Full Text PAR-94-044


NIH GUIDE, Volume 23, Number 10, March 11, 1994

PA NUMBER:  PAR-94-044

P.T. 34

  Human Genome 
  Nucleic Acid Sequencing 

National Center for Human Genome Research


[This Program Announcement supersedes the one that appeared in the
NIH Guide for Grants and Contracts, Vol, 22, No. 20, June 4, 1993.]

The purpose of this program announcement is to solicit new or renewal
applications to the Genome Science and Technology Centers (GESTEC)
program, which supports large-scale, multidisciplinary genomic
studies.  Specifically, the GESTEC program supports research to
achieve the mapping and sequencing goals of the Human Genome Project
as set forth in the New Five-Year Plan for the U.S. Human Genome
Project (Science, Vol. 262, p. 43, October 1, 1993) in order to
progress toward the ultimate goal of determining the complete
sequence of human DNA.  In order to achieve these goals GESTECs
should have a central focus that addresses a specific goal of the
Human Genome Program and should include the development of new
technology needed for genome mapping and/or sequencing, the
application of this technology to data production, informatics
solutions to data management, and outreach to the scientific
community.  The development of techniques for identifying and mapping
all of the genes and/or other functional elements in a large genomic
region may be integral to the projects.  Where appropriate,
consideration of the ethical, legal and social implications of the
Human Genome Project may also be included in a GESTEC.


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  While a single institu-
tion must be the applicant, multi-institutional arrangements
(consortia) are possible if there is a compelling reason for them and
if there is clear evidence of close interaction among the
participants.  Applications from foreign institutions will not be
accepted.  However, subcontracts to foreign institutions are
allowable, with sufficient justification.  Applications from minority
individuals and women are encouraged.

Industrial/academic collaborations are also encouraged.  In such
collaborations, the respective contributions should be well-
integrated into the design and operation of the center, to encourage
cross-fertilization of ideas and rapid application of the research to
practical purposes.


Grants in the GESTEC program may be supported by Specialized Center
Grants (P50) or Program Project Grants (P01).  The P50 mechanism will
be used for broader, more complex, multidisciplinary programs that
address the goals of the Human Genome Project.  The P01 mechanism
will be used for programs that support a minimum of three components
with a well-defined central research focus.

The term of support for GESTEC projects is normally three to five



The National Institutes of Health (NIH) is currently engaged, along
with several other federal, private, and international organizations,
in a 15-year research program designed to characterize the human
genome and the genomes of selected model organisms.  This research
program, the Human Genome Project (HGP), has the following
interrelated goals:

(1) the construction of high-resolution genetic linkage maps;
(2) the development of physical maps;
(3) the determination of the complete nucleotide sequence of the
human genome and the genomes of selected organisms;
(4) the development of efficient methods of identifying genes and for
placement of known genes on physical maps or sequenced DNA;
(5) the development of the capability to collect, store, distribute
and analyze the data and materials produced;
(6) the development of appropriate new technologies to achieve these
goals; and
(7) the identification of major issues related to the ethical, legal
and social implications (ELSI) of genome research, and the
development of policy options to address them.

The product of the Human Genome Project will be a set of information
and material resources available to the entire research community
that will facilitate further research leading to the prevention,
diagnosis, and therapy of disease, as well as to further
understanding of human biology.

In 1990, the NCHGR and the Department of Energy (DOE) jointly
published a plan that set out specific goals to be achieved in the
first five-year phase of the U.S. human genome program.  Anticipating
the attainment of much of the initial set of goals, the NCHGR and DOE
recently published the above-referenced new five-year plan extending
the goals for the U.S. Human Genome Project.  At the same time, the
NCHGR centers program, which had supported several large-scale,
multidisciplinary projects that have made significant contributions
to the initial achievements, has undergone transition.  As a part of
this transition, NCHGR has established a reformulated centers
program, the Genome Science and Technology Centers (GESTEC) program,
that is intended to build upon the success of the earlier program and
the lessons learned from it.  This announcement solicits applications
for new and continuing research that proposes to address the needs of
the project as outlined in the new five year plan, leading toward
complete sequencing of the human genome and the genomes of selected
model organisms.

