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10.2 I/O System in Mouse Genetics
The genomic DNA sequences of the mouse genome are products shaped by the course
of evolution. To decode the function of genomic DNA sequences, the alteration of the
finished product is considered to be INPUT of the
bona fide
biosimulator. There are
several ways to alter or introduce new sequences to the genomic sequences (Fig. 1).
In natural populations, many polymorphisms accumulated whereas some spontane-
ous mutations arose recently. Mutations can be artificially induced by genotoxic
agents, for instance, X-ray irradiation (Muller 1927) and chemical mutagens
(Auerbach and Robson 1946). In classical genetics, polymorphisms and mutations
represent a major resource for research studies; however, the approach is usually
limited to phenotype-driven analyses of a small number of loci. Even if a genetic
alteration is vindicated, it used to be impossible to conclude what kind of genomic
sequence change(s) is responsible for the phenotypic consequence. Eventually, in the
1980s with the development of various positional cloning methods and genetic engi-
neering technologies it became feasible to identify the causative genomic sequence
change(s).
10.2.1 Reverse Genetics
In the 1980s, new gene-driven approaches were developed to decode the genomic
sequence function in the mouse. One method that introduces an artificially designed
DNA fragment into the genome of the mouse (Palmiter, Brinster, Hammer,
Trumbauer, Rosenfeld, Birnberg, and Evans 1982) enabled the generation of trans-
genic mice (Fig. 2). Another technology that disrupts or eliminates a specified part of
genomic DNA sequences in the mouse (reviewed by Capecchi 1989) is called gene
targeting or knockout mouse (Fig. 3). Together, these approaches are defined as
“reverse genetics.” Both became practicable with the innovations of genetic engi-
neering as well as mouse embryonic technology. Conversely, classical genetics and
its phenotype-driven approach is now called “forward genetics”.
10.2.1.1 Transgenic Mouse
As shown in Fig. 2, the transgenic mouse allows us to elucidate the gain of function
due to a particular DNA sequence that has been designed and constructed
in vitro
by
using genetic engineering technology. However, some caution must be taken when
interpreting the outcome. For instance, the integration of the exogenous DNA dis-
rupts at least one site in genomic DNA sequences. The expression of endogenous
genes at and around the integrated site may be affected by this disruption. In addition,
the expression of the integrated DNA sequence often varies depending on the site
and mode of integration.
