Full Text HG-97-001
NIH GUIDE, Volume 25, Number 38, November 8, 1996
RFA:  HG-97-001
P.T. 34

  Human Genome 
  Nucleic Acid Sequencing 

National Center for Human Genome Research
Letter of Intent Receipt Date:  February 27 1997
Application Receipt Date:  March 27, 1997
The purpose of this Request for Applications (RFA) is to stimulate
the development of genomic-scale technologies for the study of genome
function and sequence variation.  Within the next decade, it is
anticipated that the complete DNA sequences of the human and numerous
model organisms will be determined and available for comprehensive
analysis.  The next challenge lies in systematically decoding the
genomic information, e.g., finding all the genes and understanding
how their gene products function; defining common alleles and
haplotypes, and associating them with phenotypes; and analyzing the
conservation of genes and other features among species.  Such
analyses will facilitate the understanding of biological processes
important in human health and disease, and the development of
improved diagnoses, preventative strategies and therapies.
The tools needed to analyze genomic DNA efficiently are just
beginning to emerge and many more robust technologies are needed.
The Human Genome Project has been successful in generating
information and resources rapidly and economically, in part, by
developing and applying high-throughput and efficient technologies.
Therefore, the National Center for Human Genome Research (NCHGR)
seeks the development of technologies that can be applied in similar
ways to the rapid and efficient analysis of genome function and
sequence variation.
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Technologies for Genome Analysis, is related to the priority areas of
cancer, heart disease and stroke, diabetes and chronic disability
conditions, and maternal and infant health.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, companies, units of State and local
governments, and eligible agencies of the Federal government.
Applications from social/ethnic minority individuals, women, and
persons with disabilities are encouraged.  Applications from foreign
institutions will not be accepted.  However, subcontracts to foreign
institutions are allowable, with sufficient justification.
This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01), program project grant (P01) and
exploratory/developmental grant (R21) mechanisms.  The total project
period for an application submitted in response to this RFA may not
exceed three years and the direct cost per year for research project
(R01) or program project (P01) grants may not exceed $500,000.
Exploratory/developmental (R21) grants will be limited to $100,000
direct costs per year for a maximum of two years.  The R21 mechanism
is used to support highly creative approaches for which substantial
preliminary data are not yet available.  Specific information about
the R21 grant mechanism can be found in the NCHGR Program
Announcement PAR-94-046, "Pilot Projects or Feasibility Studies for
Genomic Analysis." The R21 grants are not renewable, but future
project continuation is possible through other grant mechanisms such
as the R01 or P01.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant.  Awards will be administered under PHS grants policy as
stated in the Public Health Service Grants Policy Statement.  Future
unsolicited competing continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
the customary peer review procedures.  The anticipated award date is
September 30, 1997.
It is anticipated that approximately $5 million (total costs) will be
available for this initiative in fiscal year 1997.  Awards pursuant
to this RFA are contingent upon the availability of funds for this
purpose.  The amount of funding for these projects may be increased
if a large number of highly meritorious applications are received and
if funds are available. Only applications found to be of high
scientific merit will be considered for funding and all of the funds
will not be spent if there are not enough highly meritorious
applications.  Funding in future years will be subject to the
availability of funds. Because the scope of the research proposed in
response to this RFA encompasses the interest of several NIH
Institutes and Centers, applications may receive dual assignments
based on the established PHS referral guidelines.
The entire DNA sequence of the genomes of several microorganisms,
including prokaryotes (H. influenzae and M. genitalium), an archeon
(M. jannaschii), and a eukaryote (S. cerevisiae) have recently been
determined.  Rapid progress has also been made in mapping and
sequencing more complex genomes, leading to the expectation that,
within the next two to nine years, the DNA sequence of the genomes of
C. elegans, D. melanogaster, the human, and perhaps others will be
finished. The availability of this information will usher in a new
era in biomedical research.
A complete genomic DNA sequence comprises the bounded set of genetic
instructions of an organism.  Once it has been determined,
investigators will have access to every genetic element of that
organism.  This capability opens unparalleled opportunities to study
both genomic function and sequence variation.  Understanding both
function and sequence variation is essential for a comprehensive
understanding of the biology of an organism.  The amount of
information represented by genomic sequence and the underlying clone
and map data is enormous, and investigators will need a wide variety
of very robust techniques to make maximal use of these new resources.
