Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD recombinant inbred (RI) mouse strains are the largest and most deeply phenotyped inbred panel of vertebrate organisms. RIs allow phenotyping of isogenic individuals across virtually any environment or treatment. We performed whole genome sequencing and generated a compendium of SNPs, indels, short tandem repeats, and structural variants in these strains and used them to analyze phenomic data accumulated over the past 50 years.

We show that BXDs segregate >6 million variants with high minor allele which are dervied from the C57BL/6J and DBA/2J founders and use this dense variant set to define ‘infinite’ marker maps and a novel family-level pangenome. We additionally characterize rates and spectra de novo variants which have accumulated over 20-200 generations of inbreeding, and have largely been ignored previously. Overall, the uniquely rich phenome when linked with WGS enables a new type of integrative modeling of genotype-to-phenotype relations.