Full Text PA-94-045 NEW AND IMPROVED TECHNOLOGIES FOR GENOMIC RESEARCH AND ANALYSIS NIH GUIDE, Volume 23, Number 10, March 11, 1994 PA NUMBER: PA-94-045 P.T. 34 Keywords: Human Genome Nucleic Acid Sequencing National Center for Human Genome Research PURPOSE [This program announcement supersedes the previous announcement that was published in the NIH Guide to Grants and Contracts, Vol. 21, No. 9, Part 2 of 2 parts, March 6, 1992.] The National Center for Human Genome Research (NCHGR) invites applications to support research that will significantly advance progress toward achieving the extended scientific goals of the Human Genome Program (HGP). These goals are described in the article, "A New Five-Year Plan for the U.S. Human Genome Project" (Science, vol. 262, p. 43-46), which covers the years 1994-1998. Because of the need to increase the rate and efficiency and to lower the cost of mapping and sequencing, the main focus of this program announcement is to solicit projects directed to the development of new or the significant improvement of current methods, strategies and technologies for mapping, sequencing, informatics and gene identification. ELIGIBILITY REQUIREMENTS Domestic and foreign universities, medical colleges, hospitals, corporations, and other public, private, or for-profit research institutions, including state and local government units, are eligible. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minorities, women, and individuals with disabilities are especially encouraged. MECHANISM OF SUPPORT Support for this program will be through research grants, including research project grants (R01) and FIRST (R29) awards. BACKGROUND The National Institutes of Health (NIH) is currently engaged, along with several other federal, private, and international organizations, in a 15-year research program designed to characterize the human genome and the genomes of selected model organisms. This research program, the Human Genome Project (HGP), has the following interrelated goals: 1. the construction of high-resolution genetic linkage maps; 2. the development of detailed physical maps; 3. the determination of the complete nucleotide sequence of the human genome and the genomes of selected organisms; 4. the development of efficient methods of identifying genes and for placement of known genes on physical maps or sequenced DNA; 5. the development of the capability to collect, store, distribute and analyze the data and materials produced; 6. the development of appropriate new technologies to achieve these goals; and 7. the identification of major issues related to the ethical, legal and social implications (ELSI) of genome research, and the development of policy options to address them. The products of the Human Genome Project will include information and material resources, as well as new technologies, that will be available to the entire research community to facilitate further research leading to the prevention, diagnosis, and therapy of disease, as well as to further understanding of human biology. In 1990, the NCHGR and the Department of Energy (DOE) jointly published a plan that set out specific goals to be achieved in the first five-year phase of the U.S. human genome program. Anticipating the attainment of much of the initial set of goals, the NCHGR and DOE recently published the above-referenced new five-year plan extending the goals for the U.S. Human Genome Project. In particular, the new plan recognizes the need for further substantial improvements in technology in all areas of genomic research if the goals are to be reached, particularly in the area of sequencing technology. The objectives of this program announcement are to encourage investigators who have creative and innovative ideas to participate in the HGP and to solicit research projects that address the scientific goals of the HGP, particularly those that address the development of new, or improvement of existing, technology that will facilitate and accelerate achievement of both the short- and long- term scientific goals of the Human Genome Program in the most expeditious and cost-saving manner. RESEARCH OBJECTIVES Technologies for Improving Physical Maps An STS map of the human genome at a resolution of 100 kilobases remains an important goal of the U.S. human genome project. Such a map will be extremely useful for isolating and characterizing individual genes and other DNA regions of interest. An appropriate physical map will also be a pre-requisite for large-scale DNA sequencing. With respect to both uses, the quality of the map, i.e., the degree to which it faithfully represents genomic DNA, is critical. In order to achieve a fully connected, high quality physical map of the human genome, research projects in the following areas are encouraged: 1. Efficient and rapid methods to isolate and map additional STSs to achieve a resolution of 100 kilobases. The incorporation of STSs with added value (e.g., representing expressed sequences) is encouraged to the extent that it is consistent with the objective of efficiently identifying STSs and incorporating them into the map; 2. Development of methods to accurately measure physical distances between markers on cloned and genomic DNA; 3. Development of new vector systems for mapping and sequencing; 4. Construction of clone libraries in which the DNA inserts are large, stable, free of artifacts, and faithfully represent genomic DNA; 5. Development of methods or strategies to assemble contigs of cloned DNA rapidly and accurately; and 6. Development of methods and strategies to solve the