At present, however, the technology for making use of and
interpreting the complete genetic "blueprints" is rather limited.
Novel and improved technologies, developed to be cost-efficient and
applicable at a large scale, have, in large measure, been responsible
for the success of the Human Genome Project in producing detailed
genomic maps and large amounts of DNA sequence.  Analogous
"genomic-scale" technologies will be required for the interpretation
of  the genomic sequence.  Although several of these are beginning to
emerge, they require further development; beyond them, many more
novel approaches are needed.
Objectives and Scope
The purpose of this RFA is to stimulate the development of novel
"genomic-scale" technologies for the study of genomic function and
sequence variation.  Through this solicitation, NCHGR intends to
stimulate the development and implementation of innovative
technologies that will facilitate, among other things, the
elucidation of the biological roles of gene products and non-coding
functional elements; the interactions among functional elements in
the cell; the biological consequences of genome organization; the
dynamics of polymorphisms in populations; and the functional
significance of genomic variation.
This RFA is intended to support the development of technologies that
will take advantage of the genomic maps and DNA sequences for use in
systematic and comprehensive approaches to the study of genomic
function and sequence variation.  The technologies needed for these
analyses are those that are scaleable, rapid, efficient and take
advantage of economies of scale.  It is envisioned that when such
technologies are applied to large-scale analyses, a genome will
become annotated with biologic information that will, in turn, serve
as a platform for more in-depth, detailed studies.
The "process" of technology development can be considered to span a
spectrum of stages.  Initially, it involves the development of an
entirely new methodology (or the significant improvement of an
existing methodology) to the point of proof of principle.  The method
must then be reduced to practice.  For such a new method to have a
significant impact for genomic studies, it must also be shown that it
can be used efficiently on a large-scale, or genomic basis, which
requires another level of technology development.  This RFA is
intended to solicit applications that address any of these phases of
technology development.
The NCHGR will give priority to the development of technologies that
will be used to study the human genome and/or the genomes of S.
cerevisiae, C. elegans, D. melanogaster and M. musculus.  Technology
development projects that utilize other eukaryotic organisms will be
considered, but direct applicability of these technologies to the
analysis of the human genome must be evident.  An important feature
of any newly-developed technology will be the ease with which it can
be exported into other laboratories, or in other ways made readily
accessible to investigators.  The development of computational
methods for the study of genomic function and variation is encouraged
under this solicitation.  Local databases necessary to conduct
research funded under this RFA will be supported.  The development of
public, national databases, however, will not be supported under this
RFA.  In addition, applications proposing to analyze a particular
gene, gene product or non-coding functional element will not be
considered under this RFA.
This RFA seeks applications to develop efficient technologies (both
experimental and computational) for, but not limited to, the
following areas:
o  development of single nucleotide polymorphisms in human DNA for
genome-wide mapping;
o  identification and analysis of sequence variations within and
among species to study normal and disease states in humans, and
o   identification of all functional elements (both coding and
non-coding) in the genome;
o  analysis of the biological role that non-coding functional
elements play in the cell;
o  analysis of expression of gene products (RNA and/or proteins),
e.g., measurement of steady-state levels of gene products in a given
cell type,  temporal or induced changes in patterns of gene product
levels, or comparative levels of gene product in different cell
o  analysis of the biological role that gene products (RNA and/or
proteins) play in the cell, e.g., analysis of cellular localization
of proteins, protein-protein or protein-nucleic acid interactions or
comparative analysis of protein sequences and/or structures; and
o  analysis of genome organization and its effect on cellular
These examples are illustrative and should not be viewed as limiting
in any way.  Novel and innovative technologies to all areas of genome
analysis are sought.
Applicants should address the following issues:
o  advantages of the proposed approach over existing approaches;
o  value of the technology in furthering the understanding of
eukaryotic biology; and
o  plans for making data and resources broadly accessible.
The sharing of materials and data in a timely manner has been an
essential element in the rapid progress made in genome research.
Public Health Service (PHS) policy requires that investigators make
the results and accomplishments of funded activities publicly
available.  The advisors to the NIH and the DOE genome programs have
developed a set of guidelines for making data and material resources
available to the scientific community in a timely manner. The
guidelines call for material and information from genome research to
be made available within six months of the time the data or materials
are generated; more rapid sharing is encouraged and has become the
norm in the genome community. Applications submitted in response to
this RFA should include detailed plans for sharing data and materials
generated through the grant.  Where appropriate, grantees may work
with the private sector in making unique resources available to the
larger biomedical research community at a reasonable cost.  The plans
proposed for sharing and data release will be reviewed for adequacy
by NIH staff prior to award of the grant and the proposed sharing
plan will be made a condition of the award.  Applicants may request
funds to defray the costs of sharing materials or submitting data.
