QX3@CU.NIH.GOV (08/09/90)
Program Announcement
MAPPING, DNA SEQUENCING, AND TECHNOLOGY DEVELOPMENT IN SUPPORT OF
THE HUMAN GENOME PROGRAM
P.A. 90-20
National Center for Human Genome Research
PURPOSE
The National Center for Human Genome Research (NCHGR) invites
applications to support research that will significantly advance
progress toward achieving the scientific goals of the Human
Genome Program. These goals are discussed in detail in the
document, "Understanding Our Genetic Inheritance - The U.S. Human
Genome Project: The First Five Years - FY 1991-1995," available
from the Human Genome Management Information System, Oak Ridge
National Laboratory, Oak Ridge, TN 37831-6050; telephone, 615-
576-6669. A summary of the goals are: completion of a high
density genetic linkage map of the human genome; construction of
a high resolution physical map comprised of large overlapping
contigs; development of a "sequence-tagged site" map; development
of technology to reduce the expense of DNA sequencing
significantly below current cost; development of computer tools
to manage and provide access to mapping and sequencing data;
examination of the legal, ethical, and social implications of the
Human Genome Program; and research training.
INTRODUCTION
The NIH Human Genome Program is envisioned as a fifteen year
project which has very specific goals. The National Center for
Human Genome Research was established in October 1989 for the
purpose of planning and supporting the Human Genome Program and
coordinating the NIH component of this program with those of
other federal agencies and international groups. Recently a
joint advisory committee of the NIH and the Department of Energy
set forth program goals for the first five years. The goals,
outlined in "Understanding Our Genetic Inheritance - The U.S.
Human Genome Project: The First Five Years - FY 1991-1995," are:
construction of high resolution genetic linkage maps,
comprised of DNA markers with an average spacing of 2
centimorgans and gaps no greater than 5 centimorgans,
each identified by a "sequence-tagged site" (Olson et
al., Science 245:1434 (1989);
construction of high resolution physical maps of
chromosomes in which contigs of at least 2 million base
pairs are unambiguously ordered and identified by
"sequence-tagged sites," spaced about 100,000 base
pairs apart;
development of new methods for DNA sequencing that are
capable of significantly reducing the cost of
sequencing;
development of computer tools, information systems, and
strategies for collecting, storing, retrieving,
analyzing, interpreting and distributing large amounts
of mapping and sequencing data;
examination of legal, ethical, and social implications
of the Human Genome Program (see Program Announcement
in NIH Guide to Grants and Contracts, Vol. 19, No. 4,
January 26, 1990; and
research training (see Program Announcement in NIH
Guide to Grants and Contracts, Vol. 18, No. 25, July
21, 1989).
The objective of this Program Announcement is to stimulate
research that will assist the NCHGR in accomplishing both the
short- and long-term scientific goals of the Human Genome
Program. This program announcement supercedes the one which was
published in the NIH Guide to Grants and Contracts, Vol. 18, No.
26, July 28, 1989.
In planning research projects, applicants should be cognizant of
the following:
Technology Development. Most of the current approaches to
mapping and sequencing the genome utilize techniques that
were developed to map or sequence small regions of the
genome rather than for large-scale application. While a
number of these techniques have proven useful in studying
specific genomic regions, it is anticipated that new
technologies, strategies and approaches will be needed to
reach the final goal of the Human Genome Program
expeditiously and in a cost-effective manner. Therefore, in
the first five years of the human genome program, great
emphasis will be placed on technology development in all
phases of mapping, sequencing and informatics. Research
projects that focus on technology development in the context
of a particular disease gene are appropriate so long as such
projects have one or more of the overall objectives of the
Human Genome Program as their major research goal.
Collaborative Research. In order to achieve the objectives
of the Human Genome Program, collaborations between
biologists from various disciplines, including human
geneticists, as well as between biologists and non-
biologists, such as chemists, physicists, information
scientists and engineers, are essential. The Human Genome
Program strongly encourages multidisciplinary collaboration
to facilitate progress, especially in technically
sophisticated areas.
