JBA@CU.NIH.GOV (08/15/90)
REQUEST FOR RESEARCH PROJECT GRANT APPLICATIONS: RFA
INDEX MARKERS FOR A FRAMEWORK LINKAGE MAP OF THE HUMAN GENOME
RFA AVAILABLE: HG-90-02
National Center For Human Genome Research
Application Receipt Date: October 16, 1990
The National Center for Human Genome Research (NCHGR) invites
applications for assistance awards for research into the isolation
of highly polymorphic genetic linkage markers and their use for the
development of a framework linkage map of the human genome.
This program is described in the Catalog of Federal Domestic
Assistance No. 13.172. Awards will be made under the authority of
the Public Health Service Act, Sections 301 (Public Law 78-410, as
amended 42 U.S.C. 241) 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 12373 or to Health System Agency review.
BACKGROUND
The NCHGR sponsors basic and applied research concerned with the
development and application of new technologies for the
characterization and analysis of the human genome and the genomes
of important model organisms. The activities encompassed by the
NCHGR program include genetic and physical mapping, DNA sequencing,
and informatics related to mapping and sequencing. The NCHGR, in
conjunction with the Department of Energy, recently formulated a
five-year plan that identified areas where further research,
including new technology development, is needed before the
characterization of the human and other genomes can proceed to the
degree envisioned.
The five year plan, "Understanding Our Genetic Inheritance," is
available from the address given below. In it, the goal for
linkage mapping is the development of a two to five centimorgan
(cM) linkage map of the human genome (i.e., a map in which DNA
markers are spaced, on average, two cM apart and with no gaps
between adjacent markers greater than five cM). The NIH has
previously solicited applications for research projects to develop
such a high resolution linkage map under a series of program
announcements. The NCHGR will continue to accept applications for
such projects in response to the most recent program announcement,
"Mapping, DNA Sequencing, and Technology Development in Support of
the Human Genome Program" (NIH Guide for Grants and Contracts; vol.
19, no. 28, July 27, 1990).
As a result of discussions within the scientific community, it has
recently become clear the development of a high resolution linkage
map of the human genome would be greatly abetted by the
construction of a "framework map" consisting of a set of "index"
markers, each of which being much more informative than typical DNA
markers. A framework map consisting of an ordered set of highly
informative markers could be used to rapidly localize any new gene
or marker to a particular interval; efforts to map the marker to a
finer resolution could then be restricted to that interval.
Because of its expediency in the rapid localization of new entities
(markers, genes, traits, etc.) to a small chromosomal region, a
framework map of highly informative markers would be employed both
by scientists involved in the localization and identification of
specific genes, such as those associated with particular diseases
or syndromes, and those engaged in the construction of high
resolution linkage maps.
Approximately 2,000 polymorphic human markers have been isolated to
date. Many of these are restriction fragment length polymorphisms
(RFLP's). More recently, a variety of markers that can be
identified and characterized using the polymerase chain reaction
(PCR) has been developed. However, only 10% or fewer of these
existing markers are informative enough to be useful as index
markers on a framework map. This number is not adequate to develop
a maximally useful framework map. Furthermore, the distribution of
the known highly polymorphic markers is not random within the
genome. Thus, any attempt to construct a framework map with only
currently available markers would produce a map in which some
regions would contain a number of tightly clustered index markers
while other regions would have few or no index markers. These
latter regions, or gaps, would be large enough and frequent enough
that such a map would not be readily usable for rapid gene
localization.
It has been estimated that a useful framework map would consist of
markers whose heterozygosity is 70% or better, with an average
spacing of ten to fifteen centimorgans (cM) between markers.
However, the precise number of index markers needed per chromosome
and the size of the intervals defined by each pair of index markers
will vary, as the suitable spacing between adjacent markers will
depend on the specific characteristics of the individual markers.
The more highly polymorphic a marker is, the farther it can be from
the adjacent markers and still be useful for the kinds of mapping
for which a framework map is intended, i.e., markers with a
heterozygosity of 95% can be farther apart than markers with a
heterozygosity of 70%. The utility of the framework map will be
further enhanced if each marker is identified by a "sequence-tagged
site" (STS), a DNA sequence that is unique in the human genome and
is identifiable with the polymerase chain reaction (Olson et al.
[1989] Science, vol. 245, p. 1434).
Given the usefulness that a framework linkage map of the human
genome would have for laying the foundation for building a high
resolution map and for mapping and isolating functional genes, the
NCHGR is interested in supporting research projects designed to
isolate new highly polymorphic markers and assemble them into a
framework map for each human chromosome.
RESEARCH GOALS
This RFA is intended to solicit applications for research projects
designed to develop a framework linkage map of one or more human
chromosomes as described above. Issues that are appropriately
addressed in applications responding to this RFA include:
o identification and collection of existing markers;
o isolation of new index markers;
o mapping of index markers;
o the relationship between the degree of polymorphism and
spacing of index markers on the framework map;
o criteria to be used for determining when the framework
map is complete;
o error analysis and quality control issues associated with
mapping.
Each applicant responding to this solicitation should identify one
(or more) human chromosome(s) for which a framework map will be
developed and indicate the anticipated time needed to complete it.
