title: A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.
abstract: In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: McIntyre
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Santiago de Querétaro 76230, Mexico.
authors.forename: Carla Daniela
authors.initials: CD
authors.lastname: Robles-Espinoza
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065.
authors.forename: John
authors.initials: J
authors.lastname: Maciejowski
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Microbial Pathogenesis, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hill
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Verstraten
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK Tumour Profiling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, CB2 1QN, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Balmus
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK UCL Genetics Institute, University College London, WC1E 6BT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK da1@sanger.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D005260:Female; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D005838:Genotype; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012727:Sex Characteristics
keywords: Micronuclei; Outbred mice; genetic mapping; genome-wide association study (GWAS); genomic instability