Large-Scale, Functional Analysis of the Yeast Genome

Large-Scale, Functional Analysis of the Yeast Genome

Request for Applications

RFA: HG-96-001

National Human Genome Research Institute
National Cancer Institute

Letter of Intent Receipt Date: August 9, 1996
Application Receipt Date: September 6, 1996

This RFA uses the "just-in-time" concept. The full RFA includes detailed modifications to standard application instructions and must be used when preparing applications in response to this area.

Purpose

The DNA sequence of the Saccharomyces cerevisiae genome will be completed in the very near future. The availability of the entire yeast DNA sequence will provide experimental and computational biologists with an incomparable resource for systematic and comprehensive analyses of the genetic basis of biological function including, for example, analyses of gene function, the regulation of gene expression, the interactions between functional and structural elements, and the biological consequences of genomic organization. This Request For Applications (RFA) calls for research projects that will enrich the yeast sequence with biological information in rapid and comprehensive, and efficient ways and/or take advantage of the complete DNA sequence of S. cerevisiae in new, global approaches to the study of biological phenomena important for human health and disease, including cancer. These studies should be based on technologies that are efficient, cost-effective and scalable to the entire yeast genome, and that use and/or add value to the complete DNA sequence. Applications to develop new technologies that could be applied to the yeast genome in a timely manner will also be considered. It is anticipated that these studies will provide functional information, resources and infrastructure that will serve as a platform for more in-depth, specific studies in the future.

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 Request for Applications (RFA), Large-Scale, Functional Analysis of the Yeast Genome, is related to several priority areas, including cancer, heart disease and stroke, diabetes and chronic disability conditions, maternal and infant health, and others. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

Eligibility Requirements

Applications may be submitted by domestic 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. 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.

Streamlining Efforts

This RFA will use the "Just-In-Time" streamlined approach recently introduced at the NIH. 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 NIH staff. Instructions for completing the "Biographical Sketch" have been modified. In addition, "Other Support" information and the application "Checklist" page are not required as part of the initial application. If there is a possibility for an award, this information will be requested by NIH staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions.

Mechanism of Support

This RFA will use the National Institutes of Health (NIH) individual research grant (R01), program project grant (P01) and pilot project/feasibility study (R21) mechanisms. 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 total project period for applications submitted in response to the present RFA may not exceed 3 years and the direct cost per year for R01 or PO1 grants must not exceed $500,000. R21 grants will be limited to $100,000 direct costs per year for a maximum of 2 years. 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 be reviewed according to the customary peer review procedures. The anticipated award date is April 1, 1997.

Funds Available

It is anticipated that approximately $ 2.5 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 might receive dual assignments based on the established PHS referral guidelines.

Research Objectives

Background

A major milestone in genomic and genetic analysis is the imminent completion of the sequence of the yeast Saccharomyces cerevisiae; this will be the first eukaryotic genome to be sequenced in its entirety. This accomplishment will represent the efforts of an international consortium of laboratories in Europe, Canada, Japan and the United States.

S. cerevisiae is an important model organism for the genetic analysis of biological processes because the wide variety of genetic manipulations to which it is amenable readily allow determination of the function of genes and regulatory elements. The relevance of studies in yeast to human biology has been re-emphasized in recent years. There is an increasing number of examples in which homology between yeast and human genes, combined with an understanding of the function of the yeast genes, has allowed significant insight into the function of the human genes. For example, the phenotype of yeast carrying a mutant MSH2 gene was found to be similar to the phenotype of certain human tumor cells; this led to the cloning of the human homolog hMSH2, a gene implicated in one form of hereditary non-polyposis colon cancer (Strand et al., (1993) Nature 365:274-6; Fishel et al., (1993) Cell 75: 1027-38.) Similarly, the study of yeast MEC1 and TEL1 genes has provided insight into the function of the human ATM gene, mutations in which cause ataxia telangiectasia (Weinert et al., (1994) Genes Dev 8: 652-65; Morrow et al., (1995) Cell 82: 831-840). In addition to information about homology relationships, a number of human genes have been shown to function in yeast, allowing new approaches to their study.

The availability of the entire yeast DNA sequence will provide experimental and computational biologists with an incomparable resource for systematic and comprehensive analyses of the genetic basis of biological function. The ability to do these analyses on a genomic level offers the tremendous advantage of economy of scale and will significantly increase the rate at which biological information is acquired. As the DNA sequence of S. cerevisiae is annotated by such information, the increasingly comprehensive understanding of the yeast genome will provide a wealth of information that can be applied to the study of human biology, including genetic diseases and other traits.

