Genetically engineered and mutant mice

Definitions

Genetically engineered mice have induced mutations, including transgenes, targeted mutations (knockouts or knockins), and retroviral, proviral, or chemically-induced mutations.

Transgenic mice carry a segment of foreign DNA incorporated into their genome via non-homologous recombination (e.g., pronuclear microinjection), infection with a retroviral vector, or homologous insertion.

Targeted mutant mice are produced by first inducing gene disruptions, replacements, or duplications into embryonic stem (ES) cells via homologous recombination between the exogenous (targeting) DNA and the endogenous (target) gene. The genetically-modified ES cells are then microinjected into host embryos at the eight-cell blastocyst stage. These embryos are transferred to pseudopregnant host females, which then bear chimeric progeny. The chimeric progeny carrying the targeted mutation in their germ line are then bred to establish a line. If the newly established line has a disrupted or deleted gene, it is called a knockout; if it has a new or duplicated gene, it is called a knockin.

Mice with chemically-induced mutations are produced by using a variety of chemicals. One popular chemical mutagen, ethylnitrosourea (ENU), is used to induce point mutations. ENU mutagenesis involves exposing male mice to ENU and then mating the treated males to untreated females. The resultant progeny, many of which carry point mutations, are screened for phenotypes of interest.

Applications

Genetically engineered mice are useful for elucidating basic biological processes, studying relationships between gene mutations and disease phenotypes, and modeling human disease. Research applications are included on strain data sheets in the JAX® Mice Database. The applications are compiled using a number of information sources (please refer to Mouse Information Resources), but they are not all-inclusive: rapidly advancing biomedical research continually uncovers new applications and uses for genetically engineered and mutant mice strains.

Some genetically engineered and mutant mice strains have a mutation associated with a specific human disease. If the gene or mutation is orthologous to that in humans and causes the same disease in humans, the strain is designated as a model of the human disease. Manifestation of the genetic mutation (phenotypic expression) may differ between humans and mice. Investigators are strongly encouraged to research recommended mouse models to be sure they are appropriate for their research.

Mice with Spontaneous Mutations

Definition

Spontaneous mutations occur very rarely and may alter the normal phenotype of a strain.

Applications

Mice with spontaneous mutations are useful for elucidating basic biological processes, studying relationships between gene mutations and disease phenotypes, and modeling human disease. Research applications are included on strain data sheets in the JAX® Mice Database. The applications are compiled using a number of information sources (please refer to Mouse Information Resources), but they are not all-inclusive: rapidly advancing biomedical research continually uncovers new applications and uses for spontaneous mutants. Investigators are strongly encouraged to research a recommended mouse model to be sure it is appropriate for their research.

Congenic Strains

Definition

A congenic strain is an inbred strain in which a locus of interest from another strain has been introgressed. Formerly, a congenic strain was produced by backcrossing mice carrying the locus of interest to a recipient strain, identifying the offspring with the locus of interest and backcrossing them to the recipient, and repeating this procedure for a minimum of five to ten generations. Each successive generation retained the locus of interest but had less and less genomic material from the donor. A strain was considered an incipient congenic after five to nine backcross cycles (N5 to N9) and a full congenic after ten backcross cycles (N10). A full congenic was considered genetically identical to the recipient except for the following genomic elements: the donor locus of interest (intentionally introgressed), some genes linked to that locus (unintentionally introgressed), and random genetic elements from the donor genome (also unintentionally introgressed). It took three to five years to produce a full congenic this way. Today, most full congenics are produced in about one year by a marker-assisted “speed congenic” strategy that requires only five backcross cycles: offspring from each backcross are genotyped and only those with the least amount of undesirable donor genome are backcrossed to produce the next generation (learn more about our Speed Congenic Services). The generation number (N) for a congenic strain is indicated on its strain data sheet.

Applications

The features that make congenics particularly useful include the following:

  • Maintaining a mutation on a defined inbred background increases genetic and phenotypic uniformity and reduces experimental variability.
  • Congenic strains allow researchers to identify and analyze modifier genes that may be present in an inbred strain (such modifiers may change the mutant phenotype by affecting the action of a mutant protein or altering the expression of the mutant gene).
  • The background or host strain provides an accurate control
    (see Considerations for Choosing Controls).

Historically, congenics were most often generated to understand the genetics of transplantation biology. Hence, congenics were generally of the following types major histocompatibility complex (H2), minor histocompatibility (H), non–histocompatibility alloantigen, and cellular marker congenics. Today, to better understand disease pathways and to support gene mapping and positional cloning studies, an increasingly large number of congenics carry spontaneous and induced mutations.

Knockout Mouse Project

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Rare & Orphan Disease Center

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