A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains

TLDR

C57BL/6J and C57BL/6N are widely used in mouse genetics, with C57BL/6J’s genome incorporated into reference populations and C57BL/6N employed by initiatives such as the International Knockout Mouse Consortium. The study aims to comprehensively compare the genomes and phenotypes of C57BL/6J and C57BL/6N to identify differences that may influence genetic mechanisms. The authors performed genome sequencing to catalog coding SNPs, indels, and structural variants, and used the EMPReSSslim phenotyping pipeline, supplemented by secondary assessments, to compare physiological, biochemical, and behavioral traits across the two strains. They identified 34 coding SNPs, 2 indels, and 15 structural variants distinguishing the strains, and observed replicated phenotypic differences across multiple centers, suggesting these variants underlie the observed physiological, biochemical, and behavioral disparities.

Abstract

The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.