Full Text HG-97-003
 
MOUSE GENE MAP
 
NIH GUIDE, Volume 26, Number 25, August 1, 1997
 
RFA:  HG-97-003
 
P.T.


Keywords: 

 
National Human Genome Research Institute
National Institute of Alcohol Abuse and Alcoholism
National Cancer Institute
National Institute of Drug Abuse
National Institute of Mental Health
 
Letter of Intent Receipt Date:  August  18, 1997
Application Receipt Date:  September 16, 1997
 
PURPOSE
 
The purpose of this Request for Applications (RFA) is to solicit
applications for research projects to construct a gene-based physical
map of the mouse genome consisting of an ordered set of EST-derived
markers integrated with the genetic and other physical maps of the
mouse genome.
 
HEALTHY PEOPLE 2000
 
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, A
Mouse Gene Map, is related to several priority areas.  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).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
companies, hospitals, laboratories, 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.
 
MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) mechanism.  If more than one grant is funded
under this initiative, the investigators will be expected to work
cooperatively, and with any other project(s) with similar goals, so
that the resources developed will be of maximum usefulness to the
community.  The total project period for applications submitted in
response to the present RFA may not exceed 2 years. The anticipated
award date is March 2, 1998.  This RFA is a one-time solicitation.
 
This RFA is an initiative of the Institutes listed above.  However,
the awards will be made by the National Human Genome Research
Institute (NHGRI) and will be managed by the NHGRI and the other
participating institutes.
 
FUNDS AVAILABLE
 
At least $2 million (including direct and indirect costs) per year
will be available.  It is anticipated that one to three awards may be
made.  Proposed funding levels are subject to change due to
budgetary, administrative, and/or scientific considerations.
 
RESEARCH OBJECTIVES
 
Background
 
The mouse is an important model for the study of many aspects of
mammalian biology, including many human diseases.  Among its other
advantages, the mouse is the most well developed system for mammalian
genetic analysis.  In the past few years, genomics has become an
increasingly important approach to the development of the resources
necessary for molecular genetic analysis of biological questions.  In
recognition of the important role played by the mouse in modern
biomedical research, the development of resources to support study of
the mouse genome has been an integral goal of the Human Genome
Project (HGP) since its inception.  Through HGP funding, a high
resolution genetic map of the mouse based on microsatellite markers
has been completed, and a physical map including both genetic and
random STS markers is currently under development.  Although the
genomic resources currently being developed will be extremely useful,
identifying and isolating mouse genes of interest is still not
routine, and  investigators involved in such efforts would benefit
from additional resources.  In particular, a catalogue and map of
mouse genes would greatly increase the usefulness of the mouse in
studying human disease, health, and behavior.  A successful approach
to constructing such a gene map has recently been demonstrated for
the human.  Schuler et al. [Science 274:540 (1996)] used a catalog of
human genes to construct a map containing more than 16,000 gene-based
markers.  STS markers were developed from expressed sequence tags
(ESTs) which were derived, in turn, from human cDNA clones.  At
present, a large number of mouse ESTs is being generated at the
Washington University (St. Louis) Sequencing Center, with support
from the Howard Hughes Medical Institute (HHMI).  To date,
approximately 180,000 mouse  ESTs have been produced and submitted to
the public database and the Washington University-HHMI effort is
scheduled to produce a total of 400,000 ESTs  within the next two
years.  Analysis of the existing mouse  ESTs has already shown that
there are many overlaps and a number of contigs (or clusters), which
are comparable to the  UniGene clusters that were used to generate
STS-based gene markers for the Human Gene Map. The HHMI has recently
increased its investment in the mouse EST project to include full
insert sequencing of clones representing all of the unique clusters.
This will generate sequences covering the 3' ends of the cDNA
inserts, thereby increasing the usefulness of the EST information for
mapping.
 
Finally, a project to construct a mouse gene map has begun in Europe
with plans to incorporate about 15,000 mouse ESTs in the next three
years. The European project is financed by the European Commission
and will be carried out at the Mouse Genome Centre in the United
Kingdom and Genethon in France.  This effort plans to anchor the RH
panel described below using genetically mapped microsatellite markers
and then to put about 15,000 EST-based markers on the commercially
available RH panel.  Most of the ESTs to be used will be derived from
the Washington University-HHMI collection, but a fraction will be
obtained from European production efforts on specialized libraries.
The European project will focus on  ESTs that do not have a human
homologue, although approximately 20% will be human homologues in
order to relate the gene maps of the two organisms.
 