Sharing of Materials and Data. The sharing of materials and
data in a timely manner is essential for progress towards
the goals of the Human Genome Program, to avoid unnecessary
duplication, and to facilitate research in other areas of
biomedical research. The PHS policy requires the sharing of
resources at the time of publication. For some projects
that will be supported by the NCHGR, this policy is not
sufficient because certain kinds of data may not be
published in their entirety, while some information or
resources need to be shared more rapidly than at the time of
publication. Because the type of research will dictate the
conditions under which data and materials should be shared,
applicants should, in their applications, discuss plans for
sharing data and materials. It is expected that, where
appropriate, resources such as cell lines, probes, and
sequence data will be deposited expeditiously in public
repositories. Investigators may request funds to defray the
costs of sharing or submission to repositories in their
applications. However, such requests must be adequately
justified. The plans for sharing will be reviewed for
adequacy by NIH staff and the national advisory council
prior to award of a grant.
Animal Models. Research involving model systems will
contribute greatly to the Human Genome Program. The five-
year plan includes, as one of its goals, the support of
mapping and sequencing of the DNA of five specific
organisms--E. coli, S. cerevisiae, D. melanogaster, C.
elegans and the laboratory mouse. The Human Genome Program
is therefore interested in promoting research using these
organisms. However, research projects involving other model
organisms may also contribute significantly to the goals of
the Human Genome Program. Thus, applicants may propose to
study model systems other than those listed. In those cases,
the choice of organisms should be justified in terms of the
overall objectives of the Program. Whereas the "Research
Objectives" described below do not specify research to be
conducted on model organisms, such research is highly
encouraged.
Pilot Projects or Feasibility Studies. The NCHGR is
interested in supporting scientifically sound projects that
are novel, creative, or high risk/high pay-off. Applicants
who seek funding to support such research and need limited
funding to conduct preliminary studies should submit their
applications in response to the Program Announcement "Pilot
Projects or Feasibility Studies for Genomic Analysis," (see
this issue of the NIH Guide to Grants and Contracts, Vol.
19, No. 28, July 27, 1990).
RESEARCH OBJECTIVES
Genetic Linkage Maps
High density genetic linkage maps are important for attainment of
the goals of the Human Genome Program as they will (1) facilitate
the identification of gene locations and (2) the construction of
a complete physical map by allowing contigs (overlapping clones
of DNA) to be ordered with respect to one another.
The Human Genome Program has set as one of its goals during the
first five years the creation of a 2 to 5 centimorgan human
genetic linkage map. A map of this resolution would require l500
to 2000 markers evenly spaced along the genome; in addition each
DNA marker should be defined by a unique "sequence-tagged site"
(STS). An STS is defined as a DNA marker which is unique in the
genome and can be detected by the polymerase chain reaction. The
STS concept has recently been promoted as a strategy to merge or
assimilate mapping data from different laboratories and from
different types of maps.
To facilitate completion of a high density genetic map,
applications are encouraged in the following areas:
Development of methods to rapidly isolate, identify and
map highly informative markers.
Expansion of the maps of individual chromosomes with
the goal of achieving a high resolution map comprised
of DNA markers with an average spacing of 2
centimorgans and gaps no greater than 5 centimorgans,
and with each marker identified by a STS. Applications
are particularly encouraged for projects addressing
those chromosomes or regions of chromosomes where there
are presently few markers.
Improvement of methods for linkage analysis and
ordering of markers.
Physical Maps
A physical map is a very useful resource because it is the basis
for characterizing and isolating individual genes or other DNA
regions of interest and is a pre-requisite for large-scale DNA
sequencing. There are several types of physical maps including
cytogenetic maps, long-range restriction maps and contig maps.
To facilitate the construction of a complete physical map, at
least two aspects of mapping need to be improved: (1) the length
of a DNA segment that can be routinely covered by a single contig
or spanned by a set of closely spaced ordered markers must be
increased and (2) methods for closure or filling in the gaps
between contigs also need to be developed or improved.
To facilitate completion of a fully connected physical map,
research projects in the following areas are encouraged:
Development of methods for isolating large amounts of
purified human chromosomes, chromosome segments, or
restriction fragments for mapping and sequencing.
