The previous cycles of this grant have supported our efforts to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. These screens incorporated a genetic mapping component to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mice with phenotypes similar to human malformation syndromes and birth defects. Our future effort has even greater potential productivity, as the overall task of mutation discovery continues to be facilitated by rapid progress in technologies for genomic analysis. In this continuation proposal we aim to optimize several aspects of the project, while maintaining the fundamental approach that has thus far proven so productive. Specifically, we propose strategies for rapid mutant validation and for more rapidly translating gene discovery into functional analysis.

Public Health Relevance

We are able to identify mutations causing abnormalities of organ development by systematically screening mice treated with the chemical mutagen ENU. The generation of powerful tools for genome analysis allows us to rapidly identify the gene mutated in these abnormal mice. This provides insight into the causes of congenital birth defects and the basic biology of human development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036404-16
Application #
8677606
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Coulombe, James N
Project Start
1998-04-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98121
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Gallego-Llamas, Jabier; Timms, Andrew E; Geister, Krista A et al. (2015) Variant mapping and mutation discovery in inbred mice using next-generation sequencing. BMC Genomics 16:913
Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J et al. (2015) A forward genetic screen in mice identifies mutants with abnormal cortical patterning. Cereb Cortex 25:167-79
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Stottmann, Rolf; Beier, David (2014) ENU Mutagenesis in the Mouse. Curr Protoc Hum Genet 82:15.4.1-10
Tran, Pamela V; Talbott, George C; Turbe-Doan, Annick et al. (2014) Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol 25:2201-12

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