Objectives and Scope

To take advantage of the opportunities presented by the new resource that the complete DNA sequence of S. cerevisiae represents, this RFA calls for research projects that will enrich the yeast sequence with biological information in rapid, comprehensive and efficient ways and/or will use the complete DNA sequence in new, global approaches to the study of biological phenomena important for human health and disease, including cancer. These studies should be based on technologies that are efficient, cost-effective and scalable to the entire yeast genome, and that use and/or add value to the complete DNA sequence. Applications to develop new technologies that could be applied to the yeast genome in a timely manner will also be considered. Studies to determine the function of the product of a particular gene or family of genes, or that focus on computational approaches to the analysis of the yeast genome will not be considered under this RFA. Further, this solicitation is limited to studies on S. cerevisiae.

Areas of research encouraged include, but are not limited to:

• Comprehensive studies to determine whether coding sequences identified computationally are transcribed in vivo.
• Comprehensive studies that will provide insight into the biological role that gene products play in the cell.
• Comprehensive studies to elucidate the role of non-coding functional genomic elements.
• Comprehensive studies to elucidate the interactions amongst functional elements of the genome.
• Comprehensive studies to analyze genome organization and its effect on cellular functions.
• Development of new technologies, or refinement of existing technologies that are robust, and provide significant improvements over current technologies, and that can be applied to genomic analyses in a timely manner.
• Development of unique resources to carry out these types of studies.

Applicants should address the following issues:

• How the proposed research approach will use and/or add value to the complete yeast genomic sequence.
• Advantages of the proposed approach over existing approaches.
• Value of the forthcoming data and technology in furthering the understanding of eukaryotic biology.
• Value and exportability of the forthcoming resources.
• How this research will complement related studies.
• 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 accomplishment of funded activities publicly available. The advisors to the NIH and the 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. Investigators may request funds to defray the costs of sharing materials or submitting data in their application. Such requests must be adequately justified.

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 August 9, 1996, 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 NIH staff to estimate the potential review workload and to avoid conflict of interest in the review.

The letter of intent should be sent to:

Elise Feingold, Ph.D.
Mapping Technology Branch
National Human Genome Research Institute
Building 38A, Room 614
38 Library Drive MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
FAX: (301) 480-2770
E-mail: elise_feingold@nih.gov

Application Procedures

The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research or from the Office of Grants Inquiries, Room No. 1040, 6701 Rockledge Drive, Division of Research Grants, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 594- 7248; and from the program director listed under "Inquiries."

To implement the "Just-In-Time" concept, the following modifications are made to the standard PHS 398 application instructions:

• Biographical Sketch: In addition to the standard information requested on Form Page 6, the applicant has the option of providing the title and source of any sponsored support relevant to the proposed research.
• Other Support: No other support information is required on "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete "Other Support" information will be requested by NIH staff at a later date if there is a possibility of an award.
• Checklist: No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NIH staff if there is a possibility of an award.
• The applicant should provide the name, phone number and E- mail address of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review.

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 2a 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
Bethesda, MD 20892
(Express Mail zip code is 20817)

At the time of submission, two additional copies of the application must also be sent to:

Ms. Linda Engel
Office of Scientific Review
National Human Genome Research Institute
Building 38A, Room 604, MSC 6050
38 Library Drive
Bethesda, MD 20892-6050

Applications must be received by September 6, 1996. 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 announcement 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 in accordance with the criteria stated below for scientific/technical merit 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 yeast genomic sequence.
• Feasibility of the experimental approach to carry out the proposed research.
• Value of the forthcoming data and/or technology in furthering the understanding of eukaryotic biology.
• Value and exportability of the forthcoming resources.
• Likelihood that the project 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.
• Complementarity to related studies.
• Adequacy of plans to place data and/or material resources in the public domain in a timely manner.

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 April 1, 1997. Factors that will be used to make award decisions are:

• Quality of the proposed project as determined by peer review.
• Responsiveness of the proposed project to the goals of this RFA.
• 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 the following NIH staff.

For general, genomic research projects:

Elise Feingold, Ph.D.
Program Director
Mapping Technology Branch
National Human Genome Research Institute
Building 38A, Room 614
38 Library Drive MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: elise_feingold@nih.gov

For cancer-related research projects:

Cheryl Marks, Ph.D.
Program Director
Cancer Biology Branch
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 505
Bethesda, MD 20892-7385
Phone: (301) 496-7028
Fax: (301) 402-1037
E-mail: cheryl_marks@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jean Cahill
Grants Management Officer
National Human Genome Research Institute
38 Library Drive
Building 38A, Room 613, MSC 6050
Bethesda, MD 20892-6050
Phone: (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 Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.