Development of cloning techniques that improve upon
current approaches to construct complete physical maps.
Attempts should be made to reproducibly obtain cloned
inserts that are stable and are at least one megabase
in size.
Construction of overlapping sets of cloned DNA, or
closely spaced, unambiguously ordered DNA markers, with
continuity over lengths of at least 2 million base
pairs.
Assembly of STS maps of individual human chromosomes
with the goal of having the STS markers spaced at
approximately 100,000 base pair intervals.
Development of methods or strategies to solve the
problem of closure.
Sequencing
The ultimate goal of the Human Genome Program is to determine the
complete sequence of the human genome. To date, the largest
genome which has been sequenced is a viral genome that is 240,000
base pairs in length. The human genome is 3 billion base pairs
in length, four orders of magnitude larger. The current cost of
DNA sequencing, in laboratories that do it routinely, is
estimated to be between $2-$5 per base pair of finished sequence.
If the entire human genome is to be sequenced, the cost of
sequencing must be significantly reduced. This Program
Announcement focuses on stimulating technologies that will
increase the speed of sequencing megabases of DNA through
innovative approaches or automation, and thereby significantly
decrease the cost of DNA sequencing to $0.50 or less per finished
base pair within five years. Research projects are encouraged in
the following areas:
Improvement of current technologies in order to reduce
costs significantly below current costs;
z Development of new methods, technologies and strategies
for large-scale sequencing, including preparing and
sequencing the DNA and assembling the data.
Only applications which aim to develop new or significantly
improve current sequence technology should be submitted in
response to this Program Announcement. Routine sequencing will
generally not be supported, unless the region is of extreme
biological interest. Applications to support feasibility studies
for large-scale DNA sequencing using advanced state-of-the-art
technology should be submitted in response to the Request for
Applications, "Feasibility Studies for Large Scale DNA
Sequencing," which is currently being developed.
Informatics
The Human Genome Program will generate mapping and sequencing
data from many laboratories, both nationally and internationally.
While some computer tools and information systems for handling
this type of data exist, none have been tested on a large scale
to determine their capabilities to manage the voluminous and
complex data that will be generated. There is a need to develop
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 areas:
Development of effective software and database designs
to support laboratory-based, large-scale mapping and
DNA sequencing projects. Such projects should be
undertaken in the context of actual mapping and
sequencing efforts.
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 of
these specific data sets.
Development of analytical tools that can be used in the
assembly and analysis of genomic data.
MECHANISM OF SUPPORT
Support for this program will be through research grants,
including research project grants (R01), program project grants,
(P01), FIRST awards (R29), Research Career Development Awards
(K04), AREA Awards (R15), conference grants (R13), and Small
Business Innovative Research grants (R43, R44). As part of this
effort the NCHGR encourages the support of minority students and
faculty interests in the Human Genome Program through the regular
NIH mechanism as well as through minority supplements to ongoing
research grants (see Program Announcement in the NIH Guide to
Grants and Contracts, Vol. 18, No. 14, April 21, 1989).
Applications to support large complex research programs through
the Center Grant mechanism (P30 and P50) should respond to the
special Program Announcement (NIH Guide to Grants and Contracts,
Vol. 18, No. 36, October 13, 1989) and will not be considered
under this Program Announcement.
APPLICATION AND REVIEW PROCEDURES
Applications in response to this announcement will be reviewed in
accordance with the usual NIH peer review procedures. In order
to achieve the goals of the Human Genome Program, applications
which include the use and extension of state-of-the-art
techniques, as well as those which 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 five-year goals;
(2) address the state-of-the-art in their particular area;
(3) approach the problem in a comprehensive manner, irrespective
of the size of the project (e.g., in constructing a physical map
of a particular chromosome, emphasis should be placed on
constructing fully connected contigs, i.e., overlapping units
of cloned DNA, rather than just mapping available probes); and
(4) demonstrate that there are adequate plans for: (a) data
management, (b) interacting and collaborating with the rest of
the scientific community working on similar or related objectives
and (c) making data and resources publicly available in a timely
manner.