problem of closure. Advanced Sequencing Technologies The goal of the HGP is not only to complete the sequence of the human genome within the projected 15 years, but to do so with technology that will make it possible to sequence large regions of DNA, such as other genomes, rapidly and inexpensively. Achieving this goal will require the development and testing of significantly improved sequencing technology within the next several years. Increasing the overall rate of DNA sequence accumulation at least two-fold per year for the next several years will be necessary to reach the HGP's sequencing objectives. Currently, the maximum rate of sequencing of large contiguous sections of DNA by the community is approximately two megabases per year; the newly stated goal is to increase that rate to 50 Mb per year by 1998. Research projects are encouraged in the following areas: 1. Development of new approaches to DNA sequencing that offer substantial increases in the rate and cost-effectiveness of sequencing of complex genomes; 2. Significant improvement in current DNA sequencing technologies for large-scale application, with an emphasis on improving cost- effectiveness, exportability (capability of being readily adopted by additional laboratories), and assessment of the accuracy of determined sequence; 3. Development of highly automated systems for DNA sequencing, with emphasis on the integration of all process steps from preparation of DNA through sequence assembly, finishing and correcting. Only applications that aim to develop new technology or to significantly improve current technology should be submitted in response to this Program Announcement. Applications for routine sequencing will not be supported. Applications to develop sequencing capacities on the order of one to a few megabases per year should be submitted in response to the program announcement, "Genome Science and Technology Centers (GESTEC)," NIH Guide to Grants and Contracts, Vol. 23, No. 10, March 11, 1994. Technologies for Refining Genetic Linkage Maps Several current efforts, both genome-wide and chromosome-specific, are expected to allow the timely completion of the 2 to 5 centimorgan human genetic linkage map that was called for in the initial five- year plan. The extended five-year goal for linkage mapping calls for further improvement of genetic mapping technologies, such as the development of methods for rapid genotyping, and the development of new, easier-to-use markers. To facilitate the refinement of the genetic linkage map, to maximize its usefulness and to develop technology for high throughput genotyping, applications are encouraged in the following areas: 1. Development of new DNA-based markers that can readily be incorporated into existing maps and that are amenable to automated analysis; special attention should be given to map closure, the development of methods and strategies to develop DNA-based markers to fill in gaps between markers that are greater than 5 centimorgans apart; 2. Development of novel, marker-independent mapping technologies to facilitate accurate and rapid analysis of whole genomes or megabase regions of genomes; and 3. Development of high-throughput genotyping technologies that are accurate, rapid, efficient, and cost-effective. New Technologies for Gene Identification One of the long-range objectives of the Human Genome Program is to identify all coding sequences, genes and other functional elements in genomic DNA. Given that physical maps are being rapidly assembled and that the rate of accumulation of large-scale sequence data is increasing, there is a critical need for robust, high-throughput, and cost-effective methods and strategies to identify and map functional elements in the genome. Demonstration projects in the following areas are encouraged: 1. Development of methods for rapidly identifying and efficiently mapping all coding regions, genes and other functional elements in genomic and cloned DNA on the order of several megabases or greater in size. 2. Development of new methods of generating and efficiently mapping high quality, full-length cDNAs and constructing representative cDNA libraries. Informatics The Human Genome Program will generate mapping and sequencing data from many laboratories. While some computer tools and information systems for handling these types of data exist, there is a continuing need to develop and improve appropriate computer tools and information systems for the collection, storage, retrieval and distribution of mapping and sequencing data. In addition to the development of databases, it will be necessary to develop new methods and tools for the analysis and interpretation of genome maps and DNA sequences. Research projects are encouraged in the following general areas: 1. Development of effective database management systems to support large-scale mapping and DNA sequencing projects -- such projects should be undertaken in the context of actual mapping and sequencing efforts; 2. Creation of database and/or software tools that provide easy access to up-to-date physical and genetic mapping and DNA sequencing information and allow linkage or integration of these specific data sets; 3. Development of analytical tools that can be used in the assembly, analysis, and interpretation of genomic data; and 4. Development of technology to accelerate the collection, storage, retrieval, analysis and distribution of mapping and sequencing data. Because of the need to provide many of these resources to the larger scientific community, applications may request funds for distribution of software