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Mouse mutagenesis-systematic studies of mammalian gene function

S D Brown1, P M Nolan

  • 1MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Oxon OX11 ORD, UK. s.brown@har.mrc.ac.uk

Human Molecular Genetics
|September 15, 1998
PubMed
Summary

Systematic genome-wide mutagenesis in mice is crucial for understanding gene function in the post-genomics era. New genotype- and phenotype-driven approaches, including N-ethyl-N-nitrosourea (ENU) mutagenesis, will expand the mouse mutant resource.

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Area of Science:

  • Genetics
  • Genomics
  • Mammalian Biology

Background:

  • The mouse is a key model organism for mammalian gene function studies in the post-genomics era.
  • Existing mouse mutant resources are insufficient to cover the vast number of mammalian genes, highlighting a 'phenotype gap'.
  • There is a need for systematic, genome-wide mutagenesis strategies to address this gap.

Purpose of the Study:

  • To outline and compare complementary strategies for generating novel mouse mutations.
  • To emphasize the importance of both genotype-driven and phenotype-driven approaches for expanding the mouse mutant resource.

Main Methods:

  • Genotype-driven mutagenesis using gene trap embryonic stem cell libraries to identify mutated loci easily.
  • Phenotype-driven mutagenesis, particularly employing N-ethyl-N-nitrosourea (ENU), to recover novel phenotypes without prior assumptions about gene function.

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Main Results:

  • Genotype-driven approaches facilitate straightforward identification of mutated genes but require functional assumptions.
  • Phenotype-driven approaches, like ENU mutagenesis, excel at discovering novel phenotypes and uncovering unknown genes and pathways.
  • Identifying the specific mutated gene in phenotype-driven approaches remains a challenge.

Conclusions:

  • Complementary genotype- and phenotype-driven mutagenesis strategies are essential for significantly enlarging the catalogue of mouse mutations and phenotypes.
  • These combined approaches will accelerate future gene function studies and the understanding of mammalian biology.