Progress and Future Needs in Mapping

For the genetic linkage map, several current efforts, both genome-
wide or on an individual chromosome level, are expected to achieve
the timely completion of the 2 to 5 centimorgan genetic map called
for in the initial five-year plan.  The new five-year plan calls for
further development of genetic mapping technologies such as
technology for rapid genotying and development of new, easier to use,
markers.  Similarly, recent progress in physical mapping has been
very rapid.  A number of contigs for long genomic regions, including
two entire human chromosomes and parts of many others, having been
assembled; A low resolution map covering a large fraction of the
genome has recently been published.  The physical mapping goal set
forth in the new five-year plan is the attainment of a complete STS
map of the human genome at a resolution of 100 kb.

Physical maps of even higher resolution will eventually be needed as
the substrate for DNA sequencing and for other research purposes.
The new plan recognizes that continued technology development will be
necessary to produce such maps.  New techniques or strategies will be
needed to generate physical maps that are accurate enough so that the
DNA can be readily sequenced.  It is assumed that the nature of the
physical maps that will provide the substrate for DNA sequencing will
be dependent upon the precise strategy for sequencing.  Therefore,
proposals to consider development of "sequence-ready" clone sets
should be closely associated with an imminent intent to sequence.

Progress and Future Needs in DNA Sequencing

Progress has also been rapid toward the long-term goal of the Human
Genome Program, i.e., determining the complete sequence of the DNA of
certain model organisms and the human.  In 1990, the cost of
sequencing in laboratories devoted to DNA sequencing was estimated to
be about $5 per finished base and the rate at which finished sequence
could be generated was relatively low.  Since its inception, the
NCHGR has supported several efforts designed to test and refine
current methods in large-scale projects or develop entirely new
approaches to DNA sequencing that offer substantial improvements over
current methods.

Through these efforts, a number of advanced sequencing laboratories
are within reach of being able to generate contiguous finished
sequence at a rate of a few megabases per year and the cost is now
projected to be below $1 per finished base pair.  Several interesting
regions of both human and non-human DNA have been sequenced in these

To build on this significant progress, multidisciplinary centers are
needed to develop and implement visionary, integrated strategies that
will optimize the several phases of DNA sequencing, including sample
preparation, band resolution and detection, sequence assembly and
finishing, and annotation.  The new five-year plan calls for:
development of efficient approaches to sequence one to several
megabase regions of DNA in regions of high biological interest;
development of technology for high throughput sequencing focusing on
system integration of all steps; and building the sequencing capacity
to a collective rate of 50 Mb per year by the end of 1998.  The
efforts in the GESTEC centers will be needed to accomplish these
goals and must be carefully balanced between technology development
and actual testing in a production mode in order that the new
technology developed is effective and well-suited to achieving these
ambitious goals.  It is expected that, through previous feasibility
studies, applicants for GESTEC program grants to support large-scale
sequencing projects will have demonstrated their ability to sequence
at high throughput in a cost effective manner and to manage a large-
scale sequencing effort.

Objectives and scope

The GESTEC program is intended to foster and support innovative
projects in which technology development and cost effectiveness are
expected to push the limits of current capabilities.  The GESTEC
program is NOT intended to fund projects in which existing technology
is simply applied to large-scale data production or projects that
involve a consortium of investigators whose research interests are
only loosely united by a common theme.

To achieve the ambitious goals that this program is intended to
attain, it is anticipated that a Genome Science and Technology Center
must be:

o  mission-oriented, addressing in a highly integrated way, a major,
quantifiable goal(s) of the HGP, and/or going beyond those by
addressing the ultimate goal of the HGP ~ the complete sequence of a
human genome;

o  creative and innovative in terms of the proposed strategy and
development of new technology for achieving its goal(s);

o  readily adaptable to new technology and new scientific

o  focused, on an on-going basis, on issues of increased efficiency
as evidenced by a plan for improvements in the rate of output of data
and materials; at the same time, attention must be paid to
maintaining or improving the quality of the techniques, data, and
materials developed;

o  attentive to the needs of the larger scientific community, as
demonstrated by the inclusion of an outreach program that will allow
the center to act as a hub for collaboration and as a source for
materials and information.  The study of ethical, legal and social
implications (ELSI) and outreach to the general public through
education programs can be a component of such an outreach activity.
Applicants interested in conducting research relevant to the NCHGR
ELSI program should respond to the program announcement, "Ethical,
Legal and Social Implications of Human Genome Research", in the NIH
Guide to Grants and Contracts, Vol. 19, No. 4, 1990.

