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

Abstract

BackgroundThe 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.ResultsApproximately 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1024-y) contains supplementary material, which is available to authorized users.

Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

“…We took advantage of the wild-derived mouse strain MOLF, which is genetically distinct from the common laboratory C57/Bl6 mice. MOLF mice possess numerous SNPs that are distinct compared with C57/Bl6 mice (Doran et al, 2016). Within the last exon of Ptgs2, MOLF mice have 5 distinct SNPs that can be used to distinguish the C57/ Bl6 and MOLF alleles.…”

Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers

“…We identified 1,119,052 SNVs that have not been previously reported in any other mouse inbred strain (Keane et al 2011; Doran et al 2016). Of those variants, 102,561 are shared exclusively by the two strains, while 403,770 and 612,721 SNVs are private to LEWES/EiJ and ZALENDE/EiJ, respectively (Table 1), with a transition:transversion ratio of 2.14.…”

“…Sequence variants (SNVs and short indels < 10 bp in size) were ascertained using the Sanger Mouse Genomes Project pipeline (Doran et al 2016). We identified 1,119,052 SNVs that have not been previously reported in any other mouse inbred strain (Keane et al 2011; Doran et al 2016).…”

“…Of those variants, 102,561 are shared exclusively by the two strains, while 403,770 and 612,721 SNVs are private to LEWES/EiJ and ZALENDE/EiJ, respectively (Table 1), with a transition:transversion ratio of 2.14. Comparison of these totals with the number of unique variants discovered in other inbred strains reveals that sequencing of wild-derived inbred strains of M. m. domesticus origin identifies at least one order of magnitude more variants that sequencing classical laboratory strains (Table 2) (Keane et al 2011; Doran et al 2016). …”

“…SNV and short indel variants were called using the Sanger Mouse Genomes Project pipeline, the current version of which is described in detail elsewhere (Doran et al 2016). Briefly, samtools mpileup v1.1 and bcftools call v1.1 were used to generate an initial call set for the nuclear genome and mitochondrial genome.…”