With the exception of program project (P01) and conference grant
applications, applications will first be reviewed for scientific
and technical merit by the Genome Study Section or another
appropriate study section in the Division of Research Grants, as
deemed necessary. Program project and conference grant
applications will be reviewed by an initial review group
empaneled for that purpose. Following the initial scientific
review, applications will receive a second-level review by the
appropriate National Advisory Council.
REVIEW CRITERIA
Review criteria that will be used to assess the scientific merit
of an application are:
Significance and originality of the research and
methodological approaches;
Feasibility of the research and adequacy of the
experimental design;
Training, experience, research competence, and
commitment of the investigator(s);
Adequacy of the facilities and resources;
Appropriateness of the requested budget for the work
proposed; and
Provisions for the protection of human subjects, the
humane care of animals, and biosafety conditions.
AWARD CRITERIA
Applications will compete for available funds with all other
approved applications assigned to the NCHGR. The following will
be considered in making funding decisions:
Quality of the proposed project as determined by peer
review;
Value of the research for achieving the goals of the
National Center for Human Genome Research or of the NIH
component to which the application is assigned;
Adequacy of any plans proposed for managing data and
sharing data and resources in a timely manner;
Balance among research areas;
Availability of funds.
METHOD OF APPLYING
Applications should be submitted on the grant application form
PHS 398 (Rev. 10/88) except Small Business Innovative Research
grant applications which should be submitted on form PHS 6246-1.
Applications will be accepted on the receipt dates appropriate
for each mechanism. Application kits are available at most
institutional business and grant/contract offices or may be
obtained from the Division of Research Grants, Westwood Building,
Room 240, National Institutes of Health, Bethesda, Maryland
20892. The title and number of this announcement should be typed
in Item 2 on the face page of the application. Applications from
women and minority scientists are particularly encouraged.
The completed original application and six legible copies should
be delivered to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
5333 Westbard Avenue
Bethesda, Maryland 20892
INQUIRIES
The program administrator welcomes the opportunity to discuss the
NCHGR's program interests with prospective applicants and
encourages telephone, electronic or written inquiries. For
additional information please contact:
Bettie J. Graham, Ph.D.
Chief, Research Grants Branch
Building 38A, Room 613
National Center for Human Genome Research
National Institutes of Health
Bethesda, Maryland 20892
(301) 496-7531
e-mail: B2G@NIHCU.bitnet
B2G@CU.NIH.gov
----------------------------------------------------------------
Program Announcement
PILOT PROJECTS OR FEASIBILITY STUDIES FOR GENOMIC ANALYSIS
P.A. 90 - 21
National Center for Human Genome Research
Application Receipt Dates: October 1, February 1, June 1
The National Center for Human Genome Research (NCHGR) invites
applications for pilot projects or feasibility studies to support
creative, novel, high-risk/high pay-off research that will
significantly advance progress toward achieving the goals of the
Human Genome Program. These goals are discussed in detail in the
document, "Understanding Our Genetic Inheritance - The U.S. Human
Genome Project: The First Five Years - FY 1991-1995," available
from the Human Genome Management Information System, Oak Ridge
National Laboratory, Oak Ridge, TN 37831-6050; telephone (615)
576-6669. A summary of the goals are: completion of a high
density genetic map of the human genome; construction of a high
resolution physical map comprised of large overlapping contigs;
development of a "sequence-tagged site" map; development of
technology to reduce the expense of DNA sequencing significantly
below current cost; development of computer tools to manage and
provide access to mapping and sequencing data; examination of the
legal, ethical, and social implications of the Human Genome
Program; and research training.
RESEARCH OBJECTIVES
Currently, most genomic research utilizes mapping and sequencing
techniques that were not developed for large-scale application.
Although some reasonable improvements have been made in these
techniques and approaches, completion of the Human Genome Program
will require considerable increases in efficiency and cost
effectiveness of mapping and sequencing techniques, perhaps
including the development of completely new approaches.
