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 #
5U42OD011174-05
Application #
8896894
Study Section
Special Emphasis Panel (ZHG1)
Program Officer
Mirochnitchenko, Oleg
Project Start
2011-09-01
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Codner, Gemma F; Mianné, Joffrey; Caulder, Adam et al. (2018) Application of long single-stranded DNA donors in genome editing: generation and validation of mouse mutants. BMC Biol 16:70
Fan, Yanbo; Lu, Haocheng; Liang, Wenying et al. (2018) Endothelial TFEB (Transcription Factor EB) Positively Regulates Postischemic Angiogenesis. Circ Res 122:945-957
Albrecht, Nicholas E; Alevy, Jonathan; Jiang, Danye et al. (2018) Rapid and Integrative Discovery of Retina Regulatory Molecules. Cell Rep 24:2506-2519
Lanza, Denise G; Gaspero, Angelina; Lorenzo, Isabel et al. (2018) Comparative analysis of single-stranded DNA donors to generate conditional null mouse alleles. BMC Biol 16:69
Rozman, Jan; Rathkolb, Birgit; Oestereicher, Manuela A et al. (2018) Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nat Commun 9:288
Cole, Jason M; Symes, Daniel R; Lopes, Nelson C et al. (2018) High-resolution ?CT of a mouse embryo using a compact laser-driven X-ray betatron source. Proc Natl Acad Sci U S A 115:6335-6340
Meehan, Terrence F; Conte, Nathalie; West, David B et al. (2017) Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat Genet 49:1231-1238
Bowl, Michael R; Simon, Michelle M; Ingham, Neil J et al. (2017) A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Nat Commun 8:886
Boroviak, Katharina; Fu, Beiyuan; Yang, Fengtang et al. (2017) Revealing hidden complexities of genomic rearrangements generated with Cas9. Sci Rep 7:12867
Santiago-Sim, Teresa; Burrage, Lindsay C; Ebstein, Frédéric et al. (2017) Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. Am J Hum Genet 100:676-688

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