A Murine Database of Structural Variants Enables the Genetic Architecture of a Spontaneous Murine Lymphoma to be Characterized

A more complete map of the pattern of genetic variation among inbred mouse strains is essential for characterizing the genetic architecture of the many available mouse genetic models of important biomedical traits. Although structural variants (SVs) are a major component of genetic variation, they have not been adequately characterized among inbred strains due to methodological limitations. To address this, we generated high-quality long-read sequencing data for 40 inbred strains; and designed a pipeline to optimally identify and validate different types of SVs. This generated a database for 40 inbred strains with 573,191SVs, which included 10,815 duplications and 2,115 inversions, that also has 70 million SNPs and 7.5 million insertions/deletions. Analysis of this SV database led to the discovery of a novel bi-genic model for susceptibility to a B cell lymphoma that spontaneously develops in SJL mice, which was initially described 55 years ago. The first genetic factor is a previously identified endogenous retrovirus encoded protein that stimulates CD4 T cells to produce the cytokines required for lymphoma growth. The second genetic factor is a newly found deletion SV, which ablates a protein whose promotes B lymphoma development in SJL mice. Characterizing the genetic architecture of SJL lymphoma susceptibility could provide new insight into the pathogenesis of a human lymphoma that has similarities with this murine lymphoma.