The availability of a gene map will enhance the value of the mouse as
a model for studying human biology.  The map will be useful for
isolating and cloning mouse genes by the positional cloning and
positional candidate cloning methods.  Comparison of detailed mouse
and human gene maps will increase the efficiency with which
investigators can define and take advantage of the syntenic
relationships between chromosomes of the two organisms.  Adding
additional value to this approach will be a rat gene map which is
currently being developed under support from the National Heart,
Lung, and Blood Institute.  Once identified, many genes will be
better studied in the mouse (and/or the rat); the information
obtained in such studies can then be applied to human studies.
 
Objectives and Scope
 
The purpose of this RFA is to support the development of a gene-based
physical map of the mouse genome in the most efficient, timely and
cost-effective manner.  The resulting map should be cross-referenced
to the existing STS-based mouse genetic map and  integrated with the
mouse gene map being generated by the European effort.
There are several reagents that are available to facilitate
generation of the mouse gene map.
 
Mapping Reagents.  Investigators at the University of Cambridge  have
developed a mouse radiation hybrid panel, T31.  The retention rate is
27.3 percent and preliminary characterization of the panel indicates
that it has between 1,000 and 1,500 bins.  Investigators at the
Whitehead Institute have generated two mouse YAC libraries consisting
of approximately 40,000 YACs with an average insert size of 829 kb
(approximately 10 genome equivalents).  Investigators at the
California Institute of Technology have produced a mouse BAC library
consists of approximately 200,000 clones with average insert size of
130 kb (approximately 9 genome equivalents).  Currently, a non-
redundant overlapping set of  YAC or BAC clones is not available. The
radiation hybrid panel and the clone libraries are available
commercially.  It is anticipated that applicants may want to utilize
one or more of these existing resources for mapping, but NHGRI and
the collaborating NIH institutes would be willing to support the cost
of developing a new mapping resource, if the applicant presents
convincing evidence that the resulting map would be substantially
better than one produced using existing mapping resources.
 
Unique Clusters of ESTs.  The Washington University Sequencing
Center, through support from Howard Hughes Medical Institute, is in
the process of sequencing a significant number of ESTs.  These ESTs
will be reduced to a unique set of clustered ESTs by the National
Center for Biotechnology Information, National Library of Medicine,
NIH, as has been done for the human gene mapping project.  Within the
next two years, Washington University plans to have sequenced over
400,000 ESTs.  Based on the experience with the human ESTs, it is
estimated that there should be about 50,000 unique clusters of ESTs
available for mapping. There are already 2,500 unique mouse EST
clusters available for mapping.
 
Cross Reference and Integration with Other Mouse Maps.  A mouse
genetic map has already been constructed (http:\\www-
genome.wi.mit.edu).  In order for the genetic map and the gene maps
being generated by the U.S. and European efforts to be maximally
useful to the scientific community, it is essential that the
resulting gene map be cross-referenced to the genetic map and
integrated with the European gene map.
 
This RFA does not specify the desired resolution or other properties
of the gene map to be generated.  However, it is expected that most,
if not all, of the unique gene clusters emanating from the Washington
University-HHMI  mouse EST project will be mapped.  Each applicant
must propose the most cost efficient strategy for producing a mouse
gene map and should justify why a map of the proposed resolution
would be the most useful resource for studies using the mouse and
related studies of human.
 
DATA AND RESOURCE SHARING
 
The sharing of materials and data in a timely manner has been an
essential element in the rapid progress made in construction and use
of the human and mouse genetic maps.  Public Health Service 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 "NIH-DOE Guidelines
for Access to Mapping and Sequencing Data and Material Resources"
that address the special needs of genome research.  These 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.  Investigators may
request funds to defray the costs of sharing materials or submitting
data in their application.  Such requests must be adequately
justified.
 
