TECHNOLOGY DEVELOPMENT, MAPPING, AND DNA SEQUENCING IN SUPPORT OF THEHUMAN GENOME PROGRAM



NIH GUIDE, Volume 21, Number 9, March 6, 1992



PA NUMBER:  PA-92-50



P.T. 34



Keywords:

  Human Genome 

  Nucleic Acid Sequencing 

  Molecular Genetics 

  Information Science/Systems 



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.  A summary of these goals are:  completion of a high density

genetic linkage map of the human genome; construction of a high-

resolution physical map comprised of large contigs (overlapping pieces

of cloned DNA); development of a "sequence-tagged site" (STS) 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.



ELIGIBILITY REQUIREMENTS



Domestic universities, medical colleges, hospitals, and other public,

private, and for-profit research institutions, including state and

local government units, are eligible. Foreign organizations are also

eligible to apply only for the research project grants (R01).

Applications from minority individuals and women are encouraged.



MECHANISM OF SUPPORT



Support for this program will be through research project grants (R01),

pilot projects and feasibility studies (R21), program project grants

(P01), and FIRST Awards (R29).  As part of this effort, the NCHGR

encourages the support of minority students and faculty interested in

the Human Genome Program through the traditional NIH funding mechanisms

and through minority supplements to ongoing research grants (see

announcement in the NIH Guide for Grants and Contracts, Vol. 21, No. 3,

Part 1 of 2, January 24, 1992).



Applications to support large, complex research programs through the

center grant mechanism will not be considered under this Program

Announcement.  Applications for P30 and P50 center grants may respond

to the Program Announcement in the NIH Guide for Grants and Contracts,

Vol. 18, No. 36, October 13, 1989.



RESEARCH OBJECTIVES



Background



The NIH Human Genome Program is envisioned as a 15-year project that

has very specific goals.  The NCHGR was established in October 1989 for

the purpose of planning and supporting the Human Genome Program at NIH

and coordinating the NIH component of this program with those of other

Federal agencies and international groups.  The goals for the first

five years of the U.S. Human Genome Program were established by a joint

advisory committee of the NIH and the Department of Energy and are set

forth in the document, "Understanding Our Genetic Inheritance - The

U.S. Human Genome Project:  The First Five Years - FY 1991-1995."

(This document is available from the Human Genome Management

Information System, Oak Ridge National Laboratory, Oak Ridge, TN

37831-6050; telephone, 615-576-6669).  These goals are:



o  construction of high-resolution genetic linkage maps based on DNA

markers with a goal of achieving an average spacing of 2 centimorgans

and gaps no greater than 5 centimorgans between markers, each of which

is identified by an STS (Olson et al., Science 245:1434, 1989);



o  construction of high resolution physical maps of chromosomes in

which contigs of at least 2 million base pairs are unambiguously

ordered and identified by STS spaced about 100,000 base pairs apart;



o  development of new methods for DNA sequencing that significantly

reduce the cost and increase the rate of sequencing;



o  development of computer tools, information systems, and strategies

for collecting, storing, retrieving, analyzing, interpreting, and

distributing large amounts of mapping and sequencing data;



o  examination of legal, ethical, and social implications of the Human

Genome Program (see Program Announcement in NIH Guide for Grants and

Contracts, Vol. 19, No. 4, January 26, 1990); and



o  research training (see Program Announcement in NIH Guide for 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 in the most

expeditious and cost-saving manner.  This Program Announcement

supersedes the one that was published in the NIH Guide for Grants and

Contracts, Vol. 19, No. 28, 1990.



In planning research projects, applicants should be cognizant of the

following:



Technology Development.  Although a number of the techniques currently

in use for mapping have proven useful in initial successes in building

megabase-size contigs and studying specific genomic regions, it is

anticipated that new technologies, strategies and approaches are still

needed to reach the final mapping goal of the Human Genome Program most

expeditiously and in a cost-effective manner.  Similarly, the

technology currently available for sequencing and data handling is not

capable of supporting the goals of the Human Genome Program in these

areas.  Therefore, in the first five years of the Human Genome Program,

emphasis will be placed on technology development in all phases of

mapping, sequencing and informatics.  For applications with the primary

objective of map construction, those that improve or propose new

technology as a significant component will be most competitive.  This

will also be the case in mapping, sequencing, and informatics

applications.  Research projects that focus on technology development

in the context of a particular disease gene are appropriate if such

projects have one or more of the overall objectives of the Human Genome

Program as a major research goal.



