The mosaic structure of variation in the laboratory mouse genome

Abstract

Most inbred laboratory mouse strains are known to have originated from a mixed but limited founder population in a few laboratories 1,2 . However, the effect of this breeding history on patterns of genetic variation among these strains and the implications for their use are not well understood. Here we present an analysis of the fine structure of variation in the mouse genome, using single nucleotide polymorphisms (SNPs). When the recently assembled genome sequence from the C57BL/6J strain 3 is aligned with sample sequence from other strains, we observe long segments of either extremely high (,40 SNPs per 10 kb) or extremely low (,0.5 SNPs per 10 kb) polymorphism rates. In all strain-to-strain comparisons examined, only one-third of the genome falls into long regions (averaging >1 Mb) of a high SNP rate, consistent with estimated divergence rates between Mus musculus domesticus and either M. m. musculus or M. m. castaneus. These data suggest that the genomes of these inbred strains are mosaics with the vast majority of segments derived from domesticus and musculus sources. These observations have important implications for the design and interpretation of positional cloning experiments.Patterns of genetic variation provide insight into the evolutionary history of a species and define the complexity of mapping phenotypes in that organism. The commonly used inbred laboratory strains of mice constitute the primary mammalian model system and are an integral component of medical genetic research. These inbred laboratory strains were predominantly derived in the early twentieth century from mouse breeders who originally bred 'fancy' mice (for unusual coat colours and behaviours) as a hobby. Many of the most commonly used strains trace their origins to W. Castle's laboratory at Harvard University and even more strains originate from his supplier A. Lathrop of Granby, Massachusetts. Although these mice are generally thought to reflect predominantly the M. m. domesticus subspecies, there are some historical contributions from 'fancy' mice bred in Japan and China 1,2 (Fig. 1a). As a result, we would expect to see in these strains recognizable contributions from several other subspecies such as M. m. musculus (and possibly M. m. castaneus through the hybrid M. m. molossinus). Indeed, most of these inbred laboratory strains carry a M. m. musculus Y chromosome 4 (previous work had shown that most carry M. m. domesticus mitochondrial DNA 5,6 ).

On the subspecific origin of the laboratory mouse

“…In contrast with previous analyses [8][9][10][11]17 , we have directly determined that on average 9% of the genome has different subspecific origin between any given pair of classical strains while 91% of the genome shares the same subspecific origin (Fig. 5).…”

“…Although a predominant contribution of that subspecies was predicted 8 , the exceptionally high levels (range: 86-96%) observed in all strains were unexpected. The M. m. musculus subspecies has the second largest contribution to the genome of classical strains, while only 1-2% of their genome derives from M. m. castaneus.…”

“…We set out to use this exceptional resource to examine the ancestral subspecific origin of classical strains, expecting to identify a mosaic of segments that could be assigned to one of three distinct lineages: M. m. domesticus, M. m. musculus and M. m. castaneus 8,25 . We planned to use the three wild-derived strains as a reference for each subspecies and then to assign genomic segments from classical strains to a subspecies based on the pattern of SNP similarity between the query strain and the reference strains.…”

Preliminary study towards a novel experimental model to study localized cutaneous leishmaniasis caused bY Leishmania (Leishmania) mexicana

“…Although the L. major mouse model is considered by many to be the best small animal immunological model for CL, concern about its relevance suggests other models should be developed. In particular, because laboratory mice are usually reduced to homozygosity, are hybrids of three species (Mus musculus musculus, M. m. domesticus, M. m. castaneus) 37 and are not natural reservoirs of leishmaniasis parasites, the use of other, wild-type species that are naturally infected should be considered as alternative models.…”

Genetic architecture of tuberculosis resistance in a mouse model of infection

“…18 This locus clearly differs ancestrally between these strains based on whole-genome shotgun sequence comparison. 19 To directly assess the importance of the immunoglobulin genes in our model of tuberculosis infection, we used Igh knockout mice, which lack mature B-cells and produce no immunoglobulins 20 (Figure 2b and c, respectively). On two different genetic backgrounds ablation of the B cell function did not confer extreme susceptibility to tuberculosis (exemplified by rapid death of IL-12 knockout mice in Figure 2b); rather, there was a statistically significant shortening of survival in the B cell-deficient mice as compared to wild-type controls.…”