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) 435-0714.  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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