Technologies for Genomic Mapping, Sequencing and Analysis

NIH GUIDE,Volume 26, Number 8, March 14, 1997

PA NUMBER: PA-97-044
Full Text: PA-97-044

P.T.34

National Human Genome Research Institute
National Institutes of Health

NOTE: This program announcement supersedes the following two program announcements: (PA-94-045) New and Improved Technologies for Genomic Mapping and Sequencing, NIH Guide for Grants and Contracts, Vol. 23, No. 10, March 11, 1994 and (PA-92-59) Genome Informatics Program, NIH Guide for Grants and Contracts, Vol. 21, No.12, March 27, 1992.

Keywords:
0755044
0744045

PURPOSE

The National Human Genome Research Institute (NHGRI), formerly the National Center for Human Genome Research, solicits applications for research projects to develop new technologies, and/or significantly improve existing technologies, that will facilitate and accelerate the genome mapping, sequencing and analysis goals of the Human Genome Project (HGP) in the most expeditious and economical manner. The resources produced will be used to further studies of diseases and other biological phenomena.

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. Foreign organizations are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards or program project (P01) grants.

MECHANISM OF SUPPORT

Support for this program will be through research project grants (R01), FIRST awards (R29), and program project grants (P01).

RESEARCH OBJECTIVES

Background and Objectives

The NHGRI is currently engaged, along with several other federal, private, and international organizations, in a 15-year research program called the Human Genome Project (HGP). The goals are to characterize the genomes of human and selected model organisms, to develop technologies to analyze the human genome, to examine the ethical, legal, and social implications of human genetics research, and to train scientists who will be able to utilize the tools and resources developed through the HGP to pursue biological studies that will improve human health.

Significant progress toward completing these goals has been made in the past six years, with several having already been achieved. The genetic mapping goals for both the human and the mouse have been met. Progress toward the human and mouse physical mapping goals is steady, with sufficient support in place to allow the achievement of these goals ahead of schedule. The NHGRI continues, however, to be interested in improving mapping technologies, particularly for high-throughput genotyping, expansion of genetic maps to higher density, and construction of high resolution physical maps that can serve as sequencing substrates.

There has also been good progress toward completing the sequencing goals. The genomic sequence of both E. coli and S. cerevisiae have been determined (as have the sequences of several microbes that were not designated targets of the HGP), the sequence of C. elegans is expected to be finished by 1998, the complete sequence of D. melanogaster is expected to be finished shortly after the end of this century, and the genomic sequence of the human and substantial portions of the mouse genome are expected to be finished by 2005, the original target date. However, further reductions in sequencing costs and increases in throughput are needed, both to complete the human DNA sequence as inexpensively and accurately as possible, and to support the critical role that DNA sequencing will continue to play in biological research after the achievement of the goals of the HGP. Therefore, new approaches and technologies for both de novo sequencing and resequencing, as well as for optimization and integration of existing technologies, are still needed.

Given the progress to date, increased attention is now being paid to the functional analysis of genomic DNA sequence, including the identification and understanding of all coding sequences, regulatory and other functional elements in genomic DNA from both human and selected model organisms. While a few technologies for functional analysis on a genomic basis are being developed at present, additional approaches and technologies for genomic interpretation that can be applied efficiently and economically at the level of an entire genome will be required for comprehensive analyses.

Informatics will continue to play an important role in achieving all of these goals, as well as in ensuring the maintenance and accessibility of the forthcoming data. The development and application of new technologies for acquisition, management, analysis, and dissemination of genomic data are still required.

Scope

The NHGRI is interested in supporting technological advances in the following areas of research:

Refining Genetic Maps;
Analyzing Sequence Variation in Genomic DNA;
Improving Physical Maps;
Reducing the Cost of Genomic DNA Sequencing;
Interpreting Genomic Sequence; and
Improving Data Analysis and Management.

Each of these areas is described below and examples of research that would be appropriate under this Program Announcement are listed. These lists are not meant to be all-inclusive. Projects addressing other research problems will be considered as long as they address the current or long-term goals of the HGP. What is most important is that applicants propose to develop new technology, or to significantly improve existing technologies, that will facilitate and accelerate genomic mapping, sequencing and analysis in an expeditious and economical manner.

Technologies for Refining Genetic Maps

Currently, the best genetic maps are based on microsatellite markers. Further improvement of genetic mapping technologies, such as the development of methods for rapid genotyping and the development of new, easier-to-use markers, is needed.

