MoG+: a database of genomic variations across three mouse subspecies for biomedical research

Abstract

Laboratory mouse strains have mosaic genomes derived from at least three major subspecies that are distributed in Eurasia. Here, we describe genomic variations in ten inbred strains: Mus musculus musculus-derived BLG2/Ms, NJL/Ms, CHD/Ms, SWN/Ms, and KJR/Ms; M. m. domesticus-derived PGN2/Ms and BFM/Ms; M. m. castaneus-derived HMI/Ms; and JF1/Ms and MSM/Ms, which were derived from a hybrid between M. m. musculus and M. m. castaneus. These strains were established by Prof. Moriwaki in the 1980s and are collectively named the "Mishima Battery". These strains show large phenotypic variations in body size and in many physiological traits. We resequenced the genomes of the Mishima Battery strains and performed a comparative genomic analysis with dbSNP data. More than 81 million nucleotide coordinates were identified as variant sites due to the large genetic distances among the mouse subspecies; 8,062,070 new SNP sites were detected in this study, and these may underlie the large phenotypic diversity observed in the Mishima Battery. The new information was collected in a reconstructed genome database, termed MoG+ that includes new application software and viewers. MoG+ intuitively visualizes nucleotide variants in genes and intergenic regions, and amino acid substitutions across the three mouse subspecies. We report statistical data from the resequencing and comparative genomic analyses and newly collected phenotype data of the Mishima Battery, and provide a brief description of the functions of MoG+, which provides a searchable and unique data resource of the numerous genomic variations across the three mouse subspecies. The data in MoG+ will be invaluable for research into phenotype-genotype links in diverse mouse strains.

Fig. 1

Representative phenotypes of the Mishima Battery. The phenotypes are depicted by Boxplots (a, c, e, g, i) and trait-strain matrices (b, d, f, h, j). In the trait-strain matrices, a measured value was considered significant if the corrected t-test p value was less than 0.05 (pale red) and highly significant if the p value was less than 0.001 (red). (a), (b) Body weight (BW); (c), (d) Body length (BL: nose-to-anus distance); (e), (f) Blood concentration of high-density lipoprotein (HDL), (g), (h) total cholesterol (TCH), and (i), (j) triglyceride (TG). *Blood levels of HDL for the NJL males are not shown because the values exceed the measurable threshold range (corresponding rows and columns are greyed)

Fig. 2

Number of nucleotide sequence variants in each Mishima Battery strain compared to B6. The numbers of SNPs (a), insertions (b), and deletions (c) are shown. The subspecies from which the Mishima Battery strains were derived are shown by different colors: Mus m. domesticus, blue; Mus m. musculus, green; Mus m. castaneus, auburn; and Mus m. molossinus, pea green. In the bar charts, the number of heterozygous SNPs is indicated by the lighter color and of homozygous SNPs by the darker color

Fig. 3

Genomic variants in Mishima Battery strains compared to B6. Numbers of genomic variants in specific genomic locations (a) and functional classes for the effects of amino acid substitutions (b) are shown

Fig. 4

Screenshot of the top page of MoG+ showing the different functions available (a). The window named “Search for genomic variation” (b) is the entrance to information on genomic variations in Mishima Battery mouse strains and to information from gene searches; the information is retrieved from other public databases. For this search window, gene symbols are used as the search query. The search window “Search for mouse strain” enables one to find experimental mouse strains that are available from RIKEN BRC (c). In this search window, gene symbols are used as the search query. The “Chromosome and position-interval” search window is a gateway to “Map View”, a page displaying information on the distribution of genes in the designated chromosomal area (d). It is also possible to access this information by use of the chromosome ideogram (Mouse Genome Sequencing Consortium 2002) (e). The genomic region for a search query can be defined by placing the cursor in the required location of the chromosome ideogram. Geographical distribution of the ancestral subspecies of the Mishima Battery strains (f). Link to the tutorial for MoG+ (g). A gateway page named “Search result” opens following a query using the “Search for genomic variation” window; the illustrated example was produced using “Kit” as the search query (h). In this page, the first column on the left-hand side shows the search result numbers. The second column named “Gene Symbol” shows gene symbols in the database containing perfect and partial matches of the text search, and links to their IDs in the Ensembl and JAX databases. The yellow button labeled “Features and Links” links to a gateway page where the user can obtain genomic variation information on the searched gene in the database. The third column named “Type” shows the type of data available on the searched gene as gene, mRNA, and coding sequence (CDS). The fourth column named “Cross Reference” shows links to the searched gene in public databases. The fifth column named “Related Human Gene Information” shows human disease information related to the searched gene based on the match of the text search of the gene symbol. The sixth column, “Links to BioResources”, shows links to experimental mouse strains that are available from RIKEN BRC. The last column, “Location Detail”, shows the region on the chromosome where the searched gene is located. This column also contains links to “Map View” for “narrow” (< 100 kb) or “broad” (< 300 kb) ranges. “Sequence Manipulation” is linked to the “SequenceCutter” function. An example of the search results of using “Search for mouse strain” obtained using “Kit” as the search query (i)