The purpose of this program announcement is to encourage
applications from individuals who are interested in testing novel
or conceptually creative ideas that are scientifically sound and
may significantly advance progress toward the scientific goals of
the Human Genome Program. Some ideas may not be developed fully
enough for a standard R01 and can therefore be considered to be
in the category of high-risk/high pay off. Applications for such
pilot projects or feasibility studies are encouraged in all areas
in the five-year plan, which include:
construction of high resolution genetic maps, comprised
of DNA markers with an average spacing of 2
centimorgans and gaps no greater than 5 centimorgans,
each identified by a "sequence-tagged site;" (Olson et
al., Science 245:1434 (1989).
construction of high resolution physical maps of
chromosomes in which contigs of at least 2 million base
pairs are unambiguously ordered and identified by
"sequence-tagged sites," spaced about 100,000 base
pairs apart;
development of new methods for DNA sequencing that are
capable of significantly reducing the cost of
sequencing;
development of computer tools, information systems, and
strategies for collecting, storing, retrieving,
analyzing, interpreting and distributing large amounts
of mapping and sequencing data.
The sharing of materials and data in a timely manner is essential
for progress toward the Human Genome Program. All applicants are
expected to discuss in their applications plans for sharing
information and data in a timely manner. These plans will be
reviewed by the NIH staff and the national advisory council and
will become a condition of the award. For additional details,
please see the section of "Sharing of Materials and Data" in the
Program Announcement entitled "Mapping, DNA Sequencing, and
Technology Development in Support of the Human Genome Program,"
NIH Guide to Grants and Contracts, Vol. 19, No. 28, July 27,
1990.
The National Center for Human Genome Research encourages
applications from scientists who have not traditionally been
funded by the NCHGR, such as chemists, engineers, physicists, and
information scientists, as well as from molecular biologists and
other biologists. Applicants must clearly identify the
biological problem for which the technology is being developed,
and must indicate plans for demonstrating or testing the utility
of the technology. Applicants whose expertise is primarily non-
biological and who are interested in addressing problems of
genome analysis with new, non-biological tools are especially
encouraged to interact closely with biologists.
MECHANISM OF SUPPORT
This program will be supported through the exploratory/
developmental grants (R21) mechanism. Applicants may request up
to two years of support. In general, projects will be limited to
$100,000 (direct cost per annum), although exceptions will be
considered. These will be one time only awards. Continuation of
projects developed under this program will be through the regular
grant program.
REVIEW PROCEDURES AND CRITERIA
Applications will be reviewed for scientific and technical merit
by an appropriate NIH study section in accordance with the usual
NIH peer review procedures. Review criteria that will be used to
assess the scientific merit of an application are:
Originality of the approach
Soundness of the experimental design
Track record and commitment of the investigator(s)
Resources and environment
Appropriateness of the budget
Because this program is designed to support innovative ideas,
preliminary data as evidence of feasibility are not required.
However, the applicant does have the responsibility for
developing a sound research plan. Following initial review, the
applications will receive a second-level review by the
appropriate national advisory council.
AWARD CRITERIA
Limited funds will be available for this initiative.
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;
Value of the research for achieving the goals of the
National Center for Human Genome Research or of the NIH
component to which it is assigned;
Adequacy of plans for managing data and sharing data
and resources in a timely manner;
Balance among research areas;
z Availability of funds.
METHOD OF APPLYING
Applications should be submitted on the grant application form
PHS 398 (Rev. 10/88) and will be accepted at the regular
application deadlines. Application kits are available at most
institutional business and grant/contract offices or may be
obtained from the Division of Research Grants, Westwood Building,
Room 240, National Institutes of Health, Bethesda, Maryland
20892. The title and number of this announcement should be typed
in Item 2 on the face page of the application.
The completed original application and six legible copies should
be sent or delivered to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
5333 Westbard Avenue
Bethesda, Maryland 20892
INQUIRIES
Requests for further information should be directed to:
Bettie J. Graham, Ph.D.
Chief, Research Grants Branch
National Center for Human Genome Research
Building 38A, Room 613
National Institutes of Health
Bethesda, MD 20892
Telephone: 301/496-7531
e-mail: B2G@NIHCU.bitnet
B2G@CU.NIH.Gov.
The program official welcomes the opportunity to discuss the
National Center for Human Genome Research's program interests
with prospective applicants and encourages telephone, electronic
or written inquiries.