A RESOURCE OF ARRAYED BAC CLONES FOR FISH MAPPING OF THE HUMAN GENOME Release Date: January 16, 1998 RFA: CA-98-005 P.T. National Cancer Institute Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 27, 1998 PURPOSE This Request for Applications (RFA) is to solicit applications to generate a resource that will facilitate the identification of chromosome aberrations in cancer and to provide reference points for the development of a "cancer chromosome aberrations" database. The Tumor Genetics Program, Cancer Genetics Branch, Division of Cancer Biology (DCB), National Cancer Institute (NCI) invites applications for research projects to generate a resource of mapped human large-insert Bacterial Artificial Chromosomes (BAC) clones that can be used for fluorescence in situ hybridization (FISH) mapping studies, with a resolution of approximately 1 megabasepair, which is equivalent to 3,000-5,000 BAC clones for the whole human genome. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, A Resource of Arrayed BAC Clones for Fish Mapping of the Human Genome, is related to several priority areas. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and Local governments, and eligible agencies of the Federal government. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a Resource Related Support cooperative agreement (U24), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the activity of recipient(s), to generate a publicly available high quality resource, by involvement in and otherwise working jointly with the award recipient(s) in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. NCI staff will also be involved with the coordination of different groups, should there be more than one award recipient (e.g., with each PI focused on specific chromosomes). Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." The total project period for an application submitted in response to this RFA may not exceed two years. The anticipated award date is no later than September 30, 1998. This RFA is a one-time solicitation. Because the nature and scope of projects proposed in response to this RFA may vary, it is anticipated that the sizes of awards will vary also. The number of awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. FUNDS AVAILABLE Approximately $500,000 in total costs will be available for this initiative in Fiscal Year 1998, and $500,000 in total cost for the remaining year. It is anticipated that one to three awards will be made. If more than one award is made, the NCI Program Director will work with all awardees to avoid overlap and to ensure that the maximum number of reliable mapped clones will be generated. Proposed funding levels are subject to change due to budgetary, administrative and/or scientific considerations, and are dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, the issuance of awards pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background One major goal in cancer genetics is to identify every gene that is involved in cancer development. The concept that proto-oncogenes or tumor suppressor genes are involved in the various forms of microscopically discernible aberrant chromosomes has been fully supported by the numerous molecular studies that have defined many such tumor-specific changes. The investigation of balanced chromosomal rearrangements in different tumor types, primarily leukemias but also solid tumors, in particular malignant mesenchymal neoplasms, has led to the identification of many genes that are involved in cancer development. There is growing appreciation of the clinical usefulness of the identification of a recurring chromosome abnormality, by cytogenetic or molecular means, in the diagnosis, subclassification and prognosis of a neoplastic disorder, and, hence, in the selection of the appropriate treatment. Cytogenetic studies over the past few decades have revealed clonal chromosomal aberrations in almost 27,000 human neoplasms, representing 75 different types of neoplasms (Mitelman et al., Nature Genetics, 1997 Supplement). Furthermore, chromosome breakpoints in 25,547 cases analyzed showed that virtually all chromosomal bands are involved, and, presumably, are important in recurrent tumor-associated abnormalities. Thus the origin of human cancer is due to the activity of a remarkably large spectrum of different genes, all of which can contribute to malignancy. Resolution intervals of cytogenetic analyses are usually in the range of 5-10 megabases, with significant variations among different laboratories. The idea for a resource of mapped human large-insert Bacterial Artificial Chromosome (BAC) clones across the whole human genome, stems from a DCB-sponsored workshop on Cancer Chromosome Aberrations (Bethesda, March 4-5, 1997). The availability of mapped human BAC clones across the whole genome at approximately 1 megabase intervals for FISH analysis will allow the mapping of all chromosome aberrations into 1 megabase "bins." Generation of a resource of mapped human BAC clones will allow the integration of physical and cytogenetic maps, providing the ability to extrapolate from clinical data on chromosome aberrations, as established by classical cytogenetic analyses or comparative genome hybridization (CGH), and to obtain candidate BAC clone sets for gene isolation. Currently, some individual laboratories are conducting the mapping of large-insert clones, including BAC and P1 artificial chromosome (PAC) clones, to specific cytogenetic regions of interest. Progress in the Human