Allowable Components of GESTEC Grant Applications

Genomic research is defined, in part, by its emphasis on technology
development and on a high rate of data production.  Because of these
inherent characteristics, investigators in the field have
occasionally found organizational structures other than those
prescribed by traditional multi-component grant mechanisms, i.e.,
research projects and technical cores each managed by a different
principal investigator, to be more effective in managing and
effecting large-scale genome research projects.  In order to
facilitate the most rapid progress and efficient use of limited
resources, applicants will not be required to use the standard
organizational format.  Rather, each applicant is encouraged to
organize the proposed program in the manner that will best accomplish
the scientific goals of the proposed project.

Each proposed organizational component must have an identified
leader, although no minimum number of different leaders is required.
For example, the Principal Investigator of the entire grant may also
serve as leader of several, or even all, of the components, if such
an arrangement is scientifically justified and adequate supervision
of the project can be assured.  The selection of the leader for each
component should be justified in terms of the scientific and
management needs of that component and the experience of the proposed

The following is a discussion of the activities most frequently found
in multicomponent genome research projects.  Each of these will, in
some way, be integral to GESTEC programs and the organizational plan
developed by the applicant must address each of these activities
(with the exception of alterations and renovations) as well as how
the components will interact to achieve the goals efficiently and
rapidly.  Thus, while the form of the components may differ
dramatically among grants in the GESTEC program, it is essential that
the scientific and management structure (organizational plan) be
clearly presented in the application, both for the overall program
and for the individual activities.  It is also essential that the
requested budget correspond directly to the organizational plan.  The
proposed plan will be considered as an indication of the quality of
the management of the project.

Research Activities.  There are four primary activities that are
usually part of a GESTEC grant:  scientific research, technology
development, technical support of either of the preceding, and
outreach to the scientific community.  In a traditionally organized
program project or center, research and technology development
activities are normally organized as individual "research projects",
while technical support and outreach activities are presented as
"technical cores".  It has been the experience, however, in some
large-scale genome projects that it is more efficient and productive
to organize and manage efforts in other ways, for example, by
combining certain research and support activities into a single unit.
In a proposal for a GESTEC project, the applicant may design
activities to accomplish the scientific objectives most effectively.
A well thought-out data management plan is a critical element in
research projects of this size.  If data management activities are
incorporated into the research activities, it is important that the
overall management plan also describe the data management plans for
the entire GESTEC.

Technology development.  The development of new and better technology
needed to achieve the objectives of the Human Genome Project is
considered to be one of the most important aspects of a GESTEC
project.  Funds for technology development may be requested to
support (1) the design and development of prototypes for equipment
needed to increase the rate and efficiency of data production and
analysis, (2) pilot projects to take advantage of scientific
opportunities that present themselves during the course of the
project, and (3) the development of technology to meet unanticipated
needs of the research and support activities of the project.  When
requesting technology development funds, applicants should address
the issues of the exportability of and access to the instruments
being designed.

In some cases, it may be possible to present in the application a
detailed description of plans and justification for the particular
technology development projects envisioned.  Applicants are
encouraged to fully describe and justify plans to the extent
possible.  However, it is also recognized that unanticipated needs
may arise as the project develops and, thus, a complete description
of all technology development plans may not be possible.  In the
latter case, the request for technology development funds must be
justified by the inclusion of a clear, well-defined strategy for
making decisions about the use of such funds, e.g., the planning
process for the use of the funds, alternative logistical plans for
development of a variety of technologies, and the process for
evaluating projects to be supported by technology development
activities.  In an application for renewal of currently-funded NCHGR
grants, the justification for technology development funds must
include a description of the use(s) to which such funds were put
during the previous grant period.
Technical support activities.  An applicant may request shared
facilities or equipment that will be required by more than one
element of the proposed research program.  Each applicant should
examine the needs of the proposed program and request those technical
facilities that would be required to support the proposed research in
the most efficient and cost-effective manner.  In addition to
addressing the specific research, technology development and
technical support activities, the applicant should also address the
balance among these activities needed to accomplish the major goal of
the proposed center.

