Repatriation of the “Bean-Spotted” Fancy Mouse

In addition to having an ideal genetic system for experimentation, the laboratory mouse, Mus musculus, has over 100 years of history of being used in the laboratory alongside the common fruit fly (Drosophila). Within the laboratory mice, the strain most widely used is the dark chestnut-colored C57BL/6, which was established in the United States in the early 20th century. Although it was widely accepted that the strain originated from European mice, the C57BL/6 strain was also long believed to have its roots in a breed of Japanese mice.

In the beginning of the 21st century, as the human genome was sequenced, a revolutionary change shook the whole area of life science. In December 2002, an international team with researchers from six countries sequenced the entire genome of the standard mouse strain C57BL/6, as the second mammalian species to be sequenced after humans. With this, new light was shed on the origin of this strain. Here, Professor Toshihiko Shiroishi of the National Institute of Genetics, who has worked for over 30 years on this topic, introduces the studies of origin of the laboratory mouse strains along with the results of the Research Commons project, the “Genetic Function Systems”.

An overview of the global distribution of mouse strains

It All Started with Mendel’s Laws

It can be said that the field of genetics all started with the laws of Mendelian inheritance. This new theory stating innovatively, ”some unitized substance determines the properties of the parent,” rather than simply saying that a child bears similar characteristics to the parent, was not recognized immediately when published in 1866. The theory was finally re-validated by three scholars in 1900. At this time, one of the tests conducted to verify Mendel's laws was a mating experiment between a European mouse and the "bean-spotted" fancy mouse, the latter being the subject of this article. In Japanese literature, mice with similar feature, small body and black-and-white spots, appear in the book, “Chingan Sodategusa (1787),” published in Osaka during the Tenmei era of the Edo Period. Additionally, from British documents published around this time, it is known that British traders brought this domesticated mouse back from Yokohama and introduced them to mouse fanciers in their home country in the latter half of the 19th century. These mice lacked a sense of direction due to abnormalities in the semicircular canals of their inner ears. Due to this characteristic, during this time, they were called the “Japanese waltzing mice” as they moved round and round in circles.

The “Bean-Spotted” Fancy Mouse Repatriated from Denmark

In 1987, in a pet shop in the Danish capital of Copenhagen, the "bean-spotted" fancy mouse was accidentally discovered! It was still not known at this point whether this was the descendant of the indigenous Japanese mouse. However, the late Professor Kazuo Moriwaki of the National Institute of Genetics brought the mouse to Japan, and after many years, successfully established the strain of this “bean-spotted” fancy mouse as “JF1/Ms.” Around the same time, back in the laboratory, researchers were working to develop strains of wild mice from various parts of Japan, and they had succeeded in establishing the “MSM/Ms” strain derived from wild mice captured in Mishima.

Moving “Data-Centric” Research Forward

The DNA double-helix structure, discovered in 1953, and the advancement of technology led to the expansion of molecular biology and molecular genetics in the end of the 20th century and gave rise to a significant part of the genome project. Particularly catalyzed by the Human Genome Project, a global agreement was formed within the research community to release, before publication, the entire nucleotide sequence data created by the genome project for researchers to use freely. In the field of life science, it can be said that we have entered an era where a “data-centric” research has become essential, analyzing large amounts of information and letting the data “speak for itself.” From the genome data of the standard mouse strain published in 2002, it became clear that the mouse is especially genetically close to humans. The importance of laboratory mice, particularly in the medical field, was recognized anew. A Japanese team, consisted of the National Institute of Genetics and RIKEN Genomics Science Center, completed the whole genome sequencing of two established strains, JF1/Ms and MSM/Ms, in 2008, and released the data for the world to use. Subsequently, in 2011, the Sanger Institute in the UK released the entire genome sequence of the “WSB/EiJ” strain derived from Western European subspecies. It thus became possible to explore the roots of laboratory mice through a comparative analysis of the whole genome sequences of the European and Japanese mouse strains.

Specimen room for wild mice at the National Institute of Genetics. Taxonomically classified mice, collected and captured from around the world, line the drawer. “We've already prepared the genomic DNA for all the specimens here. We even have data on the coat color and morphology of these specimens,” said Professor Toshihiko Shiroishi.

The 100-Year Journey of the “Bean-Spotted” Fancy Mouse

In the “Genetic Function Systems” project, we conducted a detailed comparison between the whole genome of a standard mouse strain C57BL/6 and that of two strains of Japanese mice and the European subspecies by using a statistical technique called the Bayesian inference in order to clarify the genetic roots of the standard strain. First, the C57BL/6 strain was found to contain 6-7% of the genetic material of the Japanese mouse, which gave the genome of the standard strain a “mosaic structure,” a hybrid of two types of genomes. Furthermore, the Japanese mouse gene found in the standard mouse strain was closer in DNA sequence to that of the fancy mouse strain, “JF1/Ms,” than to the Japanese wild mouse strain, “MSM/Ms”. Based on these results, we concluded that there was little doubt that the “bean-spotted” fancy mouse, the ancestor of JF1/Ms, found its way to British fanciers and bred with European mice, and then crossed the ocean to the United States, where it became the standard mouse strain. These experimental results were published in 2013 in the journal Genome Research.

Assistant Professor Toyoyuki Takada of the National Institute of Genetics manages the operation of the genome database, “National Institute of Genetics, Mouse Genome Database (NIG_MoG)”. His specialty is in the search and functional analysis of genes related to energy metabolism, but he also works hard to refine the database so that “researchers who usually work in the lab can access it as intuitively as possible. It would be wonderful if the database is helpful in facilitating even a little more research.” For example, on the top page, moving the cursor over the chromosomal chart displays the genome number and position (coordinates) to explore the desired genomic region. The search result displays a table of genes with the nucleotide polymorphism viewable at a glance. The hyperlinks within the table allow the user to navigate to other databases to view relevant information on protein and amino acid substitutions. Dr. Takada adds, “Currently, we are adding enhancements to link the information around genome polymorphism and other phenotypic information. We hope to accelerate the elucidation of gene function.”

(Text in Japanese: Toshihiko Shiroishi, Rue Ikeya. Photographs: ERIC, Mitsuru Mizutani. Published: February 10, 2016)