Collaborative Research.  In order to achieve the objectives of the

Human Genome Program, collaborations between biologists from various

disciplines, including human genetics, as well as between biologists

and non-biologists, such as chemists, physicists, information

scientists, and engineers, are essential.  The NCHGR strongly

encourages multidisciplinary collaboration to facilitate progress,

especially in technically sophisticated areas.



Duplication/Overlap.  A certain amount of duplication in research is

inevitable and, in fact, is useful for verifying or validating

experimental results.  However, given the limited resources and the

need to accomplish the goals of the Human Genome Program within the

proposed 15-year period, duplication of research, irrespective of

funding source, while encouraged, should be kept to a minimum.  To

assist applicants with respect to what research is supported through

the NCHGR, a list of the Human Genome Program grant portfolio is

available to potential applicants.



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 Public Health

Service (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 their plans for sharing data and materials and depositing data

and materials to appropriate repositories.  It is expected that,

whenever 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

materials and submitting data to repositories in their applications.

However, such requests must be adequately justified.  For applications

assigned to the NCHGR, the plans for sharing will be reviewed for

adequacy by NIH staff and the National Advisory Council on Human Genome

Research 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 organism must 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 encouraged.



Pilot Projects or Feasibility Studies.  The NCHGR is interested in

supporting scientifically sound projects that are novel, creative, or

high risk/high payoff.  Applicants who seek funding to support such

research and need limited funding to conduct preliminary studies should

submit applications in response to the Program Announcement "Pilot

Projects or Feasibility Studies for Genomic Analysis," (see NIH Guide

for Grants and Contracts, Vol. 19, No. 28, July 27, 1990).



Specific Research Objectives



In order to achieve the goals of the Human Genome Program, applications

that propose to develop new approaches and strategies to mapping and

sequencing problems, as well as those that 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) discuss new

approaches and/or technology as part of the mapping or sequencing

strategy; (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); (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; and (5) in the case of specific

mapping and technology development applications, address how the

proposed research project will relate to or augment existing research

efforts.



Genetic Linkage Maps



High-density genetic linkage maps are important for attainment of the

goals of the Human Genome Program as they will facilitate (1) 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 1500 to 2000 informative

markers evenly spaced along the genome; in addition each DNA marker

would be defined by a unique STS.  An STS is defined as a DNA marker

that is unique in the genome and can be detected by the polymerase

chain reaction.  The STS concept has been promoted as a device that

will allow mapping data from different laboratories and from different

types of maps to be merged or assimilated.



To facilitate completion of a high-density genetic map, applications

are encouraged in the following areas:



o  Development of methods to rapidly and efficiently isolate, identify,

and map highly informative markers.



o  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 an STS.  Applications

are particularly encouraged for projects addressing those chromosomes

or regions of chromosomes where there are presently few markers or

those approaching the completion of the genetic map using a genomic,

rather than a chromosome-by-chromosome, strategy.



o  Improvement of methods for linkage analysis and ordering of markers.



o  Closure methods targeted to finding and mapping markers within gaps

in existing maps.



o  Technology development to accelerate completion of a 2-5 centimorgan

map of the human genome.



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 prerequisite 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:



o  Development of methods for isolating large amounts of purified human

chromosomes, chromosome segments, and restriction fragments for mapping

and sequencing.



o  Development of cloning techniques that improve upon current

approaches to constructing complete physical maps.  The development of

reproducible methods that:  (1) ensure that cloned inserts are stable

and are at least one megabase in size, (2) avoid artifacts, such as

dimeric clones, and (3) ensure that cloned fragments derived from a

single chromosomal location are particularly encouraged.



o  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.



o  Assembly of STS maps of individual human chromosomes with the goal

of having the STS markers spaced at approximately 100,000 base pair

intervals.



o  Development of methods or strategies to solve the problem of

closure.



o  Technology development to accelerate the completion of the physical

map of the human genome.



Sequencing



The ultimate goal of the Human Genome Program is to determine the

complete sequence of the human genome.  To date, the largest genome

that 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.