Examples of research that address this goal are:

Development of efficient technologies to generate DNA-based markers that are amenable to automated analysis.
Development of new mapping technologies for accurate and rapid analysis of whole genomes or megabase regions of genomes.
Development of high-throughput genotyping technologies that are accurate, rapid, efficient, and cost-effective.
Development of improved analytical methods for computing genetic maps and for mapping genomic regions responsible for complex phenotypes.

Technologies for Analyzing Sequence Variation in Genomic DNA

The first reference human genomic sequence will be completed within the next decade. This sequence will be a mosaic, being derived from several individuals whose DNA was used to construct clone libraries for sequencing. Having the reference sequence will provide experimentalists and computational biologists with a rich source of information about the basic structure of the genome. However, knowledge of sequence variation, both between individuals and between species, will be useful for the pursuit of many studies, including the genetic basis of complex phenotypes, gene function, population genetics, molecular evolution, diagnostics development, and treatment design and evaluation. Examples of research that address this goal are:

Development of efficient technologies for rapidly identifying the nature and extent of sequence differences in human genomic DNA.
Development of technology to identify and analyze sequence variation within and among species.

Technologies for Improving Physical Maps

Resources are in place to complete the construction of a sequence tagged site (STS) map of the human genome at a resolution of 100 kilobases. However, new conceptual approaches to constructing physical maps of the genomes of other organisms and for constructing higher resolution maps for DNA sequencing are needed. Examples of research that addresses this goal are:

Methods for the construction of clone libraries with DNA inserts that are large, stable, free of artifacts, and faithfully representative of genomic DNA.
Methods for efficient, accurate and rapid generation of high resolution physical maps.
Methods for accurately measuring physical distances between markers on cloned and genomic DNA.

Technologies for Genomic DNA Sequencing

The sequencing goals of the HGP include both the complete sequencing of the genomes of the human and specific model organisms within the projected 15 years and substantial improvement of sequencing technology. Improved technology is needed for two reasons - to rapidly and inexpensively sequence other genomes (de novosequencing) and to determine sequence variation between large numbers of individuals (re-sequencing). A wide range of technological issues require attention, including automation, system and process integration, miniaturization, parallelization, sequencing accuracy and efficient integration between physical mapping and sequencing. Examples of research that address this goal are:

Development of new approaches to genomic sequencing.
Improvement in current DNA sequencing technologies for high-throughput application, with an emphasis on improving cost-effectiveness.
Development of quantitative methods for assessing the local and long-range accuracy of DNA sequence.

Applications for large-scale sequence production will not be considered responsive to this Program Announcement. Applicants who wish to pursue large-scale production sequencing should discuss their interest with program staff.

New Technologies for the Interpretation of Genomic Sequences

Within the next decade, the genomic sequence of both the human and many non-human organisms will become available for comprehensive analysis. A major challenge will be finding all genes, regulatory elements and other functional elements in the genomic sequences. Understanding how these genetic elements function presents an ever larger challenge. To accomplish this analysis systematically and efficiently, robust, high-throughput, cost-efficient strategies and methods will be required. It can be expected that, as in the past, both experimental ("wet bench") and computational approaches will fruitfully be applied to the identification and analysis of genomic features and functions. Several technologies to monitor gene expression on a genome-wide basis are beginning to emerge and these require further development.

Additional novel approaches are needed to facilitate both biological and computational approaches to genome interpretation. Projects that address this goal should focus on technology development and be amenable to large-scale analysis and genome-wide studies. Examples of research that address this goal are:

Improvement of technology for the generation of high quality, full-length cDNAs and the construction of representative cDNA libraries.
Development of technology for the identification and/or mapping of all functional elements (both coding and non-coding) in a genome.
Development of methods for the identification of the biological role that non-coding functional elements play in the cell.
Systematic identification 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.
Development/improvement of technology for the analysis of the expression patterns 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 products in different cell types.
Development of methods to analyze genome organization and its effect on cellular functions.

Highest priority will be given 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 the mouse. Technology development projects that utilize other eukaryotic organisms will be considered, but direct applicability to the analysis of the human genome must be evident.

Technologies for Data Analysis and Management

The HGP will generate mapping, sequencing and related data from many laboratories. There is a continuing need to develop and improve appropriate computer tools and information systems for the collection, storage, retrieval and distribution of these data. New methods and tools for the analysis and interpretation of genomic data are needed, as well as new data management systems. Examples of research that address this goal are:

Development of effective data management systems to support large-scale mapping and DNA sequencing projects - such research should be undertaken in the context of actual mapping and sequencing efforts, but may be supported by independent funding.
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 data to related datasets (e.g., phenotypic, expression, structural data).
Development of analytical tools that can be used in the assembly, analysis, and interpretation of genomic data.
Development of technology to accelerate the collection, storage, retrieval, analysis and distribution of genomic 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.