Genome Project is providing ordered large-insert clones for all chromosomes. However, only a handful of chromosomes (e.g., 1,6,7,20,22 and X) are currently associated with anything approaching a mapped large-insert clone every 1 megabase. Very few of the currently mapped BAC/PAC clones are derived from the human large-insert clone library that was constructed with DNA from donors with appropriate informed consent according to the 1996-National Human Genome Research Institute (NHGRI)-Department of Energy (DOE) Guidance (see below). Furthermore, large-insert clones for the remaining chromosomes will have to be selected from the libraries. The purpose of the development of a high density large-insert clone map and a centralized mapped large-insert clone resource is to eliminate the need for individual laboratories to map from scratch regions of interest with overlapping large-insert clones, thereby reducing duplication of effort on some chromosome regions. It will also ensure that appropriate probes will be available for the whole genome. Furthermore, once the large-insert clones are arrayed by chromosome map order, they may be used to define more precisely the boundaries of cytogenetic abnormalities in clinical samples. With the explosion of information now available on chromosome aberrations, it will be necessary to establish a database for that information. The mapped large-insert clones can be used to provide the reference points for the development of such a cancer chromosome aberrations database. It is imperative that the results of this project and the arrayed clones be made available to the research community. Strong emphasis will be placed on developing means of sharing data and biological reagents with investigators who need to identify particular genes or to conduct gene transfer experiments to verify the function of those genes. NCI plans to establish an Advisory Committee on "Cancer Chromosome Aberrations." The Committee will be comprised of the NCI Program staff responsible for this RFA, NCBI scientists responsible for the setting up of a public database on "Cancer Chromosome Aberrations," and NIH intramural and extramural experts on cancer chromosome aberrations. It is envisioned that the mapped large insert-clones generated under this RFA will be useful in providing the reference points for the development of such a database. Objectives and Scope The main objective of this RFA is to solicit applications for projects that will use state-of-the-art methods to generate a high quality resource of mapped human large-insert clones that can be used for FISH mapping studies and to do so rapidly, efficiently, and at low cost. BAC clones will be the preferred resource. PAC clones may also be included in the arrayed resource. However, mapping funded under this RFA should exclusively be BAC clones selected from libraries constructed with DNA from donors with appropriate informed consents according to the 1996-NHGRI-DOE Guidance. The clones selected should have immediate utility as FISH mapping reagents. Beyond this immediate utility, this resource ultimately can be used in Comparative Genome Hybridization (CGH) arrays or as the starting point of contig assembly around regions with chromosome aberrations. The availability of mapped Sequence Tag Sites (STSs) across the human genome ordered by Yeast Artificial Chromosomes (YACs) and human radiation hybrid (RH) mapping makes it possible to derive BAC clones every 1 megabase. An example of approach is to generate the arrayed BAC resource across the whole genome by hybridization of mapped STSs with known cytogenetic band location. These in turn could be verified, analyzed for size and rearrayed by chromosome map order in microtiter dishes. The human large-insert clone resources generated by this RFA will serve as anchors on a physical human large-insert clone map, and it is essential the mapped clones should have no restrictions in terms of their availability for sequencing. Any newly-mapped clones generated under this RFA MUST be derived from large-insert clone libraries that are constructed with DNA from donors with appropriate informed consent. The confidentiality and anonymity of donors must be ensured to the extent possible (recognizing that, because each individual's DNA sequence is unique, anonymity cannot ultimately be guaranteed). These issues have been addressed in a "Guidance for the Use of DNA in Large-Scale Sequencing" that was jointly issued by the NHGRI and the DOE Human Genome Program in August 1996 (Guidance available upon request from NCI Program Director). Currently, one human large-insert BAC library constructed according to the NHGRI-DOE Guidance is publicly available. It is anticipated that additional libraries will be available in the near future. Applicants should discuss in their applications the rationale for their approach. They must also describe plans to accommodate requirements and criteria stated in this RFA. State-of-the-art approaches other than the whole genome approach described above may be proposed. However, this RFA is focused on the generation of a high quality mapped BAC clone resource and is not designed to support technology development. Some laboratories may already have BAC/PAC clones mapped to large regions of a chromosome and will only need MINIMAL funding to identify "landmark" clones at 1 megabase intervals and generate a high quality arrayed resource. The BAC/PAC clones for such a resource should still have the appropriate informed consents