Annotation of the reference human genome has identified approximately 20,000 protein coding genes as well as 3,000 non-coding RNAs. Together these genes orchestrate the development of the organism, supporting all aspects of the function of cells, tissues, organ systems as well physiology and behavior. The l000 genomes project has revealed extraordinary levels of diversity in human genomes, yet for most genes neither the function of normal version nor the disease consequence of loss-of-function variants is known. The mouse provides a route to understand the function of genes and their variants. Mice share developmental, physiological, anatomical and metabolic parallels with humans, which are evident in healthy as well as diseased states. These reflect similarities of the genes in both species. Mutant mice generated using ES cell technology are a sensitive biological assay system from which a deep understanding of function can be gleaned and they also provide a long lasting biological resource for further study. The objective of this proposal is to generate mutant mice from a resource of ES cells with conditionally targeted, lacZ-tagged alleles generated under previous NIH (KOMP) and EU (EUCOMM) funded programs. We and others will use these mice to discover the function of genes. We are proposing to carry out this work at scale and have formed a consortium of three Institutes (Baylor College of Medicine, the Sanger Institute and MRC Harwell) to work together as equal partners to achieve this objective. We will generate mice corresponding to 1500 mutant genes from ES cells distributed by the Sanger Institute. We will characterize the adult and embryonic expression pattern of the each targeted gene and by breeding determine the requirement of each for embryonic development and fertility, if any. All of the alleles will be cryo-preserved and placed in a repository and all of the data will be deposited in a centralized data coordination center to support further studies.

Public Health Relevance

Most of the 20,000 genes in a typical person are normal but we also have several hundred broken ones. While some broken genes can cause severe disease such as cystic fibrosis or cancer, others have little or no consequence, or function only under stress. Currently we have some understanding of the function of just one third of human genes. If we are to fully understand human health and disease we must expand knowledge of gene function to all of our genes.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials Resource Cooperative Agreements (U42)
Project #
8U42OD011174-02
Application #
8325929
Study Section
Special Emphasis Panel (ZHG1-HGR-M (M2))
Program Officer
Mirochnitchenko, Oleg
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$4,133,000
Indirect Cost
$860,436
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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