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 NHGRI strongly encourages interdisciplinary collaborations between biologists from various sub-disciplines and non-biologists, such as chemists, physicists, information scientists, mathematicians 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 "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.

If it is anticipated that an application submitted in response to this announcement will generate genomic data or materials suitable for sharing, then the application should include plans for sharing data and materials, for example by depositing cell lines, probes, sequence data, etc., into public repositories. Plans for sharing will become a condition of the award. Where appropriate, grantees may work with the private sector in making unique resources, such as clone libraries and probe screening services, available to the larger biomedical research community at reasonable cost. 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 by groups other than the developers to any instruments developed through this program. In projects where instrumentation and/or software development are key components, investigators should specifically address
1. exportability to other laboratories,
2. access of other investigators to unique instruments, and
3. where appropriate, integration of individual components into systems.
Evaluation of Technology. As technology matures it must be tested to demonstrate its capabilities and robustness. Plans for accomplishing such a test should be included in the application, if it is anticipated that the technology will reach the appropriate level of maturity by the end of the project period.
Human Subjects. Applicants are urged to carefully review the DHHS regulations regarding human subjects. In general, many applications responding to this Program Announcement will involve human subjects, but others may be exempt according to DHHS regulations. Applications proposing to develop resources from human materials, such as libraries of cloned human DNA, that will eventually be utilized for large scale production projects are urged to adhere to the guidelines developed by NIH and DOE, "Guidance on Human Subjects Issues in Large-Scale DNA Sequencing."

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, Number 11, March 18, 1994.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. 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 301/435-0714, e-mail: ASKNIH@od.nih.gov. The title and number of this program announcement must be typed in Item 2 on the face page of the application.

The completed original application and five legible copies must be delivered 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants. NIH (or by the review group of the relevant Institute, Center, or Division), in accordance with the standard NIH peer review procedures. Following the scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council.

Review Criteria

Scientific, technical, or medical significance, and originality of proposed research.
Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research.
Qualifications and research experience of the principal investigator and staff, particularly, but not exclusively, 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.
The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment.

Award Criteria

Applications will compete for available funds with all other approved 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. In addition, for applications assigned to the NHGRI will also take into consideration the following additional criteria:

Potential for developing technology or strategies that will accelerate progress in mapping, sequencing, or analysis of the human genome and the genomes of other organisms.
Value of the proposed research for achieving the research goals of the National Human Genome Research Institute, while maintaining programmatic balance in the NHGRI grant portfolio.
Adequacy of any plans proposed for managing and sharing data, resources and technology in a timely manner.

In addition to the above award criteria, applications from foreign institutions must present special opportunities that are not readily available in the United States.

INQUIRIES

Inquires are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Applicants who plan to submit applications with a direct cost of $500,000 or more must obtain approval from the institute staff prior to submission of the application.

Direct inquiries regarding programmatic issues to:

Lisa D. Brooks, Ph.D.
Genome Informatics and Sequence Variation
E-mail: lisa_brooks@nih.gov

Elise Feingold, Ph.D.
Functional Analysis
E-mail: elise_feingold@nih.gov

Adam Felsenfeld, Ph.D.
Large-Scale Sequencing
E-mail: adam_felsenfeld@nih.gov

Bettie Graham, Ph.D.
Mapping and Sequence Variation
E-mail: bettie_graham@nih.gov

Jane L. Peterson, Ph.D.
Large-Scale Sequencing
E-mail: jane_peterson@nih.gov

Jeffery Schloss, Ph.D.
Sequencing Technology Development
E-mail: jeff_schloss@nih.gov

The address and telephone number for the staff listed above are:

National Human Genome Research Institute
National Institutes of Health
Building 31, Room B2B07
31 Center Drive, MSC 2033
Bethesda, MD 20892-2033
[For courier deliveries, use zip code 20814]
Phone: (301) 496-7531
Fax: (301) 480-2770

Inquiries about grants management/policy issues should be directed to:

Ms. Jean Cahill
Grants Administration Branch
National Human Genome Research Institute
Building 31, Room B2B34
31 Center Drive, MSC 2031
Bethesda, MD 20892-2031
[For courier deliveries, use zip code 20814]
Phone: (301) 402-0733
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 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.

Last Reviewed: February 28, 2012

Last updated: February 28, 2012