Technologies for Genome Analysis

Technologies for Genome Analysis

NIH GUIDE, Volume 25, Number 38, November 8, 1996

RFA: HG-97-001

P.T. 34; K.W. 1215018, 0755045

National Human Genome Research Institute

Letter of Intent Receipt Date: February 27, 1997
Application Receipt Date: March 27, 1997

PURPOSE

The purpose of this Request for Applications (RFA) is to stimulate the development of genomic-scale technologies for the study of genome function and sequence variation. Within the next decade, it is anticipated that the complete DNA sequences of the human and numerous model organisms will be determined and available for comprehensive analysis. The next challenge lies in systematically decoding the genomic information, e.g., finding all the genes and understanding how their gene products function; defining common alleles and haplotypes, and associating them with phenotypes; and analyzing the conservation of genes and other features among species. Such analyses will facilitate the understanding of biological processes important in human health and disease, and the development of improved diagnoses, preventative strategies and therapies.

The tools needed to analyze genomic DNA efficiently are just beginning to emerge and many more robust technologies are needed. The Human Genome Project (HGP) has been successful in generating information and resources rapidly and economically, in part, by developing and applying high-throughput and efficient technologies. Therefore, the National Human Genome Research Institute (NHGRI) seeks the development of technologies that can be applied in similar ways to the rapid and efficient analysis of genome function and sequence variation.

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, Technologies for Genome Analysis, is related to the priority areas of cancer, heart disease and stroke, diabetes and chronic disability conditions, and maternal and infant health. 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 for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, companies, units of State and local governments, and eligible agencies of the federal government. Applications from social/ethnic minority individuals, women, and persons with disabilities are encouraged. Applications from foreign institutions will not be accepted. However, subcontracts to foreign institutions are allowable, with sufficient justification.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual research project grant (R01), program project grant (P01) and exploratory/developmental grant (R21) mechanisms. The total project period for an application submitted in response to this RFA may not exceed three years and the direct cost per year for research project (R01) or program project (P01) grants may not exceed $500,000. Exploratory/developmental (R21) grants will be limited to $100,000 direct costs per year for a maximum of two years. The R21 mechanism is used to support highly creative approaches for which substantial preliminary data are not yet available. Specific information about the R21 grant mechanism can be found in the NHGRI Program Announcement PAR-94-046, "Pilot Projects or Feasibility Studies for Genomic Analysis." The R21 grants are not renewable, but future project continuation is possible through other grant mechanisms such as the R01 or P01. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 1997.

FUNDS AVAILABLE

It is anticipated that approximately $5 million (total costs) will be available for this initiative in fiscal year 1997. Awards pursuant to this RFA are contingent upon the availability of funds for this purpose. The amount of funding for these projects may be increased if a large number of highly meritorious applications are received and if funds are available. Only applications found to be of high scientific merit will be considered for funding and all of the funds will not be spent if there are not enough highly meritorious applications. Funding in future years will be subject to the availability of funds. Because the scope of the research proposed in response to this RFA encompasses the interest of several NIH Institutes and Centers, applications may receive dual assignments based on the established PHS referral guidelines.

RESEARCH OBJECTIVES

Background

The entire DNA sequence of the genomes of several microorganisms, including prokaryotes (H. influenzae and M. genitalium), an archeon (M. jannaschii), and a eukaryote (S. cerevisiae) have recently been determined. Rapid progress has also been made in mapping and sequencing more complex genomes, leading to the expectation that, within the next two to nine years, the DNA sequence of the genomes of C. elegans, D. melanogaster, the human, and perhaps others will be finished. The availability of this information will usher in a new era in biomedical research.

A complete genomic DNA sequence comprises the bounded set of genetic instructions of an organism. Once it has been determined, investigators will have access to every genetic element of that organism. This capability opens unparalleled opportunities to study both genomic function and sequence variation. Understanding both function and sequence variation is essential for a comprehensive understanding of the biology of an organism. The amount of information represented by genomic sequence and the underlying clone and map data is enormous, and investigators will need a wide variety of very robust techniques to make maximal use of these new resources. At present, however, the technology for making use of and interpreting the complete genetic "blueprints" is rather limited.

