Format

Send to

Choose Destination
G3 (Bethesda). 2016 Aug 9;6(8):2343-54. doi: 10.1534/g3.116.030767.

A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

Author information

1
Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
2
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
3
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.
4
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065.
5
Microbial Pathogenesis, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
6
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.
7
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.
8
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK UCL Genetics Institute, University College London, WC1E 6BT, UK.
9
Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK da1@sanger.ac.uk.

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.

KEYWORDS:

Micronuclei; Outbred mice; genetic mapping; genome-wide association study (GWAS); genomic instability

PMID:
27233670
PMCID:
PMC4978889
DOI:
10.1534/g3.116.030767
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center