The ancestor of extant Japanese fancy mice contributed to the mosaic genomes of classical inbred strains

Abstract

Commonly used classical inbred mouse strains have mosaic genomes with sequences from different subspecific origins. Their genomes are derived predominantly from the Western European subspecies Mus musculus domesticus, with the remaining sequences derived mostly from the Japanese subspecies Mus musculus molossinus. However, it remains unknown how this intersubspecific genome introgression occurred during the establishment of classical inbred strains. In this study, we resequenced the genomes of two M. m. molossinus-derived inbred strains, MSM/Ms and JF1/Ms. MSM/Ms originated from Japanese wild mice, and the ancestry of JF1/Ms was originally found in Europe and then transferred to Japan. We compared the characteristics of these sequences to those of the C57BL/6J reference sequence and the recent data sets from the resequencing of 17 inbred strains in the Mouse Genome Project (MGP), and the results unequivocally show that genome introgression from M. m. molossinus into M. m. domesticus provided the primary framework for the mosaic genomes of classical inbred strains. Furthermore, the genomes of C57BL/6J and other classical inbred strains have long consecutive segments with extremely high similarity (>99.998%) to the JF1/Ms strain. In the early 20th century, Japanese waltzing mice with a morphological phenotype resembling that of JF1/Ms mice were often crossed with European fancy mice for early studies of "Mendelism," which suggests that the ancestor of the extant JF1/Ms strain provided the origin of the M. m. molossinus genome in classical inbred strains and largely contributed to its intersubspecific genome diversity.

Figure 1.

Distribution of the number of 100-kb blocks in the reference B6 genome with various sequence similarities (%) to the corresponding blocks in the MSM, JF1, and WSB genomes.

Figure 2.

Sequence similarity between the B6 and MSM and JF1 genomes. (A) Sliding window analysis of the discordance across chromosome 8 between the B6 and MSM or JF1 sequences. The reference B6 sequence was used for comparison with 500-kb windows and 100-kb sliding intervals. The horizontal blue line indicates a 99.85% sequence similarity level. Fine-scale phylogenetic discordance of chromosome 8 is shown below (PP indicates posterior probability). (B) Phylogenetic tree of the MDR sequences of wild-derived inbred strains. A neighbor-joining tree was generated for 67 concatenated MDR regions using MEGA4 software (Tamura et al. 2007). The 67 MDR regions show a single topology for B6/MSM, supported by a high posterior probability by BCA. The numbers adjacent to the branches indicate bootstrap values greater than 50 (1000 replicates). Subspecies names and the locations at which ancestors of the strains were collected are shown in parentheses. For more details, see Supplemental Table S1.

Figure 3.

The 100-kb B6 blocks with extremely high sequence similarity to the MSM and JF1 strains. (A) The number of 100-kb B6 blocks with extremely high sequence similarity to the MSM and JF1 strains. The B6 blocks were compared to their counterparts in the MSM and JF1 strains for each 0.001% block from 99.990% to 100% similarity. (B) The chromosomal locations of the 100-kb B6 blocks with sequence similarity >99.998% to the MSM and JF1 chromosomes. Horizontal black boxes depict the regions with >99.85% sequence similarity to the MSM strain. Gray boxes indicate gaps in the B6 reference sequence.

Figure 4.

SNP-based genotyping of M. m. molossinus-derived inbred strains, the B6 strain, and its related strain C57BL/10J at nucleotide sites that reside in MDRs but are polymorphic between MSM and JF1. A total of 102 randomly selected nucleotide sites from MDRs were genotyped using the MassARRAY system. M indicates MSM genotype (green); J, JF1 genotype (coral); and blank, not determined.

Figure 5.

Genome introgression from M. m. molossinus into classical inbred strains. European fancy mice originated from M. m. domesticus. In the late 18th century, a Japanese publication entitled “Chingan-sodategusa,” which means “How to breed fancy mice” (Tokuda 1935), reported small and spotted (piebald) mice reared by Japanese fanciers (lower right; courtesy of Kouwa-shyuppan, Tokyo, Japan). In the middle to late 19th century, British traders likely introduced Japanese waltzing mice carrying the “piebald” (Ednrb^s) mutant allele to Europe. The ancestor of JF1, which was referred to as the Japanese waltzing mouse, was used for early studies of the Mendelism of its coat color and waltzing behavior. The mouse with the piebald phenotype (“a” in the top right photo) resembles the JF1 mouse (photograph courtesy of Carnegie Institution for Science, Washington DC, USA). Experimental crosses of the JF1 ancestor and European fancy mice conveyed the M. m. molossinus genome into the M. m. domesticus genetic background. Later, their descendants were transported to America (Keeler 1931; Morse 1981), where they were established as classical inbred strains.