Outreach Activities.  GESTEC projects are expected to have an
interest in and a sense of responsibility for outreach to the greater
scientific community.  At a minimum, effective and rapid distribution
of data and/or materials generated by a GESTEC project to external
investigators is an essential and expected activity of each center.
Accordingly, the proposal must include a full description of plans
for accomplishing this goal.  The joint NIH-DOE Advisory Committee on
the Human Genome has recently issued a set of Guidelines for Access
to Data and Material Resources, which is available from the NCHGR
staff listed below and which would form the basis of an acceptable
although investigators are encouraged to go beyond these guidelines
whenever possible.  Funding to support data and materials
distribution may be requested in a GESTEC grant application.   Other
means of distribution, such as through a commercial vendor are also

Beyond such distribution activities, GESTEC projects are also
encouraged to provide outreach to the larger community by acting as a
hub of genomic collaboration through activities such as providing
additional services to the community, for example, visitor
laboratories or library screening services.  In addition to outreach
to the scientific community, development of public education outreach
programs and demonstration of interest in ELSI issues are also
encouraged.  Applications for renewal of currently-funded NCHGR
center grants must document their accomplishments in the outreach
activities as part of their justification for continued support.

Administrative and Management Activities.  Funds to support overall
management of the GESTEC grant may be requested.  As the GESTEC
program allows for flexibility in management to suit the scientific
purpose of the application, it is essential that the applicant
adequately describe and justify the overall management strategy
proposed and present a plan for the management of each of the

The leadership and management of a scientific enterprise as complex
as a GESTEC center will require a significant amount of attention and
effort.  Therefore, the proposed center director must serve on a
full-time or significant part-time basis.  He or she should have
authority over appointments and space within the center.  The portion
of the salaries of the principal investigator and other key
individuals corresponding to the percentage of time devoted to center
administration can be included as an allowable cost.

Costs of advisory committees, steering committees, and/or consultants
can also be included as an administrative activity.  Such committees
are not required, but it is strongly recommended that an effective
mechanism be proposed for obtaining independent advice to ensure
guidance of the center toward the attainment of its stated goals.  In
some cases, and at the request of the investigator, NCHGR may appoint
an oversight committee for the center in order to monitor progress
and the appropriate funding level.  It is not necessary for
applicants to identify external advisory committee members before
review of the application but plans for such a committee should be
discussed if one is proposed.

Alterations and Renovations.  Funds needed for renovation of existing
space may be requested, if such space is needed to house core
facilities or new or expanded research activities.  Costs of
equipping renovated laboratories may be included in the request if
the items are directly related to the research being conducted in the
center. According to the Public Health Service (PHS) Grants
Management Policy Statement, detailed justification of the need for,
and plans for the use of the renovated space must be provided in the
application and renovation plans must be approved by NIH before funds
for this purpose can be released.  In order to ensure that any
renovations or alterations are done in a timely manner, (1) the
request for alterations and renovations must include a timetable, (2)
the renovation plans must be received by NCHGR no later than three
months after the date of funding of the grant, and (3) the work must
be finished within one year from the date of NIH approval of the
plan.  The application must also outline any plans for accommodating
the project during the expected renovation period.  Such a plan
should take into account any need for accommodation of the program in
temporary space while the renovations are being done.  The
institution's commitment to the proposed plan must be well

PHS policy also limits the dollar amount for alterations and
renovations to the lesser of $150,000 or 25 percent of total direct
costs over a three year period.  Waivers to exceed this amount may be
sought by the NCHGR in exceptional cases.

Post Award Management

During the course of the grant period and as progress toward the
goals of the Human Genome Project is made, the focus of the GESTEC
grant will likely change.  In order to ensure that GESTEC projects
funded for five years remain focused on appropriate goals and make
sufficient progress, frequent scientific and programmatic reviews
will be conducted.  Yearly meetings of the Directors of GESTEC
projects and NCHGR staff will be held to discuss recent achievements
and expected future directions.  It is expected that Principal
Investigators of GESTEC grants will make the necessary adjustments in
scientific direction and management structure to accommodate to
changing requirements.  In the case of five-year awards, applications
for competitive renewal of support will be due at the first
submission date after the beginning of the fourth year.  In the event
that the review of an application is not favorable, this will allow
sufficient time for submission and review of a revised application or
for orderly phase-out of the grant.  Further support will be for a
three- to five-year period.

