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Article: A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus

TitleA multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus
Authors
Issue Date2006
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ejhg
Citation
European Journal Of Human Genetics, 2006, v. 14 n. 8, p. 932-940 How to Cite?
AbstractDespite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG) n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.
Persistent Identifierhttp://hdl.handle.net/10722/143529
ISSN
2015 Impact Factor: 4.58
2015 SCImago Journal Rankings: 2.077
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMartins, Sen_HK
dc.contributor.authorCalafell, Fen_HK
dc.contributor.authorWong, VCNen_HK
dc.contributor.authorSequeiros, Jen_HK
dc.contributor.authorAmorim, Aen_HK
dc.date.accessioned2011-12-12T03:51:32Z-
dc.date.available2011-12-12T03:51:32Z-
dc.date.issued2006en_HK
dc.identifier.citationEuropean Journal Of Human Genetics, 2006, v. 14 n. 8, p. 932-940en_HK
dc.identifier.issn1018-4813en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143529-
dc.description.abstractDespite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG) n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ejhgen_HK
dc.relation.ispartofEuropean Journal of Human Geneticsen_HK
dc.subject.meshAllelesen_US
dc.subject.meshEvolution, Molecularen_US
dc.subject.mesh*Gene Frequencyen_US
dc.subject.meshGenetic Testingen_US
dc.subject.meshHaplotypesen_US
dc.subject.meshHumansen_US
dc.subject.meshLinkage Disequilibriumen_US
dc.subject.meshLocus Control Regionen_US
dc.subject.meshMachado-Joseph Disease/*geneticsen_US
dc.subject.meshMutationen_US
dc.subject.meshNerve Tissue Proteins/*geneticsen_US
dc.subject.meshNuclear Proteins/*geneticsen_US
dc.subject.mesh*Polymorphism, Geneticen_US
dc.subject.meshRepressor Proteins/*geneticsen_US
dc.subject.mesh*Trinucleotide Repeatsen_US
dc.titleA multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locusen_HK
dc.typeArticleen_HK
dc.identifier.emailWong, VCN:vcnwong@hku.hken_HK
dc.identifier.authorityWong, VCN=rp00334en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/sj.ejhg.5201643en_HK
dc.identifier.pmid16724006en_HK
dc.identifier.scopuseid_2-s2.0-33746366792en_HK
dc.identifier.hkuros120826-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33746366792&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume14en_HK
dc.identifier.issue8en_HK
dc.identifier.spage932en_HK
dc.identifier.epage940en_HK
dc.identifier.isiWOS:000239326300011-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridMartins, S=7007089353en_HK
dc.identifier.scopusauthoridCalafell, F=7005098244en_HK
dc.identifier.scopusauthoridWong, VCN=7202525632en_HK
dc.identifier.scopusauthoridSequeiros, J=7005499969en_HK
dc.identifier.scopusauthoridAmorim, A=7006426820en_HK
dc.identifier.citeulike658653-

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