AbstractC57BL/6J is the most widely used inbred mouse strain and is the basis for the mouse reference genome. In addition to C57BL/6J, several other C57BL/6 and C57BL/10 substrains exist. Previous studies have documented extensive phenotypic and genetic differences among these substrains, which are presumed to be due to the accumulation of new mutations. These differences can be used for genome wide association studies. They can also have unintended consequences for reproducibility when substrain differences are not properly accounted for. In this paper, we performed genomic sequencing and RNA-sequencing in the hippocampus of 9 C57BL/6 and 5 C57BL/10 substrains. We identified 985,329 SNPs, 150,344 Short Tandem Repeats (STR) and 896 Structural Variants (SV), out of which 330,178 SNPs and 14,367 STRs differentiated the C57BL/6 and C57BL/10 groups. We found several regions that contained dense polymorphisms. We also identified 578 differentially expressed genes for C57BL/6 substrains and 37 differentially expressed genes for C57BL/10 substrains (FDR < 0.01). We then identified nearby SNPs, STRs and SVs that matched the gene expression patterns. In so doing, we identified SVs in coding regions of Wdfy1, Ide, Fgfbp3 and Btaf1 that explain the expression patterns observed. We replicated several previously reported gene expression differences between substrains (Nnt, Gabra2) as well as many novel gene expression differences (e.g. Kcnc2). Our results illustrate the impact of new mutations on gene expression among these substrains and provides a resource for future mapping studies.
Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats