Full Text HG-92-002

MAPPING THE MOUSE GENOME WITH EMPHASIS ON TECHNOLOGY DEVELOPMENT

NIH GUIDE, Vol. 21, No. 26, July 17, 1992

RFA:  HG-92-002

P.T. 34

Keywords: 
  Nucleic Acid Sequencing 
  Molecular Genetics 


National Center for Human Genome Research

Letter of Intent Receipt Date:  October 16, 1992
Application Receipt Date:  November 13, 1992

PURPOSE

The National Center for Human Genome Research (NCHGR) invites
applications for assistance awards to support research projects
designed to increase the rate, resolution, and usefulness of genetic
and physical maps of the mouse genome.  The specific areas of interest
are:  (1) incorporation of significant numbers of genes identified by
sequence-tagged sites (STSs) [Olson et al., Science 245: 1434, 1989]
into the genetic map; (2) development of technology to facilitate the
construction of physical maps; and (3) facilitation of the progress of
other genetic and molecular biology projects that are map-based, by
making mapping resources available to the community.

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
selected model organisms.  The activities encompassed by the NCHGR
program include genetic and physical mapping, DNA sequencing,
informatics related to mapping and sequencing, and technology
development that will facilitate all of these efforts.  Areas in which
further research, including the development of new technology, are
needed if the characterization of the human and other genomes is to be
accomplished within the established 15-year time frame, as well as
specific goals for the first 5 years of this period, are described in
a 5-year plan that the NCHGR developed in 1990, in conjunction with the
Department of Energy.  The five-year plan is available from the Human
Genome Management Information System, Oak Ridge National Laboratory,
Oak Ridge, TN 37831-6050, telephone (615) 576-6669.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit
organizations, both domestic and foreign, public and private
universities, medical colleges, research institutions, hospitals, and
laboratories, units of State and local governments, and eligible
agencies of the Federal Government. Applications from women and
minority scientists are particularly encouraged.

MECHANISM OF SUPPORT

Support for this program will be through individual research grants
(R01s), pilot projects/feasibility studies (R21), and program project
grants (P01s).  Applicants may request support for up to five years.
It is anticipated that 10 awards will be made representing a mix of
research topics and grant mechanisms.  This number may be increased if
a large number of highly meritorious applications are received and if
funds are available.  The number of awards made will be contingent upon
the quality of applications received and the availability of funds.

FUNDS AVAILABLE

The total amount of support available for grants under this Request for
Applications (RFA) will be $3.0 million (direct and indirect costs) for
the first year of the project and is contingent upon appropriation of
funds for this purpose.

RESEARCH OBJECTIVES

The study of the genomes of model organisms is an integral component of
the Human Genome Program.  Such studies are essential to the
development of the methodology and insights necessary to analyze and
understand the human genome.  Five biologically well-studied organisms
have been identified as primary foci of the U.S. program for genomic
analysis.  These are E. coli, S. cerevisiae, C. elegans, D.
melanogaster, and the laboratory mouse.  The physical map of the E.
coli genome is complete and those of the genomes of S. cerevisiae and
C. elegans are essentially so; significant progress is being made in
constructing physical maps of the genome of D. melanogaster.
Large-scale DNA sequencing projects have begun on the DNAs of the
former three organisms in laboratories in the United States, Europe,
and Japan.

With respect to the mouse genome, the five-year plan for the U.S.
genome program calls for developing a high resolution genetic map based
on DNA markers.  The NCHGR currently supports (1) a large-scale effort
to construct a genetic map of the mouse genome based on microsatellite
repeats and (2) several investigator-initiated projects to construct
genetic maps of individual chromosomes or portions of chromosomes.
There are also several laboratories in the United States that have
major research programs to incorporate genes into genetic maps.  Major
efforts to construct genetic maps are also ongoing in Europe.  The
European mouse genetics community has established the European
Collaborative Interspecific Backcross (EUCIB) panel of 1,000
interspecific backcross progeny as a mapping resource for the European
community.  In the United Kingdom, a key project in the genome program
is the generation of mouse cDNA libraries from which randomly selected
cDNAs will be sequenced and mapped on a somatic cell hybrid panel and
the EUCIB mapping panel.

Whereas the mouse genetic map has always included gene-based markers,
it is only with the recent introduction of sequence-based DNA markers
that some laboratories are using STSs to identify the genes they are
mapping.  Expansion of the genetic map by including more genes
identified by STSs would have many advantages.  PCR-based markers (1)
can be readily integrated with the microsatellite-based genetic map,
thereby increasing the quality and utility of the overall genetic map;
(2) facilitate construction of the physical map; and (3) eliminate the
costs of storing and shipping markers since the information can be
distributed electronically.  Moreover, the mapping of additional genes
would assist in localizing phenotypic deviants in the mouse that have
correlates in human traits, including diseases.

A second goal of the five-year plan is the construction of physical
maps of a few mouse chromosomes.  The NCHGR currently supports (1) a
large-scale effort to improve technology for physical mapping and (2)
several investigator-initiated projects to develop physical maps of
mouse chromosomes or portions of chromosomes.  Because the mouse and
human genomes are similar in complexity, the challenges of constructing
physical maps of either genome are similar. Major advances have
recently been made in constructing large-insert libraries of cloned
mammalian DNA.  Indeed, technology has advanced to the point at which
constructing physical maps on a genome-wide basis is conceivable.
However, the application of this approach to the mouse genome has not
yet been addressed in practice.  Nor has the degree of resolution that
can be attained either by genome- wide or single chromosome strategies
been determined.  In addition, technologies to effect map closure need
further development.

Finally, the information to be obtained by the genome program will be
a resource for studies of gene structure and function and will promote
research into the genetic aspects of human disease.  In this way, the
Human Genome Project will serve as an underlying source of information
for, and stimulus to, a wide range of studies from the most basic to
targeted and clinical programs across the spectrum of NIH interests and
responsibilities.  Thus, it is crucial to the ultimate success of the
U.S. Human Genome Program that the materials, information, and other
resources developed by the Human Genome Program are made readily
available to the wider biomedical research community rapidly and
efficiently.

All applications responsive to this RFA for genetic and physical
mapping of the mouse genome and development of mapping resources to
facilitate additional genomic and biological research must have as a
primary goal:  (1) the development of new or significantly improved
technology; (2) strategies for increasing throughput for identifying
and mapping markers; and/or (3) approaches that are rapid, efficient,
and cost-effective.  Below are examples of projects that would be
considered responsive to this RFA.

A.  Enhancement of the Mouse Genetic Map

The immediate goal of the NCHGR program is a 1 centimorgan (cM) map of
the mouse genome; a 1 cM map is defined as a map in which more than 95
percent of the loci are within 1 cM of each other.  To achieve this
resolution, an estimated 4,000 loci must be mapped.  There already
exists a substantial effort to map anonymous DNA markers.  In addition,
several laboratories are already engaged in major efforts to map genes
with sequence-based markers.  Any project submitted in response to this
section of the RFA must complement ongoing mapping activities and,
where appropriate, make maximal use of existing resources, e.g.,
existing crosses and mapping reagents.  Specifically, applications are
encouraged in the following areas:

o  Improvement or development of sequence-based technologies to map
genes and other functional elements rapidly, cost-effectively, and with
a high rate of throughput.

o  Expansion of the genetic map to include genes identified by
sequence-tagged sites (STSs); special attention should be given to
identifying genes/markers for telomeres and areas where large gaps
exist.

B.  Technologies to Facilitate Development of the Physical Map

Development of the physical map of the mouse genome presents similar
technical problems to the development of the physical map of the human
genome.  In the past several years, there have been many improvements
in the development of strategies for constructing physical maps of
mammalian genomes.  However, many technical problems remain, such as
the high level of chimerae in large-insert libraries of cloned DNA,
rapid and accurate assembly of clones into contigs, closure of gaps
between contigs, the existence of DNA fragments that are unclonable,
and the cloning and ordering of highly repetitive DNA fragments.
Therefore, applications are encouraged in the following areas:

o  Development of cloning techniques and strategies that improve upon
current approaches to constructing physical maps;

o  Technology development to accelerate the assembly of the physical
map of the mouse genome; and

o  Development of methods or strategies to address the problem of
closure.

C.  Resources

Many valuable resources have been developed for genetic and physical
mapping projects.  However, because of the expense and expertise needed
to produce these resources, some cannot readily be replicated in
individual laboratories. Consequently, many valuable resources are
available only in a few laboratories where they are not accessible to
most investigators.  Access to such resources would benefit researchers
interested in developing maps of particular regions of chromosomes or
in studying biologically interesting regions of the genome. Such access
would also be cost-effective because it would preclude the necessity of
redevelopment of useful resources.  Therefore, in an effort to
accelerate research in genetics and molecular biology and to eliminate
unnecessary duplication of resources, the NCHGR is proposing to support
activities in the area of genetic and physical mapping by encouraging
applications that propose to develop such resources as:

o  A centralized gene mapping service for the scientific community; and

o  A centralized physical mapping service for the scientific community.

This list is not all-inclusive; identification of other resources that
would accelerate research on mouse genetics and biology is encouraged.
In developing such a resource, applicants are encouraged to improve the
rate of through-put and the cost-efficiency of gene mapping and/or
screening methods. Applications in response to this part of the RFA
must state how many DNA markers are expected to be mapped or screened
annually, the criteria that will be used in determining priority, the
arrangements that will be made with requestors regarding data sharing,
and the plans for encouraging users of the service to submit the data
to public databases expeditiously.  The NCHGR expects that users of
such services will be required to pay a modest fee-for-service.  Thus,
the application should also state what this fee will be.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 16, 1992, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to which
the application is being submitted.

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 is helpful in planning for the review of applications.
It allows staff to estimate the potential review workload and to avoid
possible conflict of interest in the review.  Letters of intent are to
be sent to:

Bettie J. Graham, Ph.D.
Chief, Research Grants Branch
National Center for Human Genome Research
Building 38A, Room 610
9000 Rockville Pike
Bethesda, MD  20892
Telephone:  (301) 496-7531
E-MAIL:  B2G@CU.NIH.GOV

APPLICATION PROCEDURES

Applications are to be submitted using the form PHS 398 (rev. 9/91).
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 may not reach the
review committee in time for review.  Application kits are available in
the business or grants office at most academic or research institutions
and from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, 5333
Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441.
Applications will be accepted in accordance with the following
schedule:

Timetable

Letter of Intent:  October 16, 1992
Application Receipt Date:  November 13, 1992
IRG Review:  March 1993
Council Review:  May 1993
Earliest Funding Date:  July 1, 1993

It is essential that applicants type "Mapping the Mouse Genome" and the
RFA number, HG-92-02, on line 2a on the face page of the application
form.  The original and three copies of the application must be
submitted to:

Grant Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

To expedite the review process, it is also important to submit two
copies of the application directly to:

Office of Scientific Review
National Center for Human Genome Research
National Institutes of Health
Building 38A, Room 604
9000 Rockville Pike
Bethesda, MD  20892

It is important to send these two copies to the NCHGR at the same time
as the original and three copies are sent to the Division of Research
Grants; otherwise the NCHGR cannot guarantee that the application will
be reviewed in the RFA competition.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the Division of Research
Grants staff for completeness and by NCHGR staff for responsiveness.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is not responsive to the
RFA, NCHGR 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.

Those applications that are complete and responsive will be evaluated
in accordance with the review criteria stated below for
scientific/technical merit by the Genome Research Review Committee
(GRRC), NCHGR.  Applications may be subjected to triage by the GRRC to
determine scientific merit relative to other applications received in
response to this RFA.  The review criteria to be used for triage are
identified below.  The NCHGR will withdraw from further competition
those applications judged by triage to be noncompetitive for award and
notify the applicant Principal Investigator and institutional official.
Those applications judged to be competitive will undergo further
scientific merit review.  These applications will be reviewed for
scientific and technical merit by the GRRC, NCHGR.  Review criteria
will be the following:

o  Originality, innovativeness, efficiency, and cost effectiveness of
the approach;

o  Feasibility of the research and adequacy of the experimental design;

o  Overall scientific and technical merit of the research;

o  Adequacy of plans for data management and data sharing, if
appropriate;

o  The potential of the proposed work to attain the research objectives
outlined in this RFA;

o  Training, experience, research competence, and dedication of the
investigator(s);

o  Adequacy of available facilities;

o  Provision for the protection of human subjects and the human care of
human care of animals; and

o  Appropriateness of the requested budget for the work proposed.

The second level of review will be conducted by the National Advisory
Council for Human Genome Research.

AWARD CRITERIA

The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review;

o  Extent to which existing resources are utilized maximally;

o  Value of the research for achieving the goals of the Human Genome
Program with respect to the mouse genome;

o  Adequacy of any plans proposed for managing data and sharing data
and resources in a timely manner;

o  Balance among projects with respect to the NCHGR current grant
portfolio of mouse grants; and

o  Availability of funds.

INQUIRIES

Prospective applicants are encouraged to contact staff very early in
the planning phase of the application.  For more information regarding
specific research areas or mechanisms, contact:

Bettie J. Graham, Ph.D.
Chief, Research Grants Branch
National Center for Human Genome Research
Building 38A, Room 610
Bethesda, MD  20892
Telephone:  (301) 496-7531
E-mail:  B2G@CU.NIH.GOV

For information about PHS Grant Policy, applicants may contact:

Ms. Alice Thomas
Chief, Grants and Contracts Management Branch
National Center for Human Genome Research
Building 38A, Room 613
Bethesda, MD  20892
Telephone:  (301) 402-0733

The program and grants management officials welcome the opportunity to
clarify any issues or questions related to this RFA and encourage
written and telephone inquiries.

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, 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
12372 or to Health Systems Agency review.

.

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