Great times for mouse genetics: getting ready for
“The mouse needs no defense.” This was Salome Welch’s re-
sponse seven years ago when at a meeting in Crete a famous
Drosophila geneticist argued that if one was interested in verte-
brates, one might study the zebrafish, but certainly not the mouse.
Although most readers of Mammalian Genome probably agree
with Salome, the arguments that were used against the mouse
To study gene function in any organism, mutants are needed.
Many mutants. Drosophila geneticists had used mutants as their
major tool to work out the principles of how the basic body plan
of an organism is established. Chemical mutagenesis produced
thousands of flies and hundreds of mutants with specific phenotypes
of interest. Making mutants with suppressor or enhancer screens was
routine, and finding the mutated gene was not an obstacle.
The challenge in the mouse was to find appropriate strategies
for making and discovering mice with mutated genes and anoma-
lous phenotypes. Only a few thousand mouse mutants had been
collected in the history of mouse genetics, and positional cloning
remained challenging. The genetic map had modest resolution, and
a physical map of the genome was not available. At the time of the
meeting in Crete, Bernhard Herrmann had just cloned the Brachy-
ury gene and Sylvia Vidal, Philippe Gros, and Emil Skamene had
just cloned the BCG gene. Despite their success, the path from
phenotype to gene remained daunting. Few thought that mouse
genetics could ever be used in the systematic way to which Dro-
sophila or worm geneticists were accustomed.
At the time of the Crete meeting, the increasing numbers of
knockout and transgenic mice generated great enthusiasm among
mouse biologists. For the first time, systematic efforts could be
imagined to engineer mutations in specific genes. Gene targeting
was viewed as the future of mouse genetics. The enthusiasm was
high despite the difficulties in choosing a gene for study among the
75,000—150,000 genes in the genome, finding the affected phe-
notype in engineered mice, and scaling these efforts to the tens of
thousands of genes that need to be studied.
The world changed dramatically in the ensuing years. Micro-
satellites, cosmids, BACs, YACs, and ESTs are widely available.
The sequence of the mouse genome is expected to be complete in
the next few years. It was increasingly realized that although the
fly and the worm are essential for pathway dissection, there is no
substitute for a mammal as a disease model. No doubt that this had
to be the mouse. But what about the mutants?
Bill Russell and his colleagues at the Oak Ridge National
Laboratory had introduced chemical mutagenesis with ENU in the
mouse in the late seventies. Several groups subsequently estab-
lished efficient mutagenesis protocols. The discovery of induced
mutants by Vernon Bode, Bill Dove, Jean-Louis Gue´net and others
demonstrated the feasibility of chemical mutagenesis based on
ENU. Gene Rinchik had even tried ‘saturation’ mutagenesis on an
11-cM interval around the albino locus. Despite these successes, it
was not evident that chemical mutagenesis could be a routine tool
for large-scale studies of mouse genetics.
The discovery of the circadian rhythm mutant clock by Joe
Takahashi and its positional cloning just a few years later changed
this picture. What an interesting phenotype! It would have been
very hard to find the clock mutant via gene-targeting approaches.
Moreover, Greg Barsh and Sabine Cordes had shown that ENU
mutagenesis could be used effectively to discover new alleles of
known genes. Around 1994 Christiane Nu¨sslein-Volhard and
Wolfgang Driever initiated large-scale ENU mutagenesis screens
in zebrafish. Within a few years more than 1000 mutants were
isolated, providing a tremendously valuable resource. Together with
the pioneering studies with ENU mutagenesis in the mouse, the work
of Nu¨sslein-Volhard and Driever provided the proof-of-concept that
large-scale screens do not have to be limited to flies or worms.
Several studies of the feasibility of large-scale mutagenesis in
the mouse are now under way in several countries. Germany has
allocated substantial funding to functional genomics of model or-
ganisms. An important component of this research program is the
large-scale mouse ENU mutagenesis project at the GSF-Research
Center for Environment and Health (Munich). Similar projects are
under way at the MRC Mammalian Genetics Unit (Harwell) and at
the Oak Ridge National Laboratories (Oak Ridge). Establishment
of several ENU mutagenesis centers in the US is anticipated. Japan
has funded an ENU screen, and similar efforts are under way in
Australia and Canada. An “Action Plan of Mouse Genomics” (Bat-
tey et al., Nat. Genet. 21, 73–75, 1999) has been published, with
the NIH as a major supporter for exploiting the mouse as a model
organism for studying the pathogenesis of human disease.
Important discussions about the merits of ENU mutagenesis
have occurred at meetings of the International Mammalian Ge-
nome Society in London, Ann Arbor, Garmisch Partenkirchen, St.
Petersburg, and Philadelphia. To bring together those interested in
promoting and evaluating ENU-mutagenesis, a workshop was held
in Schloß Hohenkammer, Germany, in November 1998, after the
International Mouse Genome Meeting in Garmisch Parten-
kirchen and with the support of HUGO-Europe and the German
Ministry of Research, Technology and Education (BMBF).
HUGO-Europe sponsored a follow-up workshop at Monterotondo
(Italy) in November 1999.
The enthusiasm for large-scale mutagenesis is heralding a new
era in mouse genetics. Continuing research on the development
and refinement of phenotyping methods is critical if we are to fully
exploit the power of phenotype-based approaches to mouse muta-
genesis. Many of the contributions at the workshops at Schloß
Hohenkammer and Monterotondo, as well as many subsequent
developments in the community, have been compiled in this spe-
cial issue of Mammalian Genome. These papers evaluate the mer-
its of chemical mutagenesis and the status of projects to discover
mutant mice as new models of human disease. An important result
of the Schloß Hohenkammer workshop was the realization that
making the mutants, even at large scale, is just the beginning and
that dissecting and defining the phenotypes will yield the most
exciting insights. What is now necessary is in-depth, detailed, and
systematic phenotyping—from pathology to profiles of gene ex-
pression. Coupled with advances in genomics that will speed the
identification of underlying genes, the growing mouse mutant re-
source is set to have a major impact on functional genomics for the
Rudi Balling, Munich
Steve Brown, Harwell
Martin Hrabe de Angelis, Munich
Monica Justice, Houston
Joe Nadeau, Cleveland
Jo Peters, Harwell
Mammalian Genome 11, 471 (2000).
© Springer-Verlag New York Inc. 2000