelic complexityThe polymorphic trinucleotide repetitive region in the FMR1 gene 5'UTR contains AGG interspersions, particularly in normal-sized alleles (CGG < 45). In this range repetitive stretches are typically interrupted once or twice, although alleles without or with three or more AGG interspersions can also be observed. AGG interspersions together with the total length of the repetitive region confer stability and hinder expansion to pathogenic ranges: either premutation (55 < CGG < 200) or full mutation (CGG > 200). The AGG interspersions have long been identified as one of the most important features of FMR1 repeat stability, being particularly important to determine expansion risk estimates in female premutation carriers. We sought to compute the combined AGG interspersion numbers and patterns, aiming to define FMR1 repetitive tract complexity combinations. A mathematical model, the first to compute this cumulative effect, was developed and validated using data from 131 young and healthy females. Plotting of their allelic complexity enabled the identification of two statistically distinct groups - equivalent and dissimilar allelic combinations. The outcome, a numerical parameter designated allelic score, depicts the repeat substructure of each allele, measuring the allelic complexity of the FMR1 gene including the AGGs burden, thus allowing new behavioral scrutiny of normal-sized alleles in females.This work was supported by national funds: FCT/MCTES (Fundação para a Ciência e a Tecnologia) – Project Reference SFRH/BD/136398/2018 to BR, UMIB (Unidade Multidisciplinar de Investigação Biomédica) – Reference UIDP/00215/2020 and UIDB/00215/2020, DEFI (Departamento de Ensino, Formação e Investigação) – Reference 2015-DEFI/145/12, and CESAM (Centro de Estudos do Ambiente e do Mar) – Reference UIDP/50017/2020 and UIDB/50017/2020.Frontiers Research FoundationRepositório Científico do Centro Hospitalar Universitário de Santo AntónioRodrigues, BárbaraVale-Fernandes, EmídioMaia, NSantos, FláviaMarques, IsabelSantos, RosárioNogueira, António J. A.Jorge, Paula2021-11-23T15:04:12Z2020-11-132020-11-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2627engRodrigues B, Vale-Fernandes E, Maia N, et al. Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations. Front Genet. 2020;11:557147. doi:10.3389/fgene.2020.5571471664-802110.3389/fgene.2020.557147info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-20T11:01:22Zoai:repositorio.chporto.pt:10400.16/2627Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:49.736814Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
title |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
spellingShingle |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations Rodrigues, Bárbara AGG interspersion pattern CGG repeats FMR1 gene allelic score modeling allelic complexity |
title_short |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
title_full |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
title_fullStr |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
title_full_unstemmed |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
title_sort |
Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations |
author |
Rodrigues, Bárbara |
author_facet |
Rodrigues, Bárbara Vale-Fernandes, Emídio Maia, N Santos, Flávia Marques, Isabel Santos, Rosário Nogueira, António J. A. Jorge, Paula |
author_role |
author |
author2 |
Vale-Fernandes, Emídio Maia, N Santos, Flávia Marques, Isabel Santos, Rosário Nogueira, António J. A. Jorge, Paula |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Centro Hospitalar Universitário de Santo António |
dc.contributor.author.fl_str_mv |
Rodrigues, Bárbara Vale-Fernandes, Emídio Maia, N Santos, Flávia Marques, Isabel Santos, Rosário Nogueira, António J. A. Jorge, Paula |
dc.subject.por.fl_str_mv |
AGG interspersion pattern CGG repeats FMR1 gene allelic score modeling allelic complexity |
topic |
AGG interspersion pattern CGG repeats FMR1 gene allelic score modeling allelic complexity |
description |
The polymorphic trinucleotide repetitive region in the FMR1 gene 5'UTR contains AGG interspersions, particularly in normal-sized alleles (CGG < 45). In this range repetitive stretches are typically interrupted once or twice, although alleles without or with three or more AGG interspersions can also be observed. AGG interspersions together with the total length of the repetitive region confer stability and hinder expansion to pathogenic ranges: either premutation (55 < CGG < 200) or full mutation (CGG > 200). The AGG interspersions have long been identified as one of the most important features of FMR1 repeat stability, being particularly important to determine expansion risk estimates in female premutation carriers. We sought to compute the combined AGG interspersion numbers and patterns, aiming to define FMR1 repetitive tract complexity combinations. A mathematical model, the first to compute this cumulative effect, was developed and validated using data from 131 young and healthy females. Plotting of their allelic complexity enabled the identification of two statistically distinct groups - equivalent and dissimilar allelic combinations. The outcome, a numerical parameter designated allelic score, depicts the repeat substructure of each allele, measuring the allelic complexity of the FMR1 gene including the AGGs burden, thus allowing new behavioral scrutiny of normal-sized alleles in females. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-11-13 2020-11-13T00:00:00Z 2021-11-23T15:04:12Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.16/2627 |
url |
http://hdl.handle.net/10400.16/2627 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Rodrigues B, Vale-Fernandes E, Maia N, et al. Development and Validation of a Mathematical Model to Predict the Complexity of FMR1 Allele Combinations. Front Genet. 2020;11:557147. doi:10.3389/fgene.2020.557147 1664-8021 10.3389/fgene.2020.557147 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Frontiers Research Foundation |
publisher.none.fl_str_mv |
Frontiers Research Foundation |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133648497147904 |