Functional analysis of a chromosomal region comprising 2% of the mouse genome will be conducted by saturation mutagenesis. Complementing types of mutations, chromosome deletions and point mutations, will be combined towards this end. First a series of 4 adjacent, radiation-induced deletion complexes will be generated on chromosome 5. This will be accomplished by implementation of an ES-cell-based technology the investigators have developed for the induction and selection of deletions encompassing loci of interest. A set of deletion stocks will be established that collectively span a 30 cM region on Chr.5. Second, an ENU mutagenesis screen will be performed, whereby mutagenized animals will be used in conjuction with the deletion sets to identify novel mutations on proximal Chr. 5. The identification of mutagenized chromosomes failing to complement nested deletion sets will then be used to localize particular ENU-induced mutations to intervals of approximately 0.3 cM. The goal will be to identify mutations affecting meiosis, embryonic development, seizure resistance and hearing. In a companion IRPG proposal, a screen for mutations affecting behavior will be performed.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035984-03
Application #
6125588
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Moody, Sally Ann
Project Start
1997-12-22
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$540,423
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Ching, Yung-Hao; Wilson, Lawriston A; Schimenti, John C (2010) An allele separating skeletal patterning and spermatogonial renewal functions of PLZF. BMC Dev Biol 10:33
Ching, Yung-Hao; Munroe, Robert J; Moran, Jennifer L et al. (2010) High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5. BMC Genet 11:106
Munroe, Robert J; Prabhu, Vinay; Acland, Greg M et al. (2009) Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass. BMC Dev Biol 9:27
Mu, Weipeng; Wang, Wei; Schimenti, John C (2008) An allelic series uncovers novel roles of the BRCT domain-containing protein PTIP in mouse embryonic vascular development. Mol Cell Biol 28:6439-51
Suarez, Susan S; Marquez, Becky; Harris, Tanya P et al. (2007) Different regulatory systems operate in the midpiece and principal piece of the mammalian sperm flagellum. Soc Reprod Fertil Suppl 65:331-4
Howell, Gareth R; Shindo, Mami; Murray, Stephen et al. (2007) Mutation of a ubiquitously expressed mouse transmembrane protein (Tapt1) causes specific skeletal homeotic transformations. Genetics 175:699-707
Harris, Tanya; Marquez, Becky; Suarez, Susan et al. (2007) Sperm motility defects and infertility in male mice with a mutation in Nsun7, a member of the Sun domain-containing family of putative RNA methyltransferases. Biol Reprod 77:376-82
Wilson, Lawriston; Ching, Yung-Hao; Farias, Michael et al. (2005) Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations. Genome Res 15:1095-105
Symula, Derek J; Zhu, Yiwen; Schimenti, John C et al. (2004) Functional annotation of mouse mutations in embryonic stem cells by use of expression profiling. Mamm Genome 15:1-13
Shima, Naoko; Hartford, Suzanne A; Duffy, Ted et al. (2003) Phenotype-based identification of mouse chromosome instability mutants. Genetics 163:1031-40

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