title: Estimation of the RNU2 macrosatellite mutation rate by BRCA1 mutation tracing.
abstract: Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one 'private' mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 × 10(-3) mutations per generation, which is close to that of microsatellites.
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France Genomic Vision, Bagneux, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Tessereau
authors.affiliation: Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR5558, Université Lyon 1, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Lesecque
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Nastasia
authors.initials: N
authors.lastname: Monnet
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Buisson
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Barjhoux
authors.affiliation: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Léoné
authors.affiliation: Department of Dermatology and Huntsman Cancer Institute University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Bingjian
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Dermatology and Huntsman Cancer Institute University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.affiliation: Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR5558, Université Lyon 1, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mousset
authors.affiliation: Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR5558, Université Lyon 1, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Duret
authors.affiliation: Genetics of Breast Cancer Team, Cancer Research Centre of Lyon, CNRS UMR5286, Inserm U1052, Université Lyon 1, Centre Léon Bérard, Lyon, France sylvie.mazoyer@lyon.unicancer.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
mesh_terms: D002460:Cell Line; D056915:DNA Copy Number Variations; D004276:DNA, Satellite / Q000737:chemistry*; D019398:Genes, BRCA1; D006801:Humans; D009154:Mutation; D059645:Mutation Rate
chemical_list: D004276:DNA, Satellite