The classic means to understand the function of genes is to
mutate them and see what happens. The recent Nobel Prize-winning work of Drs.
Lewis, Nusslein-Volhard, and Wieschaus in the fruit fly clearly demonstrated
the power of mutagenesis in understanding the function of genes in driving the
behavior of cells. ORNL has been a pioneer in this work in the mouse, and it
was their presence that catalyzed the formation of the Tennessee Mouse Genome
Consortium (TMGC) in 1998. The TMGC nicely demonstrates the capacity to create
formal alliances among many of the top Tennessee research institutions,
including UTHSC, UTK, St. Jude Children’s Research Hospital, and ORNL The
consortium is producing and sharing large numbers of mutant mice that will be
used to probe normal biological function and to develop models for common human
diseases.The success of our first
grant application ($12,774,513 over 5years) is just the beginning of efforts in
this emerging field.
The CGB will make an investment in the maintenance and care
of mutant mice in order to broaden the phenotypic analyses which, for now,
concentrate on behavior and neural function. By
aiding in the support of producing a full complement of mutant mice, we will
ensure that various projects throughout the system will have mice to use for
the generation of preliminary data for various R01 and Program Project (PPG)
applications.
The TMGC
Mutagenesis Porgram - the creation of mutant mice can be an unlimited source of R01s or Programmatic grants. Our particular strategies of regional-based mutagenesis affords unique opportunities to identify test class mice and provide four powerful ingredients:
- Since mutants can be ascertained by genotyping, we can set aside identified test class mice to be aged and examined for phenotypes associated with the aging process,
- We can identify the absence of live test class mice and know we are dealing with a embryonic or perinatal lethal mutation. In this case we will identify genes critical for early development.
- The regional approach allows us to identify genes associated with complex traits because we are able to select out specific chromosomal regions for mutagenesis and can examine test class mice from such a region for the phenotype of interest. Example is QTLs associated with etoh…develop-- this can lead to an almost inexhaustible application of regional mutagenesis because the problem is so intractible with almost any other approach, but the payoff is large. We are working with the ethanol-interest group at UTHSC to develop a first grant in that endeavor. We have been encouraged by officials at NIAAA to propose such work.
- Finally, the pathway from mutation to identified gene is markedly enhanced since the regional approach prelocalizes the gene to a specific chromosomal area.
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