OPPORTUNITY FOR OBTAINING THE SEQUENCE OF MOUSE DNA OF PARTICULARLY HIGH BIOMEDICAL INTEREST Release Date: January 12, 2000 NOTICE: HG-00-001 National Human Genome Research Institute Submission dates for 2000: February 1, April 1, June 1, August 1, October 1, and December 1. BACKGROUND AND PURPOSE The National Institutes of Health (NIH), through the National Human Genome Research Institute (NHGRI), has funded a research network of large-scale sequencing centers to sequence the mouse genome. The mouse sequence is a critical resource that will provide a rich trove of information for mouse and human geneticists and for annotating the human DNA sequence. A draft sequence of the mouse genome will be produced first, with a target date of 2003. According to the current strategy, the draft sequence will then be finished to a high quality standard. While the initial emphasis of the research network will be on producing large amounts of draft sequence, some of the early sequencing capacity will be devoted to particular regions which have special significance for advancing biomedical research. Through the program described in this Notice, the NIH intends to accommodate the needs of the scientific community to obtain sequence for specific regions of biomedical interest sooner than would otherwise be possible. However, as the entire mouse genome sequence is also of very high interest, the complementary components of sequencing specific regions and generating a draft sequence of the whole genome will have to be balanced. Initially, about 10% of the sequencing capacity devoted to mouse genomic sequencing will be available for the activity described in this Notice. If the demand to sequence specific regions far exceeds the capacity, NHGRI will re-evaluate the program. As with all sequence data generated by the Human Genome Project, all of the sequence data generated by the NIH-supported Mouse Genome Sequencing Network will be subject to the "Bermuda Rules." The data will be rapidly released into GenBank; unfinished data will be submitted within 24 hours of generation of 2kb assemblies, and finished data as soon as completed. In particular, under this program of sequencing regions of high biomedical significance, no sequence data will be made available to the requestor prior to public release. All publications using this data must acknowledge the publicly funded effort. There will be no cost to investigators seeking this sequencing service; the sequencing will be done by centers that have already been funded through the NIH Mouse Genome Sequencing Network. PROGRAM DESCRIPTION In collaboration with the large-scale sequencing centers and representatives of the mouse research community, the NHGRI and its advisors have established a program to allow the international biomedical research community to identify, request and prioritize regions of the mouse genome of special interest for focused genomic sequencing. This program is intended to address the interest of the biomedical research community in obtaining sequence information about specific regions of the mouse genome in parallel with the generation of the draft sequence of the mouse and the completion of the human genomic sequence which is expected by 2003. The program will make this opportunity available to the community at large and, at the same time, will assist the NIH Mouse Genome Sequence Network in managing requests for access to its limited sequencing capacity. The program will allow any investigator interested in obtaining the sequence of a specific region to submit a short, Web-based application describing the region, its importance, and its readiness to be sequenced. A panel of peer reviewers is being established to consider the applications and advise the NHGRI on the priority of the requests. Those requests judged to be sufficiently important to warrant priority sequencing will be listed for the centers engaged in mouse genomic sequencing to choose and sequence, up to the maximum capacity available for this activity. Requests must be submitted via the website starting January 5, 2000. The NHGRI expects there to be a considerable demand for this service in the short term, but for the program to have a limited lifetime. The program will be evaluated periodically to confirm its usefulness to the community and its effect on the efficiency of production sequencing. In addition to the NHGRI program, the Department of Energy, the Medical Research Council in the United Kingdom and Genoscope in France have similar programs. Every effort will be made to coordinate with these agencies to avoid unnecessary duplication of effort. ELIGIBILITY REQUIREMENTS Any investigator may submit a request to sequence a BAC clone or BAC contig identified in the RPCI-23 library. SCOPE OF REQUEST BAC clones are the sequencing substrate used by the research network. Requests will be accepted to sequence either a single BAC clone or a single BAC contig. Only clones from the RPCI-23 BAC library (constructed from the C57 BL6/J mouse strain) will be considered. This strain was chosen in consultation with members of the mouse research community. The requestor must provide information about the biological importance of the region to be sequenced, relevant mapping information, and other pertinent information that is available about the requested clone(s). Clones must be identified using the naming convention found at http://www.ncbi.nlm.nih.gov/genome/clone/nomenclature.shtml. There will be no limit to the number of requests that an investigator may submit. However, each request must be submitted as a separate application. If the clone (or contig) requested to be sequenced in one application is related to one in another application (such as in the case of gene families, etc), the relationship should be noted. Investigators may submit requests for either draft or finished sequence. The current working definition of draft sequence is at least 4-fold coverage of a region in Phred 20-quality bases. This will contain on the order of 10 gaps per BAC and the numerous contigs may not be ordered or oriented within the BAC clone. Finished sequence is defined as sequence that is at least 99.99% accurate and contains no gaps. Because less work is involved, draft sequence projects will typically be finished more rapidly than finished sequence projects. PROCEDURE FOR SUBMITTING A REQUEST The request form that must be used is available at http://mouse.info.nih.gov. The completed form must be submitted electronically following the instructions given. The Web-based request must include: 1. A short description of the biomedical importance of the region contained within the BAC clone or BAC clone contig that is to be sequenced. 