Mus musculus and genetics

SIGNIFICANCE: Model organisms allow geneticists to investigate how genes affect organismal and cellular function. The house mouse, or Mus musculus, is an ideal organism for genetic research because of its size, short lifespan, litter size, and genetic accessibility. It shares many similarities with humans and is useful for modeling complex phenomena such as cancer and development, and for drug testing.

History of Mice in Genetic Research

The use of mice in genetic research had its origin in the efforts of mouse fanciers, who raised mice as pets and developed numerous strains with distinct coat colors. Researchers in the late 1800s who were trying to determine the validity of Gregor Mendel’s laws of heredity in animals found the existence of domesticated mice with distinct coat colors to be an ideal choice for their experiments. Through the work of early mouse geneticists such as Lucien Cuénot and others, Mendel’s ideas were validated and expanded.

Development of Inbred Strains

As genetic work on mice continued into the 1900s, a number of mouse facilities were created, including the Bussey Institute at Harvard University. One member of the institute, Clarence Little, carried out a set of experiments that would help establish the utility of mice in scientific research. Little mated a pair of mice and then mated the offspring with each other. He continued this process for many generations. After a number of generations of inbreeding, Little’s mice lost all genetic variation and became genetically identical. These mice, named DBA mice, became the first strain of inbred mice and marked an important contribution to mouse research. In an experiment using inbred DBA mice, any difference displayed by two mice could not be due to genetic variation and had to be from the result of the experiment. Through inbreeding, genetic variation was removed as a variable. Also, through careful crossing and selection of different inbred strains, populations of mice that differed by only a few genes could be created. Geneticists could then examine the effects of these genes knowing that all other genes were the same. The creation of inbred mice allowed geneticists to study genes in a carefully controlled way.

The Mouse Genome

Mice have twenty chromosomes, compared with forty-six in humans and four in flies. Maps of each of the individual chromosomes are available, and the relative map position of genes in mice and humans is known. Mice are genetically very similar to humans, but unlike humans, mice can be genetically manipulated at the molecular level. Mice and humans have roughly the same number of nucleotides/genomes, about 3 billion base pairs. This comparable DNA content implies that these animals have more or less the same number of genes. Indeed, most human genes have mouse counterparts, although gene duplications can occur in humans relative to mice and vice versa. However, there are a number of species-specific genes. Similarities between mouse and human genes average 85 percent. However, most changes between mice and humans do not yield significantly altered proteins, but some nucleotide changes contribute to disease. A single nucleotide change can lead to the inheritance of sickle-cell disease, cystic fibrosis, or breast cancer. Single nucleotide changes are also linked to hereditary differences in many traits including height, brain development, facial structure, and pigmentation.

The first use of inbred mice was in the study of cancer. As inbred strains of mice were created, it was noticed that certain strains had a tendency to develop cancer at a very high frequency. Some of these strains developed tumors that were very similar to those found in human cancers. These mice became some of the first mouse models used to study a human disease.

Unique Aspects of the Mouse Model

The ability of mice to acquire cancer illustrates why the mouse is a unique and valuable tool for research. Although mice are not as easy to maintain as other model organisms, they are vertebrates and thus share a number of physiological and developmental similarities with humans. They can be used to model processes, such as those involved in cancer and skeletal development, that do not exist in simpler organisms. In this capacity, mice represent a balance between the need for an animal with developmental complexity and the need for an animal with a quick generation time that is easily bred and raised. Other organisms, such as chimpanzees, may more closely resemble humans, but their lengthy generation time and small litter size make them difficult to use for the many and repeated experiments needed for genetic research.

The use of the mouse model has advanced considerably since the early 1900s. Initially, geneticists relied on the random occurrence of natural mutations to generate mice with traits that mirrored aspects of human biology and disease. Careful crossbreeding and the use of inbred strains allowed the trait to be isolated and maintained. Although this process was slow and tedious, a large number of inbred strains were identified. Later, it was discovered that X-rays and other chemicals could increase the rate of mutation, leading to an increase in the rate at which mice with interesting traits could be found. However, the discovery of a mouse strain that modeled a particular human disease was still a matter of chance.

The advent of molecular biology removed this element of chance and brought the mouse to its full prominence as a model organism. Molecular biology provided a mechanistic understanding of gene function and offered tools that allowed for the direct manipulation of genes.

Transgenic Mice

The technique of transgenics allows geneticists to create mice that carry specific mutations in specific genes. Using technology, a geneticist can construct a piece of DNA containing a mutant form of a chosen gene, then use the mutated gene to modify the existing DNA of mouse embryonic stem cells. These modified embryonic stem cells can be combined with a normal mouse embryo to form a transgenic embryo that can be implanted into the uterus of a female mouse. The transgenic mouse that is born from this process carries in every tissue a mixture of normal cells and cells with the specific DNA alteration introduced by the researcher. These mice are referred to as chimeras. Careful crossing of the transgenic mouse with mice of the same inbred strain can then be done to create a new line of mice that carry the DNA alteration in all cells. These mice will then express a that results directly from the modified gene. Transgenics has allowed geneticists to custom design mice to display the genetic defects they desire.

