Human Molecular Genetics, Vol 7, 1627-1633, Copyright © 1998 by Oxford University Press
SD Brown and PM Nolan
The mouse will play a pivotal role in mammalian gene function studies as we
enter the post-genomics era. The challenge is to develop systematic,
genome-wide mutagenesis approaches to the study of gene function. The
current mouse mutant resource has been an important source of human genetic
disease models. However, despite an apparently large catalogue of mouse
mutations, we have access to mutations at only a small fraction of the
likely total number of mammalian genes-there is a phenotype gap that needs
to be filled by the establishment of new mutagenesis programmes. Two
routes, genotype- and phenotype-driven, can be used for the recovery of
novel mouse mutations. For the former, gene trap embryonic stem cell
libraries appear set to deliver a large number of mutations around the
mouse genome. The advantage of genotype-driven approaches is the ease of
identification of the mutated locus; the disadvantage that a priori
assumptions have to be made concerning the function and likely phenotype of
the mutated gene. In contrast, phenotype-driven mutagenesis emphasizes the
recovery of novel phenotypes. One phenotype-driven approach that will play
an important role in expanding the mouse mutant resource employs the
mutagen N-ethyl- N-nitrosourea (ENU). The phenotype-driven route makes no
assumptions about the underlying genes involved, and ENU mutagenesis
programmes can be expected to play a significant role in uncovering novel
pathways and genes; the disadvantage is that the identification of the
mutant gene is still not trivial. Together, the complementary routes of
genotype- and phenotype-driven mutagenesis will provide a much enlarged
catalogue of mouse mutations and phenotypes for future gene function
studies.
REVIEWS
Mouse mutagenesis-systematic studies of mammalian gene function
MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Oxon OX11 ORD, UK. s.brown@har.mrc.ac.uk
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