Why mouse genetics?
The ability to model human disease in the mouse makes it such a valuable experimental system. Genetically and genomically, the human and the mouse are very similar — about 98% identical in the genetic code.
What is a mouse model?
The mouse is the foremost mammalian model for studying human disease and human health. The mouse is small, making it an economical choice, and it also breeds very well. Scientists have amassed tremendous knowledge about mouse physiology, anatomy, and its genes, stemming from more than 100 years of work on the mouse. More importantly, we can manipulate mouse genes; the mouse is among the first mammalian species to have its genes modified with molecular tools.
Mice are the most commonly used animal model for studying human disease, and for many good reasons:
- Mice are biologically very similar to humans. We share 95 percent of the same genes, and our immune systems are even more compatible. Mice and humans get many of the same diseases, for the same genetic reasons.
- Mice can be genetically manipulated to mimic virtually any human disease or condition. The Jackson Laboratory now maintains more than 9,000 genetically defined strains of mice.
- Mice can be inbred to yield genetically identical strains. This uniformity allows for more accurate and repeatable experiments.
- Mice have an accelerated lifespan, with one mouse year equaling about 30 human years. Therefore, their entire life cycle can be studied within only two or three years.
- Mice are well understood because they have been used in biomedical research for nearly a century. The Jackson Laboratory began using and developing mice in 1929.
- Mice are a cost-effective and efficient research tool. They are small, they reproduce quickly, and they are relatively easy to handle and transport.
Many diseases can be modeled through the alteration of a specific gene central to a normal biological process. Thousands of disease models that have either arisen spontaneously in The Jackson Laboratory production colonies or that have been genetically engineered are available from The Jackson Laboratory.
Practically, mice are small, have a short generation time and an accelerated lifespan (one mouse year equals about 30 human years), keeping the costs, space and time required to perform research manageable. In addition to these clear benefits, the greatest advantages associated with using the mouse are:
- Ability to genetically engineer new strains, including mice that can host patient tumors or specific gene mutations or a human immune system
- Availability of pure, inbred lines
- Opportunity to identify disease-causing gene mutations
- Platform for identifying modifying genes and background effects.
- Mouse models play an essential role in the drug discovery process. In preclinical trials, mouse models are key to demonstrating the metabolism and absorption, general safety and even efficacy of new medicines. The FDA insists that drug trial designs rely heavily on clinical measures of efficacy. A mouse strain with relevant disease symptoms provides a primary, effective and efficient model that is vital to the process of drug discovery.
Mice are the model of choice not just because they are strikingly similar to humans at the genomic level, but also because the pathophysiology of disease in mice is similar to that of humans. Mice are a cost-effective and efficient tool to speed research and drug testing.
These combinations of features provide researchers with a uniquely powerful tool for understanding the mechanisms of human disease and testing of novel drug therapies.
The history of mouse genetics might have begun in the 1860s if Gregor Mendel had not been forbidden to breed mice within the monastery and, thus, carried out his classic genetic studies with sweet peas. Rather, French geneticist Lucien Cuénot was the first to demonstrate Mendelian inheritance in mammals using the inheritance of coat colors in mice (1902). In 1903 William Castle at the Bussey Institute at Harvard also published a paper on coat color genetics in mice. Castle’s student, Clarence Cook (“C.C.”) Little, is credited with conceiving of and creating the first inbred strain of laboratory mice (DBA, named for its coat color genes: dilute, brown, nonagouti) to unravel the genetics of cancer. Little also created the C57/C58 family of strains at the Bussey and later went on to found The Jackson Laboratory in 1929.
Mouse fanciers of the late 19th and early 20th centuries in Asia and, later, Europe and America were the origin of most laboratory mice of today. Because of their beginnings in the mouse fancy trade, laboratory mouse strains are a genetic mix of four different subspecies: Mus musculus musculus (eastern Europe), Mus musculus domesticus (western Europe), Mus musculus castaneus (Southeast Asia) and Mus musculus molossinus (Japan). Within common inbred strains, the largest contribution of each strain’s genome originates from Mus musculus domesticus.
Many inbred strains derive from the colonies of Miss Abbie Lathrop, a mouse fancier who bred and sold mice in Granby, Massachusetts, from ~1900 to her death in 1918. Not only was Lathrop an avid mouse breeder, she was a scientist, carrying out experiments in collaboration with scientists such as William Castle and C.C. Little. She was one of the first to discover a link between hormones and cancer susceptibility back in 1916. Lathrop’s breeding records and notebooks, including many published observations, are preserved in the library at The Jackson Laboratory.
Because of the early development of inbred lines, the mouse provides a robust tool to identify the genetic basis of both normal and disease traits. In 1915, the first genetic linkage identified in the mouse (and first autosomal linkage in mammals) established that genes for pink-eyed dilution and albino are inherited together.
Early genetic maps of the mouse genome, based on recombinational estimates from linkage crosses, were created using histocompatibility genes and spontaneous mutations that produced visible phenotypes. The major mapping centers during the 1930s-1970s were the Harwell MRC Genetics Unit in the U.K., the Biology Unit at the Atomic Energy Commission’s facility in Oak Ridge, Tennessee, and The Jackson Laboratory in Bar Harbor, Maine.
