This Program Announcement expires three years from the Release Date shown directly below. TECHNOLOGIES FOR CLOSING DNA SEQUENCE GAPS AND IMPROVING METHODS FOR OBTAINING THE SEQUENCE OF DIFFICULT-TO-SEQUENCE REGIONS Release Date: June 27, 2000 PA NUMBER: PAS-00-112 National Human Genome Research Institute THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Human Genome Research Institute (NHGRI) invites applications to develop strategies and technologies for obtaining DNA sequence in the gaps that, due to limitations in available cloning and sequencing technology, will remain in essentially finished genomic sequence. Such gaps may arise from an inability to clone a region in any available vector system or to an inability to obtain sequence from all or part of an available clone. Such gaps that remain have been encountered in every large genome sequencing effort to date. NHGRI is encouraging development of novel approaches that will allow completion of the DNA sequence within the gaps that are left by current sequencing methods and that will improve the efficiency of sequencing in genomic regions that have proved difficult to sequence. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Program Announcement (PA), Technology for Closing DNA Sequence Gaps, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) regular research grant (R01) and exploratory/developmental grant (R21) mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed three years. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE Approximately $2 million is available for funding grants directed at this problem and five to ten awards may be made during the first year of the program, contingent upon the availability of funds and receipt of a sufficient number of high quality applications. The anticipated award dates are December 1, April 1 and July 1. This program announcement will be in effect for three years; additional announcements to continue this program may be issued in the future. RESEARCH SCOPE AND OBJECTIVES BACKGROUND The NHGRI is currently engaged, along with several other federal, private, and international organizations, in a multi-year research program called the Human Genome Project (HGP). Many of the initial goals of the HGP, including genetic and physical maps of the mouse and human, and the DNA sequences of E. coli, S. cerevisiae, C. elegans and D. melanogaster, have been realized. A working draft version of at least 90% of the euchromatic part of the human genome will be completed in 2000, and the complete high quality human sequence will follow within the next couple of years. By the end of May 2000, more than 20% of the human sequence had been finished, including all of chromosomes 21 and 22, and approximately 90% of the genome was in "working draft" form. Mouse genome sequencing has also begun; an intermediate version will be generated within the next couple of years and the complete sequence will follow by 2005 or sooner. In the course of trying to complete the sequence of some of the larger genomes such as that of C. elegans and human chromosomes 21 and 22, investigators have encountered a number of regions that they have not been able to finish with their current capabilities, resulting in gaps in the otherwise finished, contiguous high-quality sequence. There are a number of problems that lead to gaps. Certain genomic regions apparently cannot be cloned in any of the large-insert vectors routinely used in high-throughput sequencing (BACs, PACs, or cosmids) or the other large-insert vectors sometimes used to complement these systems (e.g., YACs or fosmids). Gaps may also originate from the inability of shorter regions to be cloned into the smaller sequencing vectors (plasmids, M13) routinely used for subcloning or in whole-genome shotgun approaches. Finally, small gaps may arise when currently available sequencing chemistries are unable to completely read through the sequence of an available clone. The reasons for these small gaps may include the presence of repetitive elements, high GC content, high AT content, or other sequence features. Thus, despite the best efforts of genome sequencing centers to use all available methods, some gaps have remained refractory to closure, apparently due to the limits imposed by the current technology. In recognition that such problematic regions exist, the standard that has been adopted by the international sequencing effort for declaring that the sequence of a genome is "essentially complete" is that the sequence of all regions that can be cloned in standard vectors has been determined, and that all remaining gaps have been mapped, sized, and annotated. Thus, for example, the published chromosome 22 sequence (Nature 402:6761 (1999)) actually contains eleven gaps for which sequence could not be obtained, because clones covering the regions could not be found despite considerable effort to find them in several clone libraries. These gaps were sized and shown to be small. The published chromosome 21 sequence included three clone gaps and seven sequencing gaps (Nature 405: 311 - 319 (2000)). In addition, genomic sequencing projects have also encountered numerous regions that, although they can be closed, require significant and prolonged efforts to do so. The genomic sequencers have developed numerous techniques/strategies that can be applied to these regions. These include directed sequencing using oligonucleotide primers, the construction and sequencing of very short insert shotgun libraries ("shatter" libraries), transposon-based approaches, PCR sequencing across gaps, and the use of alternative sequencing chemistries. Similarly, a certain amount of experience in sequencing highly repeated regions has been obtained. This has allowed the sequencing of the large tandem repeats in the C. elegans genome that are similar to centromeres in other organisms, although even in these cases it has not been possible to determine if the repeats have been entirely covered. Other focused efforts to sequence centromeres in Arabidopsis and Drosophila have found that some sequencing of centromeric DNA has been possible and have revealed very interesting results. The existence of genes in such regions has been documented, and data that have contributed to the understanding of centromere function have been obtained. SCOPE Overall, there are at present no methods that can be successfully used to resolve all difficult-to-sequence regions, and there are still regions that cannot be sequenced by any available method in almost every large genome sequenced to date. The purpose of this solicitation is to stimulate the development of novel, innovative approaches to the sequencing of regions that are currently refractory, or very difficult, to sequence by existing methods. In order to provide access to clones containing regions that contain gaps or DNA that was difficult to sequence, the large-scale sequencing centers have provided lists of clones containing such regions that are posted at http://www.nhgri.nih.gov/About_NHGRI/Der/gapPA.html. Investigators applying for this PA may use this information to find clones on which they may develop and demonstrate their strategy/technology. This PA is limited to proposals to develop and obtain proof of principle for new technologies, rather than to large-scale application of any method. Support for production-scale application of methods developed through this PA should be sought through a subsequent, separate program. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLs IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Applications will be accepted at the standard application deadlines as indicated in the application kit. Application 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 301/435-0714, email: GrantsInfo@nih.gov. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the Institute staff that the Institute will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998, at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev 4/98) is to be used in applying for these grants, with modifications noted below. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request Direct Costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE- Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) Costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative Page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the Total Direct Costs requested for each year. This is not a Form Page. o PERSONNEL - List key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. o CONSORTIUM/CONTRACTUAL COSTS - Provide an estimate of total costs (direct plus F&A costs) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and their role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. o Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm o Complete the educational block at the top of the form page; o List position(s) and any honors; o Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; o List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A Costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The title and number of this program announcement 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 five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o For R21 applications, preliminary data are not required. However, the applicant does have the responsibility for developing a sound research plan and for presenting any other information that can be considered as evidence of feasibility. Award Criteria Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jane L. Peterson, Ph.D. Division of Extramural Research National Human Genome Research Institute 31 Center Drive, Room B2B07 Building 31, MSC 2033 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: Jane_Peterson@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jean Cahill Grants Management Office National Human Genome Research Institute 31 Center Drive, Room B2B34 Building 31, MSC 2031 Bethesda, MD 20892-2031 Telephone: (301) 402-0733 FAX: (301) 402-1951 E-mail: Jean_Cahill@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.172. 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 52 and 45 CFR Part 74. 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 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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