Novel and improved technologies, developed to be cost-efficient and applicable at a large scale, have, in large measure, been responsible for the success of the HGP in producing detailed genomic maps and large amounts of DNA sequence. Analogous "genomic-scale" technologies will be required for the interpretation of the genomic sequence. Although several of these are beginning to emerge, they require further development; beyond them, many more novel approaches are needed.

Objectives and Scope

The purpose of this RFA is to stimulate the development of novel "genomic-scale" technologies for the study of genomic function and sequence variation. Through this solicitation, NHGRI intends to stimulate the development and implementation of innovative technologies that will facilitate, among other things, the elucidation of the biological roles of gene products and non-coding functional elements; the interactions among functional elements in the cell; the biological consequences of genome organization; the dynamics of polymorphisms in populations; and the functional significance of genomic variation.

This RFA is intended to support the development of technologies that will take advantage of the genomic maps and DNA sequences for use in systematic and comprehensive approaches to the study of genomic function and sequence variation. The technologies needed for these analyses are those that are scaleable, rapid, efficient and take advantage of economies of scale. It is envisioned that when such technologies are applied to large-scale analyses, a genome will become annotated with biologic information that will, in turn, serve as a platform for more in-depth, detailed studies.

The "process" of technology development can be considered to span a spectrum of stages. Initially, it involves the development of an entirely new methodology (or the significant improvement of an existing methodology) to the point of proof of principle. The method must then be reduced to practice. For such a new method to have a significant impact for genomic studies, it must also be shown that it can be used efficiently on a large-scale, or genomic basis, which requires another level of technology development. This RFA is intended to solicit applications that address any of these phases of technology development.

The NHGRI will give priority to the development of technologies that will be used to study the human genome and/or the genomes of  S. cerevisiae, C. elegans, D. melanogaster and M. musculus. Technology development projects that utilize other eukaryotic organisms will be considered, but direct applicability of these technologies to the analysis of the human genome must be evident. An important feature of any newly-developed technology will be the ease with which it can be exported into other laboratories, or in other ways made readily accessible to investigators. The development of computational methods for the study of genomic function and variation is encouraged under this solicitation. Local databases necessary to conduct research funded under this RFA will be supported. The development of public, national databases, however, will not be supported under this RFA. In addition, applications proposing to analyze a particular gene, gene product or non-coding functional element will not be considered under this RFA.

This RFA seeks applications to develop efficient technologies (both experimental and computational) for, but not limited to, the following areas:

• development of single nucleotide polymorphisms in human DNA for genome-wide mapping.
• identification and analysis of sequence variations within and among species to study normal and disease states in humans, and evolution.
• identification of all functional elements (both coding and non-coding) in the genome.
• analysis of the biological role that non-coding functional elements play in the cell.
• analysis of expression of gene products (RNA and/or proteins), e.g., measurement of steady-state levels of gene products in a given cell type, temporal or induced changes in patterns of gene product levels, or comparative levels of gene product in different cell types.
• analysis of the biological role that gene products (RNA and/or proteins) play in the cell, e.g., analysis of cellular localization of proteins, protein-protein or protein-nucleic acid interactions or comparative analysis of protein sequences and/or structures.
• analysis of genome organization and its effect on cellular functions.

These examples are illustrative and should not be viewed as limiting in any way. Novel and innovative technologies to all areas of genome analysis are sought.

Applicants should address the following issues:

• advantages of the proposed approach over existing approaches.
• value of the technology in furthering the understanding of eukaryotic biology.
• plans for making data and resources broadly accessible.

The sharing of materials and data in a timely manner has been an essential element in the rapid progress 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 Department of Energy (DOE) genome programs have developed a set of guidelines for making data and material resources available to the scientific community in a timely manner. The guidelines call for material and information from genome research to be made available within six months of the time the data or materials are generated; more rapid sharing is encouraged and has become the norm in the genome community. Applications submitted in response to this RFA should include detailed plans for sharing data and materials generated through the grant. Where appropriate, grantees may work with the private sector in making unique resources 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 NIH staff prior to award of the grant and the proposed sharing plan will be made a condition of the award. Applicants may request funds to defray the costs of sharing materials or submitting data. Such requests must be adequately justified.