and database designs and for maintenance and user- support. Such requests must be adequately justified in the application. These research topics supplement those described in the program announcement, "Genome Informatics Program," which was published in the NIH Guide to Grants and Contracts, Vol. 21, No. 12, March 27, 1992. Model Organisms The mapping and sequencing of the genomes of model organisms are central to the goals of the HGP. In the initial five-year plan, the mapping and sequencing of the genomes of E. coli, S. cerevisiae, C. elegans, D. melanogaster, and the laboratory mouse were identified as goals of the model organism component of the U.S. HGP for two reasons. Because of the conservation of gene information, a comprehensive analysis of the genomes of these organisms will contribute significantly to our understanding of the human genome. Model systems are also useful in the development of new analytical technologies applicable to the analysis of the human genome. Sufficient progress has been made so that the physical maps of the four non-mammalian systems are essentially complete or close to completion. The sequencing of the DNAs of those organisms is under way and the extended goals call for the completion of the E. coli and S. cerevisiae sequences by or before 1998, for the C. elegans sequence to be approaching completion by 1998, and for the D. melanogaster sequence to be approaching completion by 2000. Applications that propose to contribute to the sequencing of the genomes of any of these organisms must address the way in which a new project would interact with or take into account any existing sequencing programs with similar objectives. Similarly, an application that proposed to contribute to the physical map of the mouse genome must address the way in which it would interact with existing mapping programs. As for sequencing mouse DNA, the extended goals for the HGP emphasize the usefulness of parallel sequencing of homologous regions of mouse and human DNA. Applicants may also propose to study model systems other than those listed. The choice of organism, however, must be justified as contributing significantly to achieving the overall objectives of the HGP, must have technology development as the primary focus, and must be applicable to the analysis of the human genome. Additional Considerations In planning research projects, applicants are strongly encouraged to consider the following: Interdisciplinary Research. The problems that must be solved in genomic analysis may require technically demanding solutions. Accordingly, interdisciplinary approaches are particularly appropriate. The NCHGR strongly encourages interdisciplinary collaborations, which may involve biologists from various sub- disciplines, as well non-biologists, such as chemists, physicists, mathematicians, information scientists and engineers. Sharing of Materials and Data. The sharing of materials and data in a timely manner is essential for optimal progress towards the goals of the HGP, for avoiding unnecessary duplication, and for facilitating application of genome resources in other areas of biomedical research. Public Health Service (PHS) policy requires that investigators make the results and accomplishments of funded activities publicly available. The advisors of the NIH and the DOE genome programs have also developed a set of "NIH-DOE Guidelines for Access to Mapping and Sequencing Data and Material Resources" that address the special needs of the HGP. The guidelines call for materials and information from HGP-supported projects to be made available within six months from the time the data or materials are generated; more rapid sharing is encouraged. The guidelines are available from the NCHGR staff listed below. Applications submitted in response to this program announcement should include plans for sharing data and materials, for example by depositing cell lines, probes, sequence data, etc. into appropriate repositories. Where appropriate, grantees may work with the private sector in making unique resources, such as cloned libraries and probe screening services, available to the larger biomedical research community at reasonable cost. The plans for sharing will be reviewed for adequacy by NIH staff and the National Advisory Council on Human Genome Research prior to award of a grant and the proposed sharing plan will be made a condition of the award. Investigators may request funds to defray the costs of sharing materials or submitting data to repositories in their applications. Such requests must be adequately justified. Instrumentation. Proposals for instrument development are expected to address the issues of access to any instruments developed through this program. In projects where automation, robotics and/or software development are key components, investigators should specifically address the issues of (1) exportability to other laboratories, (2) access of other investigators to unique instruments, and (3) integration of individual components into systems. Additional Considerations. In order to achieve the goals of the HGP, applications that propose to develop new approaches and strategies to mapping and sequencing problems, as well as those that propose creative, novel, high-risk/high-payoff strategies are highly encouraged. All researchers applying for support should (l) address how the proposed research will help accomplish the current five-year goals as well as the long-range goals; (2) discuss incorporation of new approaches and/or technology into any mapping or sequencing strategy; (3) approach the problem in a comprehensive manner, irrespective of the size of the project; and (4) propose adequate plans for managing data, interacting and collaborating with the rest of the scientific community working on similar or related objectives, and making data and resources publicly available in a timely manner. APPLICATION PROCEDURES Applications submitted in response to this program announcement will be reviewed in accordance with the usual NIH peer review procedures. Applications are to be submitted on the grant application form PHS 398 (Rev. 9/91). Submission dates for new applications are February 1, June 1, and October 1; competing continuation applications and amended applications are accepted on March 1, July 1, and November 1. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. The title and number of this program announcement must be typed in Item 2a on the face page of the application. Applicants for R29 awards must include in the application three letters of reference and a letter or memorandum from an appropriate department head or dean. The completed original application and five legible copies must be delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will first be reviewed for scientific and technical merit by an appropriate study section in the Division of Research Grants. Following the initial scientific review, applications will receive a second-level review by the appropriate National Advisory Council or Board. o Review criteria that will be used to assess the scientific merit of an application are: o Significance and originality of the research and methodological approaches; o Feasibility of the research and adequacy of the experimental design; o Training, experience, research competence, and commitment of the investigator(s); o Adequacy of the facilities and resources; and o Appropriateness of the requested budget for the work proposed. AWARD CRITERIA Applications assigned to the NCHGR will compete for available funds with all other approved applications assigned to the NCHGR. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review and potential for developing technology or strategies that will accelerate progress in mapping and sequencing the human genome; o Value of the proposed research for achieving the research goals of the NCHGR, while maintaining programmatic balance in the NCHGR grant portfolio; o Adequacy of any plans proposed for managing data and sharing data, resources and technology in a timely manner; and o Availability of funds. In addition to the above award criteria, applications from foreign institutions must present special opportunities for research accomplishments that are not readily available in the United States. INQUIRIES The program staff and grants management officer welcome the opportunity to discuss the program interests and PHS grant policy, respectively, with prospective applicants and current grantees. Telephone, electronic and/or written inquiries are strongly encouraged. Specific questions regarding the following programmatic areas should be directed to: Technology development for physical mapping and gene identification: Dr. Bettie Graham, Chief, Mapping Technology Branch Internet: Bettie_Graham@occshost.nlm.nih.gov Dr. Elise Feingold, Program Director, Mapping Technology Branch Internet: Elise_Feingold@occshost.nlm.nih.gov Large-scale sequencing and mapping of the mouse and human genomes: Dr. Jane L. Peterson, Chief, Mammalian Genomics Branch Internet: Jane_Peterson@occshost.nlm.nih.gov Dr. Jeffery Schloss, Program Director, Mammalian Genomics Branch Internet: Jeffery_Schloss@occshost.nlm.nih.gov Sequencing technology development; large-scale mapping and sequencing of non-mammalian genomes: Dr. Robert Strausberg, Acting Chief, Sequencing Technology Branch Internet: Robert_Strausberg_@occshost.nlm.nih.gov Dr. Carol Dahl, Program Director, Sequencing Technology Branch Internet: Carol_Dahl@occshost.nlm.nih.gov Informatics: Dr. David Benton, Assistant to the Director for Informatics Internet: David_Benton@occshost.nlm.nih.gov The address and telephone number for the staff listed above are: National Center for Human Genome Research Building 38A, Room 610 Bethesda, MD 20892 Telephone: (301) 496-7531 FAX: (301) 480-2770 Inquiries about grants management/policy issues may be directed to: Ms. Jean Cahill Grants and Contracts Management Branch National Center for Human Genome Research Building 38A, Room 613 Bethesda, MD 20892 Telephone: (301) 402-0733 Related NCHGR Program Announcements Information about other NCHGR grant programs can be found in the following program announcements: Pilot/High Risk Projects. NIH Guide for Grants and Contracts, Vol. 23, No. 10, March 11, 1994. Genome Science and Technology Centers (P01 and P50 mechanisms). NIH Guide for Grants and Contracts, Vol. 23, No. 10, March 11, 1994. Ethical, Legal and Social Implications Projects. NIH Guide for Grants and Contracts, Vol. 19, No. 4, 1990. Training. NIH Guide for Grants and Contracts, Vol. 20, No. 46, December 12, 1991. Research Career Development. NIH Guide for Grants and Contracts, Vol. 20, No. 34, Part 1, September 13, 1991. Supplements for Minorities and Individuals with Disabilities. NIH Guide for Grants and Contracts, Vol. 21, No. 3, January 24, 1992. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.172. Awards will be made under the authority 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 Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirement of Executive Order 12372 or to Health Systems Agency review. .
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