Dissection Of Population Genomic Linkage Disequilibrium Of Wild-Derived CHR1 CSS Mice

Mouse models have been extensively used for identification of susceptibility genes to complex trait diseases. The established laboratory mouse strains have well defined genomic background, however, the existing strains are mainly originated from one subspecies called M.m.domesticus, and the genetic diversity of the laboratory strains is quite limited. Previous studies reported the general distribution pattern of two subspecies M. m. castaneus and M. m. musculus in China. Northeastern and northern populations were found to be of M. m. musculus haplotype. While distribution of the mice with M. m. musculus haplotype covers southern China and even extends to the northwest. The mice in regions along the Yangtze River are the mixture of two subspecies. Therefore the Chinese taxa are extremely important to complement the genetic diversity of the laboratory stocks.Our lab is establishing the population of specific chromosome substitution strains, which transfers the specific chromosomes from wild mice to laboratory mouse C57BL/6J. The CSS is the new method for complex traits study, which could increase the variability of genotypes but the genome background remains the same.In this study crosses between 24 wild mice and the laboratory mouse strain C57BL/6J were performed, and F1 offsprings were obtained. DNA sequencing were performed to evaluate the value of wild mice in complex traits studies through fine analysis of the linkage disequilibrium in a chosen chromosomal region on the basis of the identified SNPs.The sampling regions of this study covered 9 provinces and 24 localities, which represents 4 zoological regions in China, namely Northeastern region, Northern region, Central region and Southern region. The study captured a enormously large number of SNPs through DNA sequencing of F1 hybrids derived from C57BL/6J and wild mice on Chr 1, which addressed the following critical questions: as donors for chromosome substitution strain constructions, the density of SNP distribution determines the application spectrum of the novel genetic models; second, the LD in the donor mice was investigated which therefore gives an answer to the most important question on the gene mapping resolution of the newly developed model.What the analysis with reference to known structures of the M. m. castaneus and M. m. musculus subspecies found are as follow:Firstly, southern populations are found to be M. m. castaneus subspecies, while northern populations are found to be M. m. musculus subspecies; sometimes, both of the two subspecies were found in one sample. Secondly, the DNA sequence variations of southern populations are richer than that of northern populations; there ate more special SNPs in the mice from Daxin. Thirdly, the average density of SNPs in wild mice is 7/kb; that of inbred mice is 3.06/kb, while that of classic mice is just 2.08/kb. Lastly, in one haplotype block, there are two dominant haplotypes; the rest are a little different from the two dominant haplotypes because of mutations. In addition, the lengths of haplotype blocks are from 1.1 kilobases to 20 kilobases. Otherwise, those of classic mice are from 16.4 kilobases to 80 kilobases.Both laboratory mice and wild mice have their advantages, and will be important genetic resources for identifying genes in complex traits. Generally, extensive linkage disequilibrium is beneficial to perform gene mapping with a few markers at the initial stage. On the contrary, however, less extensive linkage disequilibrium is critical to perform fine mapping.