Genome Sequencing of Chromosome 1 Substitution Lines Derived from Chinese Wild Mice Revealed a Unique Resource for Genetic Studies of Complex Traits

Mouse resources such as Collaborative Cross (CC), Outbred Stocks (OS), Hybrid Mouse Diversity Panel (HMDP), and Chromosome Substitution Strains (CSSs) have been instrumental to many progresses in the studies of complex traits genetics. We have established a population of chromosome 1 (Chr 1) substitution lines (C1SLs) in which donor chromosomes were derived from Chinese wild mice. Genome sequencing of 18 lines of this population showed that Chr 1 had been replaced by donor chromosome. About 4.5 million unique single nucleotide polymorphisms (SNPs) and indels were discovered on Chr 1, of which, 1.3 million were novel. Compared with sequenced classical inbred (CI) strains, Chr 1 of each C1SL had five fold more variants, and more loss of function and potentially regulatory variants. Further haplotype analysis showed that donor chromosome accumulated more historical recombination events with the largest haplotype block being only 100kb and about 57% of the blocks were less than 1kb. Subspecies origin analysis showed that these chromosomes had mosaic genome structure which dominantly originated from M. m. musculus and M. m. canstanes subspecies except for C57BL/6J-Chr 1^KM (KM) line from M. m. domesticus. In addition, phenotyping four of these lines on blood biochemistry suggested that there were substantial phenotypic variations among our lines, especially line C57BL/6J-Chr 1^HZ (HZ) and donor strain C57BL/6J (B6). Further GO enrichment revealed that the differentially expressed genes among liver expressed genes between B6 and HZ were enriched in lipid metabolism biological processes. All these characteristics enabled C1SLs to be a unique resource for identifying and fine mapping quantitative trait loci (QTLs) on mouse Chr 1, and carrying out systems genetics studies of complex traits.

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