Fig. 4

Screenshot of the top page of MoG+ showing the different functions available (a). The window named “Search for genomic variation” (b) is the entrance to information on genomic variations in Mishima Battery mouse strains and to information from gene searches; the information is retrieved from other public databases. For this search window, gene symbols are used as the search query. The search window “Search for mouse strain” enables one to find experimental mouse strains that are available from RIKEN BRC (c). In this search window, gene symbols are used as the search query. The “Chromosome and position-interval” search window is a gateway to “Map View”, a page displaying information on the distribution of genes in the designated chromosomal area (d). It is also possible to access this information by use of the chromosome ideogram (Mouse Genome Sequencing Consortium 2002) (e). The genomic region for a search query can be defined by placing the cursor in the required location of the chromosome ideogram. Geographical distribution of the ancestral subspecies of the Mishima Battery strains (f). Link to the tutorial for MoG+ (g). A gateway page named “Search result” opens following a query using the “Search for genomic variation” window; the illustrated example was produced using “Kit” as the search query (h). In this page, the first column on the left-hand side shows the search result numbers. The second column named “Gene Symbol” shows gene symbols in the database containing perfect and partial matches of the text search, and links to their IDs in the Ensembl and JAX databases. The yellow button labeled “Features and Links” links to a gateway page where the user can obtain genomic variation information on the searched gene in the database. The third column named “Type” shows the type of data available on the searched gene as gene, mRNA, and coding sequence (CDS). The fourth column named “Cross Reference” shows links to the searched gene in public databases. The fifth column named “Related Human Gene Information” shows human disease information related to the searched gene based on the match of the text search of the gene symbol. The sixth column, “Links to BioResources”, shows links to experimental mouse strains that are available from RIKEN BRC. The last column, “Location Detail”, shows the region on the chromosome where the searched gene is located. This column also contains links to “Map View” for “narrow” (< 100 kb) or “broad” (< 300 kb) ranges. “Sequence Manipulation” is linked to the “SequenceCutter” function. An example of the search results of using “Search for mouse strain” obtained using “Kit” as the search query (i)

Fig. 5

The “VariantTable” function is accessed from the common header present in MoG+ (a). When the “VariantTable” browser link is clicked, a gateway page is opened where the user can select which strains and genomic regions to display (b). “Source” can be used to obtain SNP information on searchable mouse strains: the reference B6 strain; Mishima Battery strains; and 36 selected strains from public databases (dbSNP) (c). The “VariantTable” function supports searches of genome coordinates and gene symbol-based SNP searches and provides access to any region of the genome of interest (d). An example of search results using the “Kit” gene region (chromosome 5: 75,606,700–75,607,400) as the search query (e). In this page, the first column on the left-hand side indicates the type of data available (gene, mRNA and CDS) and the user-selected strains. The genomic coordinates on each chromosome are indicated at the top of each column, with the most proximal in the first column on the left side. The information in the columns is highlighted according to the data type: gene, blue; mRNA, Turkish blue; CDS, pea green. The seventh line labeled “C57BL/6J” and highlighted in magenta shows reference SNPs. The rows for Mishima Battery strains are colored blue, green, vermilion, and moss green, for M. m. domesticus, M. m. musculus, M. m. castaneus, and M. m. molossinus, respectively. In this page, where nucleotides of the searched strain differ from the reference, the substituted nucleotide is displayed. A period (full stop) is displayed where the nucleotide is the same as the reference; the label “n.d.” is displayed when no data is available