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Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis

Mutation at most human minisatellites is driven by complex interallelic processes that give rise to a high degree of length polymorphism and internal structural variation. MSY1, the only highly variable minisatellite on the non-recombining region of the Y chromosome, is constitutively haploid and th...

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Autores principales: Shanks, Morag E., May, Celia A., Dubrova, Yuri E., Balaresque, Patricia, Rosser, Zoë H., Adams, Susan M., Jobling, Mark A.
Formato: Texto
Lenguaje:English
Publicado: Elsevier 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2599865/
https://www.ncbi.nlm.nih.gov/pubmed/18929582
http://dx.doi.org/10.1016/j.mrfmmm.2008.09.008
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author Shanks, Morag E.
May, Celia A.
Dubrova, Yuri E.
Balaresque, Patricia
Rosser, Zoë H.
Adams, Susan M.
Jobling, Mark A.
author_facet Shanks, Morag E.
May, Celia A.
Dubrova, Yuri E.
Balaresque, Patricia
Rosser, Zoë H.
Adams, Susan M.
Jobling, Mark A.
author_sort Shanks, Morag E.
collection PubMed
description Mutation at most human minisatellites is driven by complex interallelic processes that give rise to a high degree of length polymorphism and internal structural variation. MSY1, the only highly variable minisatellite on the non-recombining region of the Y chromosome, is constitutively haploid and therefore precluded from interallelic interactions, yet maintains high diversity in both length and structure. To investigate the basis of its mutation processes, an unbiased structural analysis of >500 single-molecule MSY1 PCR products from matched sperm and blood samples from a single donor was undertaken. The overall mutation frequencies in sperm and blood DNAs were not significantly different, at 2.68% and 1.88%, respectively. Sperm DNA showed significantly more length mutants than blood DNA, with mutants in both tissues involving small-scale (1–3 repeat units in a 77 repeat progenitor allele) increases or decreases in repeat block lengths, with no gain or loss bias. Isometric mutations altering structure but not length were found in both tissues, and involved either the apparent shift of a boundary between repeat unit blocks (a ‘boundary switch’) or the conversion of a repeat within a block to a different repeat type (‘modular structure’ mutant). There was a significant excess of boundary switch mutants and deficit of modular structure mutants in sperm. A comparison of mutant structures with phylogenetically matched alleles in population samples showed that alleles with structures resembling the blood mutants were unlikely to arise in populations. Mutation seems likely to involve gene conversion via synthesis-dependent strand annealing, and the blood-sperm differences may reflect more relaxed constraint on sister chromatid alignment in blood.
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spelling pubmed-25998652008-12-16 Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis Shanks, Morag E. May, Celia A. Dubrova, Yuri E. Balaresque, Patricia Rosser, Zoë H. Adams, Susan M. Jobling, Mark A. Mutat Res Article Mutation at most human minisatellites is driven by complex interallelic processes that give rise to a high degree of length polymorphism and internal structural variation. MSY1, the only highly variable minisatellite on the non-recombining region of the Y chromosome, is constitutively haploid and therefore precluded from interallelic interactions, yet maintains high diversity in both length and structure. To investigate the basis of its mutation processes, an unbiased structural analysis of >500 single-molecule MSY1 PCR products from matched sperm and blood samples from a single donor was undertaken. The overall mutation frequencies in sperm and blood DNAs were not significantly different, at 2.68% and 1.88%, respectively. Sperm DNA showed significantly more length mutants than blood DNA, with mutants in both tissues involving small-scale (1–3 repeat units in a 77 repeat progenitor allele) increases or decreases in repeat block lengths, with no gain or loss bias. Isometric mutations altering structure but not length were found in both tissues, and involved either the apparent shift of a boundary between repeat unit blocks (a ‘boundary switch’) or the conversion of a repeat within a block to a different repeat type (‘modular structure’ mutant). There was a significant excess of boundary switch mutants and deficit of modular structure mutants in sperm. A comparison of mutant structures with phylogenetically matched alleles in population samples showed that alleles with structures resembling the blood mutants were unlikely to arise in populations. Mutation seems likely to involve gene conversion via synthesis-dependent strand annealing, and the blood-sperm differences may reflect more relaxed constraint on sister chromatid alignment in blood. Elsevier 2008-12-15 /pmc/articles/PMC2599865/ /pubmed/18929582 http://dx.doi.org/10.1016/j.mrfmmm.2008.09.008 Text en © 2008 Elsevier B.V. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Shanks, Morag E.
May, Celia A.
Dubrova, Yuri E.
Balaresque, Patricia
Rosser, Zoë H.
Adams, Susan M.
Jobling, Mark A.
Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title_full Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title_fullStr Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title_full_unstemmed Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title_short Complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
title_sort complex germline and somatic mutation processes at a haploid human minisatellite shown by single-molecule analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2599865/
https://www.ncbi.nlm.nih.gov/pubmed/18929582
http://dx.doi.org/10.1016/j.mrfmmm.2008.09.008
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