Abstract
BackgroundThe laboratory mouse is the most commonly used model for studying variation in complex traits relevant to human disease. Here we present the whole-genome sequences of two inbred strains, LG/J and SM/J, which are frequently used to study variation in complex traits as diverse as aging, bone-growth, adiposity, maternal behavior, and methamphetamine sensitivity.ResultsWe identified small nucleotide variants (SNVs) and structural variants (SVs) in the LG/J and SM/J strains relative to the reference genome and discovered novel variants in these two strains by comparing their sequences to other mouse genomes. We find that 39% of the LG/J and SM/J genomes are identical-by-descent (IBD). We characterized amino-acid changing mutations using three algorithms: LRT, PolyPhen-2 and SIFT. We also identified polymorphisms between LG/J and SM/J that fall in regulatory regions and highly informative transcription factor binding sites (TFBS). We intersected these functional predictions with quantitative trait loci (QTL) mapped in advanced intercrosses of these two strains. We find that QTL are both over-represented in non-IBD regions and highly enriched for variants predicted to have a functional impact. Variants in QTL associated with metabolic (231 QTL identified in an F16 generation) and developmental (41 QTL identified in an F34 generation) traits were interrogated and we highlight candidate quantitative trait genes (QTG) and nucleotides (QTN) in a QTL on chr13 associated with variation in basal glucose levels and in a QTL on chr6 associated with variation in tibia length.ConclusionsWe show how integrating genomic sequence with QTL reduces the QTL search space and helps researchers prioritize candidate genes and nucleotides for experimental follow-up. Additionally, given the LG/J and SM/J phylogenetic context among inbred strains, these data contribute important information to the genomic landscape of the laboratory mouse.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1592-3) contains supplementary material, which is available to authorized users.
Highlights
The laboratory mouse is the most commonly used model for studying variation in complex traits relevant to human disease
Small nucleotide variants (SNVs) identified for the LG/J strain are available in Additional files 3 and 4 and for the SM/J strain in Additional files 5 and 6
LG/J and SM/J are frequently compared in quantitative trait loci (QTL) mapping studies because of their great phenotypic diversity, and because this diversity is normally distributed in intercrosses of these two strains
Summary
The laboratory mouse is the most commonly used model for studying variation in complex traits relevant to human disease. SM/J was created from a pool of mice derived from four crosses of seven inbred strains: dilute brown agouti (dba), silver chocolate (sv ba), black and tan (at), pinkeyed, short-eared dilute brown agouti (pse dba), albino (c), cinnamon spotted (bs), and agouti (a) [4]. It is unclear whether any of these strains are related to current laboratory inbred strains. Attempts to fix the SM/J strain or its Recombinant Inbred Strain offspring for the SM/J allele at agouti have resulted in strain failure [5]
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