title: Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114.|UnIGENe, Instituto de Biologia Molecular e Celular and Instituto de Investigação e Inovação em Saúde, Porto 4200, Portugal.|Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050, Portugal.
authors.forename: João Luís
authors.initials: JL
authors.lastname: Neto
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114.|Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Ali
authors.initials: A
authors.lastname: Afridi
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Jolene R
authors.initials: JR
authors.lastname: Guide
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Stephani
authors.initials: S
authors.lastname: Dempsey
authors.affiliation: CHDI (Cure Huntington's Disease Initiative Foundation), Princeton, New Jersey 08540.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lager
authors.affiliation: UnIGENe, Instituto de Biologia Molecular e Celular and Instituto de Investigação e Inovação em Saúde, Porto 4200, Portugal.|Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 Wheeler@helix.mgh.harvard.edu RMouroPinto@mgh.harvard.edu.|Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114 Wheeler@helix.mgh.harvard.edu RMouroPinto@mgh.harvard.edu.|Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ricardo Mouro
authors.identifier: 0000-0001-6744-2805
authors.initials: RM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D005260:Female; D055879:Gene Knock-In Techniques; D060045:Genes, Modifier; D000068617:Genetic Background; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019680:Trinucleotide Repeat Expansion
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein
keywords: HD knock-in mouse models; Huntington’s disease; genetic background; intergenerational CAG repeat instability