2. Evidence that the region described lies within the requested clone(s). 3. Evidence, e.g., restriction digest, that the clone(s) picked using the library address specified is the requested clone. 4. Evidence that confirms that the requested region has not already been sequenced, and that the requested BAC is not already in the sequencing pipeline. Information on the status of individual BACs within the research network sequencing pipeline can be found at: http://www.ncbi.nlm.nih.gov/genome/clone/. 5. In the case of a single BAC, all known underlying and overlapping clones must be identified. In the case of a BAC contig where significant map building may have been done, all known underlying and overlapping clones must be identified and evidence for the structure of the BAC contig described. 6. Any other additional information about the clone(s), if available, such as: the size of the region to be sequenced; genomic map location, available marker information; sequence information; restriction digest fingerprint pattern; clone instability, repeats, deletions, and problems growing the clone(s) and the conditions used to overcome them. 7. The sequence coverage required (draft or complete). If complete sequence is required, a strong justification must be presented. All requestors must agree to the following terms and conditions: (a) Data will be released according to the "Bermuda Rules"(All sequence data generated by the publicly funded effort will be rapidly released into the public domain. Unfinished data will be released within 24 hours of generation of 2 kb assemblies and finished data will be released as soon as completed.). No sequence data will be made available to the requestor prior to public release. (b) All publications using this data must acknowledge the publicly funded effort using the following statement: "The sequence data were generated through the NIH-funded Mouse Genome Sequencing Network." REVIEW FOR DESIGNATION AS A PRIORITY REGION The reviews will be conducted by a panel of biologists with a broad range of biomedical interests. Requests will be reviewed approximately one month after the submission dates listed above. Because of the accelerated review and frequent deadlines, the submission dates will not be waived for any reason. The criteria for determining the relative priority of the requests will be: - biomedical significance of the region contained in the clones identified for sequencing. Why is this region of particular importance to the rapid advancement of biomedicine? Is the genetic information in this region of particularly widespread relevance?; and - evidence that this region(s) is contained in those clones. Requests will receive one of three designations: highest priority; moderate priority; and declined. In the case where the review panel decides that an application is of moderate priority or should be declined, NHGRI program staff will provide the investigator with written comments indicating which of the review criteria were not adequately addressed. Because of the rapid review cycle, resubmission will be the only means for re-consideration of a request. There will be no limit on the number of times a request for a specific region can be resubmitted, but each iteration will be required to contain additional significant information. POST-REVIEW AND PROGRAMMATIC CONSIDERATIONS NHGRI staff will inform all requestors of the results of the review, approximately two weeks after the review meeting. NHGRI program staff listed below will act as the contact point for the investigator during the remainder of the sequencing process. Program staff will provide information about the expected timing for the sequencing of a particular project. Requestors SHOULD NOT contact the sequencing centers directly unless program staff advises them to do so. The sequencing centers will be focused on high throughput production of sequence data and should therefore be shielded from any unnecessary distractions. The identity of clones (using standard nomenclature) that have been designated as highest or moderate priority will be listed on a public Web site with an indication of the priority recommended. The name of the investigator who requested that the clone(s) be sequenced and the significance of the region(s) contained in the clones will not be given. Once a sequencing center has chosen a BAC clone or contig for sequencing, that change in status will be indicated on the public Web site. Clones to be sequenced will then be entered into the sequencing pipeline: http://www.ncbi.nlm.nih.gov/genome/clone/. This is a new program and the exact work flow cannot be entirely predicted. Every effort will be made to sequence the clones that are designated highest or moderate priority. Some BACs may be finished within two months of entering the sequencing pipeline but some BACs may require longer periods of time. There may be regions that are found to be so difficult to sequence that it will be necessary to archive the clone until new methods for sequencing are available. It is expected that such clones will be rare, but in such a case, NHGRI staff will notify the investigator who submitted the request. It is also possible that a BAC with significant overlap to the one requested, containing the requested sequence, will be in the sequencing pipeline prior to the request entering the sequencing pipeline. In this case, NHGRI staff will discuss with the submitting investigator how to proceed. INQUIRIES Telephone, electronic and/or written inquiries are welcomed. To discuss programmatic issues related to this program, please contact: Bettie J. Graham, Ph.D. National Human Genome Research Institute Building 31, Room B2B07 National Institutes of Health Bethesda, MD 20892-2033 Telephone: (301) 496-7531 Fax: (301) 480-2770 E-mail: bettie_graham@nih.gov To discuss review issues related to this program, please contact: Jerry Roberts, Ph.D. National Human Genome Research Institute National Institutes of Health Building 31, Room B2B37 Bethesda, MD 20892-2032 Phone: (301) 402-0838 Fax: (301) 435-1580 E-mail: jerry_roberts@nhgri.nih.gov
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