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Chromosome Engineering and ENU Mutagenesis: Their Use for Defining Gene Function

[ Vol. 4 , Issue. 1 ]

Author(s):

Jan Klysik, Monica J. Justice and Allan Bradley   Pages 37 - 50 ( 14 )

Abstract:


Recent progress in mammalian genomics raises enormous expectations for rapid advances in global understanding of the genetic program. The Human Genome Sequencing Project and parallel sequencing efforts addressing other genomes are in their final stages and will bring to the public domain an influx of tens of thousands of previously unknown genes whose cellular function will remain to be evaluated. Although DNA sequence information may assist and facilitate functional and comparative analyses of model organisms, a combination of systematic genotype- and phenotype-driven functional approaches will play a critical role in the upcoming research defining the gene function. For its physiological similarity to humans and for its genetic manipulability, the mouse emerges as a key model mammalian organism in these efforts. One powerful strategy for phenotype-driven mutagenesis studies in mice combines chromosome engineering techniques with mutagenesis. There are three key elements of this strategy. First, using the LoxP / Cre recombination system in embryonic stem (ES) cells, coat color-tagged segmental deletion s and inversions are generated on selected chromosomes, and mouse strains are derived from these cells using conventional ES cell technology. These mice can serve as very potent and extremely convenient genetic tools that narrow the search area for gene(s) of interest to a limited chromosomal segment. Second, N-ethyl-N-nitrosourea, ENU, is used to mutagenize male mice in order to generate a source of genome-wide germ-line transmissible mutations. Third, mutagenized animals are crossed with inversion or deletion carriers to produce pedigrees uncovering ENU-induced recessive phenotypes. The genomic position of induced mutations underlying recessive phenotypes is instantly mapped to the chromosomal inversion or deletion intervals. Several large-scale projects have been launched using ENU alone or in combination with engineered chromosomes. A rapidly growing set of new phenotypes has begun to emerge from these studies which will ultimately provide insights into gene function.

, Chromosome, Engineering, and, ENU, Mutagenesis:, Their, Use, for, Defining, Gene, Function

Affiliation:

Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, Texas 77030, USA



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