Chapter 062. Principles of
Human Genetics
(Part 10)

Transgenic Mice as Models of Genetic Disease
Several organisms have been studied extensively as genetic models,
including Mus musculus (mouse), Drosophila melanogaster (fruit fly),
Caenorhabditis elegans (nematode), Saccharomyces cerevisiae (baker's yeast),
and Escherichia coli (colonic bacterium). The ability to use these evolutionarily
distant organisms as genetic models that are relevant to human physiology reflects
a surprising conservation of genetic pathways and gene function. Transgenic
mouse models have been particularly valuable, because many human and mouse
genes exhibit similar structure and function, and because manipulation of the
mouse genome is relatively straightforward compared to those of other
mammalian species.
Transgenic strategies in mice can be divided into two main approaches: (1)
expression of a gene by random insertion into the genome, and (2) deletion or
targeted mutagenesis of a gene by homologous recombination with the native
endogenous gene (knock-out, knock-in) (Fig. 62-6; Table 62-3). Transgenic mice
are generated by pronuclear injection of foreign DNA into fertilized mouse
oocytes and subsequent transfer into the oviduct of pseudopregnant foster mothers.
Figure 62-6

Transgenic mouse models. Left. Transgenic mice are generated by
pronuclear injection of foreign DNA into fertilized mouse oocytes and subsequent
transfer into the oviduct of pseudopregnant foster mothers. Right. For targeted
mutagenesis (gene knock-out/knock-in), embryonic stem (ES) cells are transfected
with the targeted (mutagenized) transgene. The transgene undergoes homologous
recombination with the wild-type gene. After selection, positive ES cells are
introduced into blastocysts and implanted into foster mothers. Chimeric mice can
be identified based on the mixed coat color of the offspring. Heterozygous mice

Inducible expression possible
(Tetracycline, ecdysone)
Applicable to several species

Predominantly used in mice (Targeted)
Knock-out
Substitution of
functional gene with
inactive gene by
homologous
Tissue-specific knock-
out
possible (Cre/lox)
recombination in
embryonic stem cells
Absence of
phenotype
possible due to redundancy
Predominantly used in mice (Targeted)
Knock-in
Introduction of
subtle mutation(s) into
gene by substitution of
endogenous gene with
gene carrying a specific
mutation. Homologous
recombination in
embryonic stem cells
Can accurately model human
disease

May affect life-span
Cloning
Introduction of
nucleus into enucleated
eggs (nuclear transfer)
Ethical concerns