POST-AWARD MANAGEMENT
 
During the course of the grant period, technologies will improve,
genomic technologies will evolve, 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 adjustment in
scientific direction to accommodate the changing environment.  In
order to ensure that the project(s) remain(s) focused on appropriate
goals, maintain(s) excellent coordination with the other projects
funded under this RFA, incorporate(s) new technological advances and
make(s) sufficient progress, scientific and programmatic visits to
the grantee(s) may be conducted at a frequency to be negotiated with
the awardee(s).  In addition, applications should include travel
funds for the Principal Investigators and the other investigators on
the grant to meet annually with NIH staff in the metropolitan
Washington D.C. area, should such meetings be advisable.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by August 18,1997, 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 may be submitted.  Any applicant planning to
submit an application for more than $500,000 direct cost in any one
year must contact the NHGRI staff listed under INQUIRIES in order for
the application to be accepted by NIH.
 
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 IC 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:
 
Bettie J. Graham, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 614
38 Library Drive, MSC 6050
Bethesda, MD  20892-6050
Tel: (301) 496-7531
Fax: (301) 480-2770
e-mail: [email protected]
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone (301) 710-0267; e-mail: [email protected] 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, including
the Checklist, and three signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC7710
BETHESDA, MD  20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
At the time of submission, two additional copies of the application
must also be sent to
 
Ken Nakamura, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
Building 38A, Room 613, MSC 6050
38 Library Drive
Bethesda, MD  20892-6050
 
Applications must be received by September 16, 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.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness to the RFA by NHGRI program staff.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA,
NHGRI 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
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NHGRI.  As
part of the initial merit review, a process may be used by the
initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  All applicants will receive a summary
statement consisting of the reviewer's written comments essentially
unedited.  Summary Statements for competitive applications will also
contain a summary of the review committee's discussion.  The second
level of review will be provided by the appropriate national advisory
council or board.
 
Review criteria will include the following:
 
* scientific and technical merit of the research proposed to meet the
objectives of this RFA;
 
* the value of the proposed gene map to the scientific community;
 
* 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;
 
* adequacy of plans to integrate the resulting gene map with the
European gene map;
 
* adequacy of plans to make resources/data available to the community
in a timely manner;
 
* availability of the resources and technology necessary to perform
the research;
 
* adequacy of facilities and resources and the level of institutional
commitment; and
 
* appropriateness of the proposed budget and duration in relation to
the proposed research.
 
AWARD CRITERIA
 
The anticipated date of award is March 1, 1998.  Factors that will be
used to make award decisions are as follows:
 
* Quality of the proposed project as determined by peer review; *
Promise of the proposed program to accomplish the goals of this RFA;
 
* Cost effectiveness of the proposed strategy;
 
* Quality of the plans to cooperate with other projects that may be
funded under this RFA and  with the European effort;
 
* Nature and extent of the plans for sharing and distributing data
and resources in a timely manner ; and
 
* Availability of funds.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Bettie J. Graham, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 610, MSC 6050
Bethesda, MD 20892-6050
Phone:  (301) 496-7531
FAX:  (301) 480-2770
Email: [email protected]
 
Robert Karp, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD 20892-7003
Telephone:  (301) 443-2239
Fax:  (301) 594-0673
Email: [email protected]
 
Grace L. Shen, Ph.D.
Cancer Genetics Branch
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 501, MSC 7381
Rockville, MD  20892-7381
Telephone:  (301) 435-5226
Fax: (301) 496-8656
Email: [email protected]
 
Theresa Lee, Ph.D.
Division of Basic Research
National Institute of Drug Abuse
5600 Fishers Lane, Room 10A-19
Rockville, MD  20857
Telephone:  (301) 443-6300
Fax: (301) 594-6043
Email:  [email protected]
 
Stephen H. Koslow, Ph.D.
Division of Neuroscience and Behavioral Science
National Institute of Mental Health
5600 Fishers Lane,
Rockville, MD 20857
Telephone:  (301) 443-3942
Fax: (301) 443-3563
Email: [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Ms. Jean Cahill
Grants Management Officer
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 613, MSC 6050
Bethesda, MD  20892-6050
Telephone: (301) 402-0733
Fax: (301) 402-1951
e-mail: [email protected]
 
AUTHORITY AND REGULATIONS
 
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
review.
 
The Public Health Service (PHS) strongly encourages all grant
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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