In the era of genomics, transgenic mice have become a powerful tool in the effort to understand the function of human genes. Since the complete sequences of the mouse and human genomesare known, it is possible to compare the genes of mice and humans directly. Approximately 80 to 90 percent of the genes in humans have a counterpart in the mouse. Using transgenics to target genes in the mouse that are similar to humans can help geneticists understand their functions. However, care must be used in drawing comparisons. There are a number of examples of mouse genes that carry out functions different from their human counterparts. Despite this concern, comparison of mouse and human genes has provided tremendous insight into the function of the human genome.

Mice as Model Organisms

When human genes with unknown functions are isolated, mice are often used to investigate the role of these genes. The distribution of the gene product hints to the function of that gene. If a gene is expressed in brain but not skin, then that gene is anticipated to play some role in brain function but not skin function. Mouse mutants can be generated to investigate the role of that gene. The creation of so-called knockout mice, with a mutation in a gene of interest, allows the mutant phenotype to be defined. Moreover, when a gene is expressed hints to the function of that gene. If a gene is expressed in a mouse embryo, then it may be essential for embryonic development, whereas lack of expression in the fetus would strongly suggest that the gene is not essential for embryonic development. If a gene is recessive, then mice with only one mutant allele may be wild-type, whereas mice with mutations in both alleles can present with a malformation, or die in utero. However, the requirement for a gene may be masked by the compensatory activity of a gene with similar activity.

Human genes can be introduced into transgenic mice, and their function examined. Proof that a human and mouse gene are functionally equivalent is presented when a human gene can rescue a mouse mutation and restore the compromised mutant animal to a “wild-type” phenotype. Knockout mice not only allow researchers to determine gene function and understand diseases at the molecular level but also aid scientists in testing new drugs and devising novel therapies. For instance, a disease resembling multiple sclerosis can be induced in mice by immunizing the animals with a central nervous system (CNS)-specific autoantigen. Whether different chemicals affect disease presentation can then be tested in animals before introducing potential life-saving drugs into humans. Likewise, injection of blood into the basal ganglia of mice can prevent oxygen from going to the brain and thus generate an for ischemia or stroke. Disturbances in associated with a specific disease can now be easily identified by taking advantage of expressed sequence tags (ESTs), tiny stretches of DNA unique to an individual gene. Microarray technology, in which expression of all the genes within the mouse genome can be monitored on a single silica plate, has revolutionized understanding human disease in animal models, such as the mouse.

Economic and Ethical Considerations

The demand for mice in research has resulted in a $100 million industry devoted to the maintenance and development of mouse models. Companies specializing in mice have developed thousands of inbred strains for use in research. The economic impact of mice has led to patents on transgenic mice and has caused controversy over who has the right to own a particular mouse strain. Also, the extensive use of mice in research has raised concerns by some for the welfare of mice and questions about the ethics of using them in research.

Research Using the Mouse Model

The study of cancer was the first area of research to benefit from the use of mice. Early mouse geneticists were able to learn about the genetic and environmental factors that influenced the development of cancer. Early twenty-first-century cancer research relies heavily on the mouse model as a way of determining how genes affect the interaction between cancer and the body. Understanding the function of tumor-suppressor genes has come in part from the use of transgenic mice. Mice have also been important in investigating the role of the immune system and angiogenesis in tumor progression.

Mouse work in cancer also made contributions to immunology, which relies heavily on the mouse as a model of an intact immune system. Inbred strains of mice with defective immune systems have been developed to help geneticists understand the role of the immune system in disease progression and transplant rejection. Mice have also been instrumental in studying how genes in pathogenic microorganisms allow the microbes to cause disease. The mouse model has been used to understand how diseases such as and are able to infect and cause damage.

The study of many genetic diseases, such as sickle-cell disease and phenylketonuria (PKU), has benefited from the existence of mouse models that mimic the disease. The genetic components of such complex phenomena as heart disease and obesity have also been elucidated using the mouse model.

Developmental biology has relied heavily on the mouse to determine how gene expression leads to the formation of multicellular organisms. Work that has shown the role genes play in determining mammalian body structure and how genes affect development of organs has been done in mouse models.

The mouse has also proven to be a valuable model in investigating the effects of various genes on brain development and function. Mouse models have provided insights into the way the brain develops and functions, as well as genetic contributions to complex behaviors. Genes have been identified that play roles in complex behaviors such as raising young and predisposition toward addiction.

Key terms

• embryonic stem cellscultured cells derived from an early embryo
• genomicsthe study of the entire DNA content of an organism, called its genome
• inbreedingthe process of mating brothers and sisters to create genetically identical offspring
• model organisman organism well suited for genetic research because it has a well-known genetic history, a short life cycle, and genetic variation between individuals in the population
• phenotypean observable trait
• transgenicsthe technique of modifying an organism by introducing new DNA into its chromosomes

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