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


CONCLUSIONS
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.
Mahler
Kimberly L
KL
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, OH, USA. kimberly.mahler@osumc.edu
Fleming
Jessica L
JL
Dworkin
Amy M
AM
Gladman
Nicholas
N
Cho
Hee-Yeon
HY
Mao
Jian-Hua
JH
Balmain
Allan
A
Toland
Amanda Ewart
AE
D019943:Amino Acid Substitution; D000818:Animals; D002874:Chromosome Mapping; D019143:Evolution, Molecular; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051379:Mice / Q000235:genetics*; D010802:Phylogeny; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics*; D013045:Species Specificity