As noted above, GESTEC projects are encouraged to use advisory
committees as a means to obtain independent advice.  In renewal
applications, continued support of this activity must be justified by
the demonstration that the advisory committee mechanism has been used



NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements include minorities and women in study
populations so that research findings can be of benefit to all
persons at risk of the disease, disorder, or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and subjects of appropriate gender in studies of diseases,
disorders, and conditions which disproportionately affect them.  This
policy is intended to apply to males and females of all ages.  If
women or minorities are excluded or inadequately represented in
clinical research, particularly in proposed population-based studies,
a clear, compelling scientific rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to carefully assess
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans (including American Indians or Alaskan
Natives), Asian/Pacific Islanders, Blacks, Hispanics).  Rationale
must be provided for studies on single minority population groups.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders, or conditions including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include tissue from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Although it is not required or binding, applicants are strongly urged
to contact NCHGR staff by telephone or by letter of intent.  This
will enable staff to provide clarification of programmatic and
budgetary issues regarding these often-complicated applications and
will also assist review staff in planning the review workload.
Applications received without prior staff contact may be delayed in
the review process or may be returned to the applicant without

This communication will be most useful if it is submitted at least
three months before the receipt date on which the application is to
be submitted.  It need only include the names of the principal
investigator and principal collaborators, a descriptive title of the
proposed application and identification of the organization(s)
involved.  This information will not be part of the material that
will be peer reviewed and is to be directed to appropriate NCHGR
staff member listed under INQUIRIES.


Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the application deadlines as
indicated in the application kit.  Application kits are available
from most institutional offices of sponsored research and from the
Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD
20892, telephone 301/710-0267.  The title and number of the program
announcement must be typed in Section 2a on the face page of the
application.  The completed original and five legible copies must be
sent or delivered to:

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

Additionally, two copies of the full application must be sent to:

Office of Scientific Review
National Center for Human Genome Research
Room 604, Building 38A
Bethesda, MD  20892


Upon receipt, applications will be reviewed by DRG staff for
completeness and, for those applications assigned to the NCHGR, by
NCHGR staff for appropriateness with respect to expressed NCHGR
programmatic interests.  Incomplete applications will be returned to
the applicant without further consideration.

The regular NIH receipt dates for center grant and program project
applications and renewals are as follows:  February 1, June 1 and
October 1.  Applications will be evaluated for scientific merit by
the Genome Research Review Committee (GRRC) or an appropriate review
committee constituted for the purpose of evaluating GESTEC grant
applications.  Site visits are frequently conducted as part of the
review process but are not routine.  Therefore, applicants should
present a complete and well-justified written proposal and not depend
on site visits to amplify their application.

Review criteria will include the following:

o  Significance and originality of the research and methodological
o  Feasibility of the research and adequacy of the experimental
o  Training, experience, research competence and commitment of the
o  Adequacy of the facilities and resources;
o  Provisions for the protection of human subjects, the humane care
of animals and biosafety conditions.

Subsequent to evaluation by the initial review group, applications
will be reviewed by the appropriate National Advisory Council.


For those applications assigned to NCHGR, the following will be
considered in making funding decisions:

o  Quality of the proposed project as determined by peer review;
o  Value of the proposed research and of the proposed technology
development for achieving the goals of the Human Genome Program;
o  Adequacy of the proposed management structure including the
leadership capabilities of the center director;
o  Nature and extent of the outreach program, including the adequacy
of any plans proposed for sharing and distributing data and resources
in a timely manner;
o  Balance among projects within the NCHGR's grant portfolio;
o  Availability of funds.


Written and telephone inquiries are strongly encouraged.  The
opportunity to clarify any issues or questions from potential
applicants is welcome.

Inquiries regarding the GESTEC Program may be directed to:

Jane L. Peterson, Ph.D.
Chief, Mammalian Genomics Branch
National Center for Human Genome Research
Internet:  Jane_Peterson@occshost.nlm.nih.gov

Specific questions regarding the following programmatic areas may be
directed to the staff identified below:

Large scale sequencing and mapping of mouse and human genomes:

Dr. Jane L. Peterson, Chief
Internet:  Jane_Peterson@occshost.nlm.nih.gov

Dr. Jeffery Schloss, Program Director, Mammalian Genomics Branch
Internet:  Jeffery_Schloss@occshost.nlm.nih.gov

Sequencing technology development and large-scale mapping and
sequencing of nonmammalian model organisms:

Dr. Robert Strausberg, Acting Chief
Internet:  Robert_Strausberg@occshost.nlm.nih.gov

Dr. Carol Dahl, Program Director, Sequencing Technology Branch
Internet:  Carol_Dahl@occshost.nlm.nih.gov

The address and telephone number for the staff listed above is:

National Center for Human Genome Research
Building 38A, Room 610
Bethesda, MD  20892
Telephone:  (301) 496-7531

Inquiries regarding fiscal matters may be directed to:

Ms. Jean Cahill
Grants Management Office
National Center for Human Genome Research
Building 38A, Room 613
Bethesda, MD  20892
Telephone:  (301) 402-0733


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


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