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Open Access Research article

Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus

Kimberly L Mahler1, Jessica L Fleming2, Amy M Dworkin3, Nicholas Gladman1, Hee-Yeon Cho2, Jian-Hua Mao4, Allan Balmain4 and Amanda Ewart Toland15*

Author Affiliations

1 Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, OH, USA

2 Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, OH, USA

3 Integrated Biomedical Science Graduate Program, The Ohio State University, OH, USA

4 Cancer Research Institute, University of California, San Francisco, San Francisco, CA, USA

5 Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

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BMC Genomics 2008, 9:626  doi:10.1186/1471-2164-9-626

Published: 23 December 2008

Abstract

Background

Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross.

Results

To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.

Conclusion

Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.