The discovery of polymorphic genes enabled rapid genetic mapping, because a newly discovered gene could be tested for linkage with many other genes. In the 1960s and 1970s, biochemical (isoenzyme) genetic marker systems were developed. In the 1980s and 1990s, DNA markers revolutionized genetic mapping: restriction fragment polymorphisms (RFLPs), simple sequence length polymorphisms (SSLPs) detected by polymerase chain reaction (PCR) amplification (e.g. MIT markers), and single nucleotide polymorphisms (SNPs). All, especially SNPs, are widespread throughout the genome. With DNA markers, newly discovered genes or mutations can be tested for linkage with many DNA markers on all chromosomes in a single cross. Also, stored DNAs from linkage crosses, mapping panels, or recombinant inbred strains can be typed repeatedly for new markers. These advances enable the rapid identification of potential human disease-causing genes through comparative mapping.
Historically, perhaps the most important advantage to using the mouse for biomedical research has been the ability to experimentally manipulate the mouse genome. Genes can be injected directly into the fertilized egg of a mouse, creating what is known as a transgenic animal. This approach allowed scientists to create a new set of models and experimental tools based on the manipulation of specific genes thought to be important in the pathology of certain diseases.
And the toolkit continues to expand. Mouse genes can be replaced with human genes to study gene function or to produce more human-like model systems in the mouse. For example, the so-called “NOD scid gamma” mouse developed by Leonard Shultz at The Jackson Laboratory lacks mature T or B cells and functional NK cells, is deficient in cytokine signaling, and can accept transplantation of virtually any human tissue. And just within the past few years, low-cost high throughput sequencing (HTS) and genomic engineering using CRISPR-Cas9 has launched a revolution in mouse model development, allowing researchers to engineer mouse models for human disease with unprecedented speed, precision and efficiency. The ability to directly relate human patient data with mouse model development at the nucleotide level is opening an exciting new chapter in biomedical research, with enormous potential benefit.
Despite the increasing sophistication of genetically manipulating the mouse genome, naturally occurring spontaneous and chemically induced mutations continue to provide valuable human disease models in mice. Naturally occurring mutations resemble human disease-causing mutations and often mimic the resulting disease well. Analysis of spontaneous mutations at The Jackson Laboratory has provided models for such human diseases as muscular dystrophies, craniofacial and skeletal abnormalities, Lou Gehrig’s disease, and blindness from cataracts, retinal degeneration and glaucoma.
Until recently, determining the causative mutated gene was a long and costly process. In 2002, the genome sequence of the C57BL/6J mouse strain was completed and now, the Mouse Genomes Project, an international collaborative effort, has sequenced and made publicly available genome-level characterization of 17 additional inbred mouse strains.
Most recently, HTS has made possible the once unimaginable goal of identifying spontaneous mutations rapidly, efficiently and economically. Current technologies enable HTS of large intervals, whole exomes and the entire genome using interval-specific array capture, exome capture and whole genome sequencing in both mice and humans. In collaboration with technology companies, Jackson Laboratory scientists have been instrumental in developing mouse exome capture technologies and have established a high throughput DNA sequence collection and data analysis pipeline to identify spontaneous mutations. Scientists at The Jackson Laboratory continue to collaborate with external scientists to enhance the bioinformatic analysis of HTS data and assess other methods, such as array comparative genome hybridization and RNASeq, for identifying large duplications and deletions not currently identified by HTS analysis. Thus, the complete sequencing data of diverse inbred mouse strains, the capability to sequence de novo new mutant strains or human patient mutations and the availability of bioinformatics resources will offer rapid and precise exploration of the genetic variation underlying spontaneous mutations in mouse and human.
In both humans and mice, genetic background can strongly influence the clinical symptoms or phenotype caused by disease genes. Genetic differences among human beings are one reason that genetically complex diseases like cancer or diabetes vary in severity from one individual to another. Analysis of such variability in the mouse can reveal the underlying genetic basis in human beings.
For example, multiple genes that lead to atherosclerosis have been discovered in the mouse; many of the same genes were subsequently identified in human beings. Scientists must be aware of the possible effect of modifying genes when transferring genes to new strain backgrounds, but their discovery also can reveal metabolic pathways and identify genes that contribute to variability in human diseases. For example, homozygotes for the spontaneous dactylaplasia mutation die prenatally or around the time of birth on some backgrounds and are viable on others; the lethality is controlled by a second major modifying gene. Similarly, homozygotes for the curly bare mutation have two different phenotypes depending on the alleles present at a modifier gene. Determining what genes modify a phenotype can identify genes that contribute to variability in a trait or disease in human beings and often reveal digenic or multigenic systems of interacting genes and molecular pathways.
Some modifier genes can totally suppress the phenotypic effect of a mutant gene. For example, the thrombocytopenia and cardiomyopathy (cmp) mutation causes a severe cardiomyopathy on the A/J background, where the mutation was discovered, but the disease disappears when the mutation is placed on the C57BL/6J background. Identification of such suppressive modifier alleles can provide insight into therapeutic approaches for protecting individuals against disease. In the case of cmp, the modifier effect is diet-dependent, suggesting manipulating the diet could ameliorate a similar condition in humans. Finally, when genetically engineered mutations are inbred or transferred to an inbred background, the phenotype on the new background can vary dramatically from the original phenotype reported in the literature.