Such requests must be adequately justified.
Recently, it has become evident that special human subjects issues
are raised by the large-scale sequencing of human genomic DNA because
large amounts of DNA sequence information from single individuals may
be generated.  The NCHGR and the DOE have recently issued a document,
"Guidance on Human Subjects Issues in Large-Scale DNA Sequencing" to
address these issues.  This document can be found on the NCHGR Home
tml).  As a result of the research supported under this RFA, it is
possible that an analogous situation might exist, i.e., that a large
amount of information about a single individual's genome might be
generated and be made publicly available. Applicants should address
these special human subjects issues, if applicable.
Because of the specialized interest of this RFA, prospective
applicants are strongly encouraged to discuss their research
objectives and the appropriate grant mechanism with NIH staff.
Prospective applicants are asked to submit, by  February 27, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the principal
investigator, and the identities of other key personnel and
participating institutions.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows NCHGR staff to estimate the potential review
workload and to avoid conflict of interest in the review.
The letter of intent is to be sent to:
Elise Feingold, Ph.D.
Division of Extramural Research
National Center for Human Genome Research
Building 38A, Room 614, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Elise_Feingold@nih.gov
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267,
email:  ASKNIH@odrockm1.od.nih.gov; and from the program director
listed under INQUIRIES.
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must
be marked.
Submit a signed, typewritten original of the application and three
signed photocopies, in one package to:
Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
At the time of submission, two additional copies of the application,
including appendices, must also be sent to:
Dr. Ken Nakamura
Office of Scientific Review
National Center for Human Genome Research
Building 38A, Room 613, MSC 6050
38 Library Drive
Bethesda, MD  20892-6050
Applications must be received by March 27, 1997.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.  The applicants should
also ensure that their revised applications respond to the review
criteria by which the applications in response to this RFA will be
Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness to the RFA by NIH program staff. Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA, NIH
staff will contact the applicant to determine whether to return the
application to the applicant or submit it for review in competition
with unsolicited applications at the next review cycle.
Those applications that are complete and responsive will be evaluated
for scientific/technical merit in accordance with the criteria stated
below by an appropriate peer review group convened by the NCHGR.  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:
o  scientific and technical merit of the proposed research;
o  extent to which the experimental approach makes use of and/or adds
value to the complete genomic sequence;
o  value of the forthcoming data and/or technology in furthering the
understanding of eukaryotic biology;
o  value and exportability of the forthcoming methodologies and
resources (for software tools, portability at the source code level);
o  likelihood that the technology will be able to scale to a genomic
level efficiently and in a timely manner;
o  qualifications and research experience of the principal
investigator and staff in the area of the proposed research;
o  availability of the resources necessary to perform the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o  adequacy of plans for dissemination of software tools developed
under grant support;
o  adequacy of plans to place data and/or material resources in the
public domain in a timely manner; and
o  adequacy of plans to protect human subjects, if applicable.
For R21 applications, preliminary data are not required. However, the
applicant does have the responsibility for developing a sound
research plan and for presenting any other information that can be
considered as evidence of feasibility.
The earliest anticipated date of award is September 30, 1997. Factors
that will be used to make award decisions are:
o  quality of the proposed project as determined by peer review;
o  balance among the projects in addressing different experimental
approaches and their complementarity to other ongoing efforts;
o   adequacy of data/material release plan; and
o   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.
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
For biological research projects on genome function:
Elise Feingold, Ph.D.
Division of Extramural Research
National Center for Human Genome Research
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Elise_Feingold@nih.gov
For biological research projects on sequence variation:
Bettie J. Graham, Ph.D.
Division of Extramural Research
National Center for Human Genome Research
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Bettie_Graham@nih.gov
For all computational research projects:
David Benton, Ph.D.
Genome Informatics Program
National Center for Human Genome Research
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  David_Benton@nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Jean Cahill
Grants Management Office
National Center for Human Genome Research
Building 38A, Room 613, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 402-0733
FAX:  (301) 402-1951
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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