Full Text PA-97-044
NIH GUIDE, Volume 26, Number 8, March 14, 1997
PA NUMBER:  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.]
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.
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)
Support for this program will be through research project grants
(R01), FIRST awards (R29), and program project grants (P01).
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.
The NHGRI is interested in supporting technological advances in the
following areas of  research: (1) Refining Genetic Maps; (2)
Analyzing Sequence Variation in Genomic DNA; (3) Improving Physical
Maps; (4) Reducing the Cost of Genomic DNA Sequencing; (5)
Interpreting Genomic Sequence; and (6) 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; and
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; and
 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; and
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; and
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
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
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; and
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; and
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
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. The guidelines can be found on the NHGRI
Home Page:
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." This document can be found on the  NHGRI
Home Page:
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.
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 301/710-0267,
email:  ASKNIH@odrockm1.od.nih.gov.  The title and number of this
program announcement must be typed in Item 2  on the face page of the
The completed original application and five legible copies must be
delivered to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
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; and
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.
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; and
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.
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
Direct inquiries regarding programmatic issues to:
David Benton, Ph.D.
Genome Informatics
Email: david_ benton@nih.gov
Elise Feingold, Ph.D.
Genomic Analysis
Email: elise_feingold@nih.gov
Bettie Graham, Ph.D.
Genetic Mapping and Sequence Variation
Email: bettie_graham@nih.gov
Jane L. Peterson, Ph.D.
Large-Scale Sequencing
Email: jane_peterson@nih.gov
Jeffery Schloss, Ph.D.
Technology Development/Genome Sequencing
Email: jeff_schloss@nih.gov
The address and telephone number for the staff listed above are:
Building 38A, Room 614
National Human Genome Research Institute
National Institutes of Health
38 Library Drive
Bethesda, MD 20892-6050
Telephone: (301) 496-7531
Fax: (301) 480-2770.
Inquiries about grants management/policy issues should be directed
Ms. Jean Cahill
Grants Management Officer
National Human Genome Research Institute
Building 38A, Room 613
National Institutes of Health
38 Library Drive
Bethesda, MD 20892-6050
Telephone: (301) 402-0733
Email: jean_cahill@nih.gov
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
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.

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