in terms of their availability for sequencing. SPECIAL REQUIREMENTS Data and Resource Dissemination The sharing of materials and data in a timely manner has been an essential element in the rapid progress that has been made in genome research. Public Health Service (PHS) policy requires that investigators make the results and accomplishments of funded activities publicly available. The advisors to the NIH and the DOE genome programs have encouraged more rapid sharing, and this has become the norm in the genome community. NCI encourages applicants who respond to this RFA to develop and propose specific plans for sharing data and materials generated through the cooperative agreement. Dissemination of mapping data from individual laboratory web sites is not sufficient. It is anticipated that data obtained, upon verification that the clones are true positives, should be placed in a public database. For example, the National Center for Biotechnology Information, National Library of Medicine (NCBI, NLM) has already in place a database that links the BAC/PAC physical map with the cytogenetic map and will be willing to include in that database the mapping information generated under this RFA. Applicants need to describe plans for dissemination of their mapping data, and the compatibility of their database with other public databases. Where appropriate, awardees may work with the private sector in making the mapped clones available to the larger biomedical research community at a reasonable cost. The plans proposed for sharing and data release will be reviewed for adequacy by reviewers as well as NCI staff prior to award of the cooperative agreement and will be considered as a criterion for award. Funds to defray the costs of submitting data and distribution of reagents may be included in the application. Such requests must be adequately justified. The following terms and conditions will be incorporated into the award statements(s). Terms and Conditions of Award A. Applicability These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. Part 92 applies when state and local governments are eligible to apply as a "domestic organization." The administrative and funding instrument used for this program is a Resource Related Support Cooperative Agreement (U24), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared between the awardees and the NCI Program Director. B. Awardee Rights and Responsibilities 1) Awardees will have primary and lead responsibilities for the project as a whole, including research design and the actual performance of the experiments, final data analysis, interpretation and submission to a public database, preparation of publications, as well as collaboration with other awardees, with assistance from the NCI Program Director. The Principal Investigator(s) is expected to make any necessary adjustments in the overall research strategies to accommodate the changing environment resulting from improved technologies during the course of the project period. 2) If there is more than one awardee, a Steering Committee will be formed, consisting of the NCI Program Director and individual Principal Investigators. Through the Steering Committee, awardees will meet, at the beginning of the Award period and after the first year of research, with the Program Director and other Principal Investigators funded under this RFA in the Washington D.C. area to plan the details of the project and to report progress. Ongoing collaboration between multiple awardees and NIH staff is described in item 5 below. 3) Awardees will retain custody of and have primary rights to the data and reagents developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 4) Multiple awardees are expected to collaborate on common research designs to avoid duplications of efforts in specific chromosome regions. C. NIH Staff Responsibilities 1) The NCI Program Director will have substantial scientific- programmatic involvement during the conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. 2) The NCI Program Director will have substantial scientific- programmatic involvement in ensuring the maximum number of mapped clones will be generated across the genome. However, applicants are expected to include in the applications the proposed mapping approach, strategies and the scope of mapping (e.g. whole genome or specific chromosomes). The dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although there should be frequent interactions between the awardees and the NCI Program Director regarding the progress and focus of the project. 3) NCI intends to foster extramural-intramural partnership in research. For example, intramural scientists who are experts in fluorescence in situ hybridization (FISH) mapping techniques may participate in the generation of the mapped large-insert clone resource by the cytogenetic verification of mapped clones generated under this RFA. The NCBI scientists may participate by the incorporation of the mapping data of the large-insert clones in the public database established by the NCBI. The NCI Program Director will facilitate such partnership. 4) The NCI reserves the right to terminate or curtail the study (or an individual award) in the event of inadequate progress, data reporting, or willingness to release materials at reasonable costs. D. Collaborative Responsibilities 1) During the course of the award period, the awardee(s) may be invited to meet with the NCI Program Director, other Principal Investigators and/or other uninvolved experts in Bethesda, MD, to review scientific progress. 