Computational Biology 21
the Nba2 interval, interferon-inducible genes Ifi202 and Ifi203, were identified
by comparison of gene expression in congenic and parental NZB mice (67). These two
co-linear genes were differentially expressed when NZB and NZW spleen cells were
compared. Analysis of different cell types within the spleen indicated that increased
Ifi202 expression was localized to splenic B cells and to non-T/non-B cells. The NZBderived IFI202 allele was preferentially expressed in F1 mice relative to the NZW allele.
These results, along with analyses of promoter region polymorphisms and differential
IFI202 protein expression implicated Ifi202 as a candidate gene. B cells from NZB
and B6.Nba2 congenic mice were resistant to apoptosis induced by crosslinking surface
IgM, which coincided with high expression of IFI202 in the apoptosis-resistant B cells.
Increased expression of IFI202 has been shown to inhibit apoptosis (68,69), and
decreased expression led to increased susceptibility to apoptosis under certain
physiological conditions (70). Inhibition of B-cell apoptosis provides a mechanism by
which increased IFI202 expression enhances lupus susceptibility. Apoptosis is critically
involved in the maintenance of B-cell tolerance, and inhibition of B-cell apoptosis
through mutations in another gene (Fas[lpr]) was shown to contribute to a lupus-related
phenotype in another mouse strain (71). The integrated approach to analysis of the
NZB/W murine genetic model identified a novel genetic mechanism regulating
autoantibody production.
4. NEW MOUSE STRAINS AND TOOLS
TO ACCELERATE GENETIC ANALYSIS
The last two examples demonstrate the utility of congenic mice for identification
of a genetic locus within a linked region. Congenic mouse strains are constructed by
repeated backcrossing of a donor strain onto a background strain, with selection at each
generation for the presence of a desired donor chromosomal region. Because this
involves serial backcrossing and selection among progeny, construction of congenic mice
is a process that is costly in both dollars and time. Therefore, the availability of a series
of wellcharacterized congenic mouse strains, with different chromosomal regions
from one strain placed onto the genetic background of a recipient strain, provides
a valuable tool for genetic analysis. They will be useful for rapidly assessing the impact
of genotypic changes within a defined chromosomal region on the phenotype and for
identification of the genetic locus regulating the phenotype. As one example, a set of
congenic mice were produced, with each strain having a single A/J-derived chromosome
placed on the C57BL/6 host background. Each of the 21 chromosome substitution
strains had one of its 19 autosomes or one of two sex chromosomes derived from the A/J
donor strain. The rest of the chromosomes were from the C57BL/6 mice (72). Recently,
this congenic strain set was used to analyze 53 different traits, and over 150
chromosomal regions regulating these traits were identified (73). Two other groups have
produced overlapping sets of congenic strains with smaller chromosomal regions from
the donor strain introgressed into the genome of another recipient strain (74,75). These
sets of congenic substrains, in which a single identified segment of the genome of one
mouse strain is replaced by that of another strain, provide a useful tool for analysis
of the effect of genetic variation on phenotypic responses. Application of wellcharacterized experimental strategies for genetic mapping (76) to the genome-wide
congenic strain sets will enable genetic regions regulating complex traits in experimental
mouse models to be rapidly identified. This requires characterization of the phenotype
in the parental strains and in each congenic substrain. In one example, this approach
was used to identify a genetic locus for susceptibility to malaria using a set of A/J and
C57BL/6 congenic strains (77).