Notice Number: NOT-HG-10-005
Release Date: September 24, 2009
Response Date: October 15, 2009
National Human Genome Research Institute (NHGRI), http://www.nhgri.nih.gov
National Center for Research Resources (NCRR), http://www.ncrr.nih.gov
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), http://nichd.nih.gov
The purpose of this RFI is to seek input and feedback from the scientific community in order to inform and guide future large-scale phenotyping of knockout mice. Specifically, the NIH is seeking advice and recommendations on the scope, depth, and breadth of a phenotyping effort, and to provide rationale and justification on how this effort would benefit research.
The goal of the NIH-sponsored Knockout Mouse Project (KOMP) is to produce a library of knockouts in the C57BL/6 background. In collaboration with parallel mutagenesis programs (the North American Conditional Mouse Mutagenesis project [NorCOMM] and the European Conditional Mouse Mutagenesis program [EUCOMM]) the intent is to produce a combined library of knockouts for all the genes in the mouse genome for which a knockout can be made, i.e., at least 15,000 knockouts. KOMP was organized in 2 phases: the goal of phase I, which is midway to completion, is to generate knockout mutations for 8,500 genes in C57BL/6 mouse embryonic stem (ES) cells; the goal of phase II is to conduct a coordinated, large-scale, high-throughput, and cost-effective phenotypic analysis of KOMP mutant mouse lines, and to make that data and information freely and readily available to the scientific research community. As envisioned in a meeting report from The Banbury conference on Mouse Knockouts (Austin et. al., Nature Genetics, 36 (9), September 2004, p921 and Auwerx et. al., Nature Genetics, 36 (9), September 2004, p925), by providing genetic data, molecular resources, and phenotyping information, the international mouse knockout program will greatly benefit the biomedical research community and enhance our understanding of human disease.
A well-conceived plan to functionally phenotype knockout mice, that considers both the breadth and depth of baseline screening, is essential for realizing the full potential of the knockout resource. However, to date, such a plan has not been developed in the U.S., although private and public funding sources in Canada and Europe have already embarked on pilot programs (e.g., EUMODIC, see http://www.eumodic.org/) to functionally annotate targeted and trapped alleles. The Europeans are currently consulting with their research community about expanding the phenotyping programs, but the NIH has not yet sought input and feedback to initiate a NIH-supported mouse phenotyping program. Thus, this RFI seeks input from the research community to determine the scope, depth, and breadth of phenotyping analysis that would maximize utility of the entire knockout resource. Recommendations from potential users as to the principles, characteristics, and scientific relevance of phenotyping a large and unique collection of targeted knockouts will be essential to determine the value, feasibility, and extent of a coordinated plan and concerted effort to phenotype the entire knockout resource.
For the purposes of this survey, assume that a high throughput phenotyping effort will go forward on all genes over a ten year period. The goal of the survey is to ascertain what area-specific information researchers would need from a primary phenotype screen to enhance research efforts and advance the field of study in their area of interest.
The NIH is requesting feedback and input on the following 5 areas:
1. What are the essential tests, analyses, and/or examinations, and under what conditions and environments (basal and/or challenge) would the utility of a mutant mouse line be revealed, convincing you to obtain that mouse line for further hypothesis-driven analysis in your research laboratory?
2. What phenotypes would motivate you to take mice and begin work on them in your own lab?
3. A fundamental question is the value of naïve and/or challenge models. Are there challenge models that would be more effective as a screen for your work than baseline phenotyping?
4. Should knockouts be selected for specific assays or should we test all lines in all assays? If the former, how would such selection be accomplished?
5. If you had financial support, would you be willing supervise a person to mine the data and identify mutant mouse lines that your lab would use for more sophisticated, in-depth analysis?
6. How would you value an NIH-subsidized program of standardized phenotypes in a high throughput manner, at a lower cost per gene and encompassing more fields than individual labs could perform? Would the availability of data (regardless of the outcome of the experiment) be of benefit to the larger community? Would this effort help individual PIs focus on custom phenotyping of fewer but very relevant genes? Approximately what range of costs does your lab invest in phenotyping, with or without challenges (please include all personnel and overhead cost, as well as mouse production)?
How to Submit a Response
Responses will be accepted through October 15, 2009. Responses by e-mail are strongly preferred. Please use the address firstname.lastname@example.org to submit a response. The submitted information will be assembled, analyzed, summarized, and presented at an October 2009 meeting of KOMP grant participants, scientific advisors, NIH program staff, and invited members of the research community.
Colin Fletcher, Ph.D.
Knock Out Mouse Program (KOMP)
National Human Genome Research Institute National Institutes of Health
5635 Fishers Lane, Suite 4076, MSC 9305
Bethesda, Maryland, 20892-9305
Phone: (301) 496-7531
FAX: (301) 480-2770
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