2) Applicants are expected to be willing to redirect efforts to ensure that the maximum number of reliable human large-insert clones may be mapped across the whole genome. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Steering Committee (with the NCI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. LETTER OF INTENT Prospective applicants are asked to submit, by February 19, 1998, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NCI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Grace L. Shen, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 501 Bethesda, MD 20892-7381 Rockville, MD 20852 (express/courier service) Telephone: (301) 435-5226 FAX: (301) 496-8656 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/95) is to be used in applying for these projects. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: ASKNIH@od.nih.gov. The RFA label available in the PHS 398 (rev.9/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892-7399 Rockville, MD 20850 (for express/courier service) Applications must be received by March 27, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. Budget and Related Issues Applicants are expected to provide a detailed breakdown of the proposed budget to include categorical breakdown of such items as personnel, supplies, consultants, etc. Additional breakdown of such items as set-up cost, cost per STS screening, cost per verified clone, etc. should also be provided. Applicants should include travel funds for the Principal Investigator and the other key investigators on the grant to meet annually with the NCI Program Director, other awardees and maybe the Advisory Committee on "Cancer Chromosome Aberrations" in the Washington D.C. area. Applicants are required to submit a statement about willingness to participate in such activities. REVIEW CONSIDERATIONS General Considerations All applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. The technical merit of the proposed approach for generating the large- insert clone resource is extremely important, although it will not be the sole criterion for evaluation of an application. Other considerations, such as feasibility and merit of the strategy, the timeliness of the release of data and plans for making the mapped large-insert clones accessible, the source of large-insert clones (BAC clones from "approved" libraries are preferred) will be part of the evaluation criteria. Review Method Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NCI. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications may receive a preliminary scientific review by an NCI peer review group to determine their relative competitiveness. The NCI will withdraw from further competition those applications judged to be noncompetitive for an award and notify the applicant Principal Investigator and institutional official. Those applications that are complete and responsive, and judged to be competitive, will undergo further scientific merit review in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NCI. The second level of review will be provided by the National Cancer Advisory Board (NCAB). Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the RFA and their specific protocols, and are expected to address issues identified under SPECIAL REQUIREMENTS of the RFA. The review group will assess the scientific merit of the application and related factors, including: --scientific and technical merit of the proposed project; --appropriateness and adequacy of the experimental approach and methodology proposed to generate a high quality arrayed large- insert clone resource; --qualifications and experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; --availability of the resources/scientific environment necessary to perform the research in a cost effective manner; --appropriateness of methods and demonstrated willingness to work as part of the cooperative production of resource and with the NCI Program Director; --plans to distribute forthcoming resources in a timely manner, preferably with track-record of willingness to release data and reagents; --adequacy of the proposed protection for human subjects; --appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA Applications will be considered for award based upon (1) scientific and technical merit; (2) program balance including, in this instance, sufficient compatibility of features to make a successful collaborative resource a reasonable likelihood and, (3) availability of funds. Schedule Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 27, 1998 Review by NCAB September 1998 Anticipated Award Date: September 30, 1998 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Grace L. Shen, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, 501 Rockville, MD 20892-7381 Rockville, MD 20852 (express/courier service) Telephone: (301) 435-5226 FAX: (301) 496-8656 Email: gs35r@nih.gov Direct inquiries regarding fiscal matters to: Mr. Bill Wells Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892 Rockville, MD 20852 (express/courier service) Telephone: (301) 496-7800, ext. 250 FAX: (301) 496-8601 Email: WW14J@NIH.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.396. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74 [and Part 92 when applicable for State and Local governments. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities ( or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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