It is not necessary that all of the index markers be isolated or
mapped in the applicant's own laboratory; collaboration with other
laboratories for the collection and mapping of index markers is
encouraged. Although the time required to complete a framework map
will vary by chromosome, it is estimated that it should be possible
to complete a framework map of the entire human genome in two to
three years.
MATERIALS AND DATA RELEASE
The purpose of this RFA is to encourage the construction of a
framework map of particularly useful linkage markers for each human
chromosome. It would be of most benefit to the entire scientific
community for the maps, the markers comprising them, and the data
supporting the localization of the markers to become available as
rapidly as possible. The policy of the U.S. Public Health Service
(PHS) states that "when resources are developed with PHS funds and
the associated research findings have been published...it is
essential that they be made readily available for research purposes
to the scientific community." In many cases, however, the
interpretation of this policy is problematic, e.g., in cases in
which only selected data are published. This is an area of active
discussion within the scientific community. Currently, there
appears to be a consensus that material resources and certain
unpublished data should available for distribution at a reasonable
time after they are developed. In this context, the NCHGR is
interested in the applicant's discussion of the issues involved in
making index markers and supporting data available and in plans for
doing so.
In considering these issues and developing such plans, applicants
should be aware that, in order to assist investigators in
distributing markers and mapping data, the NCHGR will identify and
support an appropriate repository and/or database that is qualified
and suitable for collecting and distributing the index markers and
supporting mapping data. The NCHGR will also support any
additional costs required by investigators for deposition of
markers and data in this repository/database.
To assist communication among investigators developing framework
maps of individual chromosomes, semi-annual meetings of all
grantees receiving funds under this RFA are planned.
MECHANISM OF SUPPORT
Support for this program will be through research project grants
(R01). The award period will be three years. Support for grants
under this RFA is contingent upon the appropriation of funds for
this purpose. It is anticipated that three million dollars will be
awarded during fiscal year 1991, although the number of awards is
contingent upon the quality and scope of the applications received.
Between awards made under this RFA and grants already funded by the
NCHGR, it is anticipated that sufficient resources will be provided
to develop a framework map of each human chromosome.
REVIEW PROCEDURES
Applications submitted in response to this RFA will be reviewed in
accordance with the normal NIH peer review procedures.
Applications will first be reviewed by NCHGR staff for
responsiveness. Those that are deemed non-responsive will be
returned to the applicant. If a large number of applications is
received, there will be a preliminary peer review to identify the
most meritorious ones. Applications that are deemed non-competitive
by this peer review will receive only a brief critique and will not
be reviewed further. The remaining applications will be reviewed
for scientific merit by an initial review group (IRG) organized for
this purpose by the Office of Scientific Review, NCHGR. A second-
level review will be conducted by a national advisory council.
Criteria that will be used to assess the scientific merit of
applications are:
o Overall scientific and technical merit of the research;
o Training, research track record, and dedication of the
principal investigator;
o Potential for achieving the goals of this RFA;
o Adequacy of the available facilities;
o Provision for the protection of human subjects and the
humane care of animals; and
o Appropriateness of the requested budget for the work
proposed.
AWARD CRITERIA
Funding decisions will be based on the recommendations of the IRG
and the advisory council regarding the scientific merit and program
relevance of the proposed research. It is expected that no more
than one award will be made for the framework map of each human
chromosome. The adequacy of the proposed plans for public access
to materials and data generated during the course of research
supported in response to this RFA will also be considered before an
award is made.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent by
September 10, 1990. This letter should identify the chromosome(s)
for which a framework map will be developed and include a brief
outline of the proposed strategy planned to achieve the research
scope of this RFA. The letter of intent is requested in order to
provide an indication of the number and scope of applications to be
reviewed. The letter of intent does not commit the sender to
submit an application, nor is it a requirement for submission of an
application. Please send letters of intent to:
Mark S. Guyer, Ph.D.
Assistant Director for Program Coordination
National Center for Human Genome Research
Room 605, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
E-mail: gy4@nihcu.bitnet; gy4@cu.nih.gov
APPLICATION PROCEDURES
Applications should be submitted using the new form PHS 398 (rev.
10/88). The RFA label available in the revised application kit
MUST be affixed to the bottom of the face page. Failure to use
this label could result in delayed processing of the application
such that it might not reach the review committee in time.
Application kits are available in the business or grants office at
most academic or research institutions, or from the Division of
Research Grants, National Institutes of Health. Applications will
be accepted in accordance with the following schedule:
Receipt of applications October 16, 1990
Initial review November/December 1990
Council review January 1991
Earliest award date April 1, 1991
It is essential that the applicant type "A Framework Linkage Map
of the Human Genome" and the RFA number HG-90-02 on line 2 of the
face page of the application form. The original and four copies of
the application should be submitted to the following office:
Grant Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, Maryland 20892
To expedite the review process, it is important to submit two
additional copies of the application directly to:
Office of Scientific Review
National Center for Human Genome Research
Room 604, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
It is strongly recommended that potential applicants contact NCHGR
staff to discuss research objectives. Any additional information
required can be obtained from:
Mark S. Guyer, Ph.D.
Assistant Director for Program Coordination
National Center for Human Genome Research
Room 605, Building 38A
National Institutes of Health
Bethesda, Maryland 20892
(301) 496-0844
E-mail: gy4@nihcu.bitnet; gy4@cu.nih.gov