Recently, it has become evident that special human subjects issues are raised by the large-scale sequencing of human genomic DNA because large amounts of DNA sequence information from single individuals may be generated. The NHGRI and the DOE have recently issued a document, "Guidance on Human Subjects Issues in Large-Scale DNA Sequencing" to address these issues. As a result of the research supported under this RFA, it is possible that an analogous situation might exist, i.e., that a large amount of information about a single individual's genome might be generated and be made publicly available. Applicants should address these special human subjects issues, if applicable.

LETTER OF INTENT

Because of the specialized interest of this RFA, prospective applicants are strongly encouraged to discuss their research objectives and the appropriate grant mechanism with NIH staff. Prospective applicants are asked to submit, by February 27, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the principal investigator, and the identities of other key personnel and participating institutions.

Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NHGRI 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:

Elise Feingold, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 614, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: Elise Feingold, Ph.D.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, e-mail ASKNIH@odrockm1.od.nih.gov and from the program director listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 5/95) 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 and three signed photocopies, in one package to:

Division of Research Grants
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, including appendices, must also be sent to:

Dr. Ken Nakamura
Office of Scientific Review
National Human Genome Research Institute
Building 38A, Room 613, MSC 6050
38 Library Drive
Bethesda, MD 20892-6050

Applications must be received by March 27, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. The applicants should also ensure that their revised applications respond to the review criteria by which the applications in response to this RFA will be evaluated.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness to the RFA by NIH program staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIH staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle.

Those applications that are complete and responsive will be evaluated for scientific/technical merit in accordance with the criteria stated below by an appropriate peer review group convened by the NHGRI. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed and assigned a priority score. All applications will receive a second level of review by the National Advisory Council for Human Genome Research.

Review criteria will include:

• scientific and technical merit of the proposed research.
• extent to which the experimental approach makes use of and/or adds value to the complete genomic sequence.
• value of the forthcoming data and/or technology in furthering the understanding of eukaryotic biology.
• value and exportability of the forthcoming methodologies and resources (for software tools, portability at the source code level).
• likelihood that the technology will be able to scale to a genomic level efficiently and in a timely manner.
• qualifications and research experience of the principal investigator and staff in the area of the proposed research.
• availability of the resources necessary to perform the research.
• appropriateness of the proposed budget and duration in relation to the proposed research.
• adequacy of plans for dissemination of software tools developed under grant support.
• adequacy of plans to place data and/or material resources in the public domain in a timely manner.
• adequacy of plans to protect human subjects, if applicable.

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

The earliest anticipated date of award is September 30, 1997. Factors that will be used to make award decisions are:

• quality of the proposed project as determined by peer review.
• balance among the projects in addressing different experimental approaches and their complementarity to other ongoing efforts.
• adequacy of data/material release plan.
• availability of funds.

Post-award Management

During the course of the grant period, technologies will improve and the rate of progress and focus of work supported by the grant(s) may change. It is expected that the principal investigator(s) will make any necessary adjustments in scientific direction to accommodate the changing environment. During the course of the award period, the principal investigator(s) may be invited to meet with NIH program staff in Bethesda, MD to review scientific progress. Other scientists external to and knowledgeable about these studies may also be invited to participate.

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:

For biological research projects on genome function:

Elise Feingold, Ph.D
Division of Extramural Research
National Human Genome Research Institute
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: Elise Feingold, Ph.D

For biological research projects on sequence variation:

Bettie J. Graham, Ph.D
Division of Extramural Research
National Human Genome Research Institute
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: Bettie J. Graham, Ph.D

For all computational research projects:

David Benton, Ph.D.
Genome Informatics Program
National Human Genome Research Institute
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: David Benton, Ph.D

Direct inquiries regarding fiscal matters to:

Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
Building 38A, Room 613, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 402-0733
Fax: (301) 402-1951
E-mail: Ms. Jean Cahill

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 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.