Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations

Abstract

Background: The Mouse Genomes Project is an ongoing collaborative effort to sequence the genomes of the common laboratory mouse strains. In 2011, the initial analysis of sequence variation across 17 strains found 56.7 M unique single nucleotide polymorphisms (SNPs) and 8.8 M indels. We carry out deep sequencing of 13 additional inbred strains (BUB/BnJ, C57BL/10J, C57BR/cdJ, C58/J, DBA/1J, I/LnJ, KK/HiJ, MOLF/EiJ, NZB/B1NJ, NZW/LacJ, RF/J, SEA/GnJ and ST/bJ), cataloguing molecular variation within and across the strains. These strains include important models for immune response, leukaemia, age-related hearing loss and rheumatoid arthritis. We now have several examples of fully sequenced closely related strains that are divergent for several disease phenotypes.

Results: Approximately 27.4 M unique SNPs and 5 M indels are identified across these strains compared to the C57BL/6 J reference genome (GRCm38). The amount of variation found in the inbred laboratory mouse genome has increased to 71 M SNPs and 12 M indels. We investigate the genetic basis of highly penetrant cancer susceptibility in RF/J finding private novel missense mutations in DNA damage repair and highly cancer associated genes. We use two highly related strains (DBA/1J and DBA/2J) to investigate the genetic basis of collagen-induced arthritis susceptibility.

Conclusions: This paper significantly expands the catalogue of fully sequenced laboratory mouse strains and now contains several examples of highly genetically similar strains with divergent phenotypes. We show how studying private missense mutations can lead to insights into the genetic mechanism for a highly penetrant phenotype.

Keywords: Biological pathways; Cancer; Disease; Genomic variation; Laboratory mouse; Mouse genomes; Sequencing; arthritis.

Fig. 1

Phenotypes and variant statistics for each of the 13 strains. The strains sequenced in this project with a short description and notable phenotypes, followed by the total number of SNPs, indels and large deletions. Individual strain images provided by The Jackson Laboratory (ME, USA). The phylogenetic tree is a genome-wide summary built using all of the HapMap genotypes for each strain [22] and does not reflect local haplotype structure

Fig. 2

SNP, indel and SV densities for chromosome 1 of all strains. SNP, indel and SV (insertions and deletions) densities (per MB) for all variants identified on chromosome 1 for each of the 13 strains