Applications responding to this Program Announcement must address

innovative approaches, including automation, that will increase the

speed of sequencing megabases of DNA and 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:



o  Improvement of current technologies in order to reduce costs

significantly below current costs;



o  Development of new methods, technologies, and strategies for

large-scale sequencing including preparing and sequencing the DNA and

assembling the data.



Only applications that aim to develop new or significantly improved

current sequence technology should be submitted in response to this

Program Announcement.  Applications for routine sequencing will not be

supported by the NCHGR.  Applications to support feasibility studies

for large-scale DNA sequencing using advanced state-of-the-art

technology may be submitted only in response to a Request for

Applications that is issued periodically in the NIH Guide for Grants

and Contracts.



Informatics



The Human Genome Program will generate mapping and sequencing data from

many laboratories, both national and international. 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 amount and complexity of the 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 general

areas:



o  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.



o  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.



o  Development of analytical tools that can be used in the assembly and

analysis of genomic data.



o  Technology development to accelerate the collection, storage,

retrieval, analysis, and distribution of mapping and sequencing data.



APPLICATIONS PROCEDURES



Applications are to be submitted on the grant application form PHS 398

(rev. 9/91).  Applications will be accepted on the receipt dates for

research grant applications (February 1, June 1, October 1).

Application kits are available at most institutional business and

grant/contract offices and may be obtained from the Division of

Research Grants, National Institutes of Health, Westwood Building, Room

240, Bethesda, MD 20892, telephone 301/496-7441.  The title and number

of this announcement must be typed in Item 2 on the face page of the

application.



The completed original application and five legible copies must be

delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical

research grants and cooperative agreements will be required to 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 should be placed on the need

for inclusion of minorities and women 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 rationale should 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 should be included in the form PHS 398 in

Section 2, A-D of the Research Plan AND summarized in Section 2, E,

Human Subjects.



Applicants are urged to assess carefully 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).



The rationale for studies on single minority population groups should

be provided.



For the purpose of this policy, clinical research includes 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 human tissues 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

minorities.



If the required information is not contained within the application,

the application will be returned.



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 policies.



REVIEW CONSIDERATIONS



Applications in response to this announcement will be reviewed in

accordance with the usual NIH peer review procedures.



With the exception of program project (P01) applications, applications

will be reviewed for scientific and technical merit by an appropriate

study section in the Division of Research Grants.  Program project

applications will be evaluated by an appropriate review committee

managed by an Institute or Center.  Following the initial scientific

review, applications will receive a second-level review by the National

Advisory Council for Human Genome Research or another Council or Board.



Review Criteria



Review criteria that will be used to assess the scientific merit are:



o  Significance and originality of the research and methodological

approaches;

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

o  Training, experience, research competence, and commitment of the

investigator(s);

o  Adequacy of the facilities and resources;

o  Appropriateness of the requested budget for the work proposed.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding

decisions:



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

o  Balance among research areas;

o  Availability of funds.



For those applications assigned to the NCHGR, the following additional

criteria will be used in making award decisions:



o  Potential for developing technology or strategies for accelerating

progress in mapping and sequencing the genomes of human and select

model organisms;



o  Value of the research for achieving the goals of the National Center

for Human Genome Research;



o  Adequacy of any plans proposed for managing data and sharing data

and resources in a timely manner;



In addition, priority will be given to applications from U.S.

institutions.



INQUIRIES



The program administrators and grants management officer welcome the

opportunity to discuss the program interests of the NCHGR and PHS

grants policy, respectively, with prospective applicants and current

grantees and encourages telephone, electronic and written inquiries.

For additional information, contact:



Genetic and Physical Mapping Grant Applications



Bettie J. Graham, Ph.D.

Chief, Research Grants Branch

National Center for Human Genome Research

Building 38A, Room 613

Bethesda, MD  20892

Telephone:  (301) 496-7531

E-mail:  B2G@CU.NIH.GOV



Sequencing and Technology Development Grant Applications



Robert L. Strausberg, Ph.D.

Program Director, Technology Development Program

National Center for Human Genome Research

Building 38A, Room 610

Bethesda, MD  20892

Telephone:  (301) 496-7531

E-mail:  CXR@CU.NIH.GOV



Informatics Applications



David Benton, Ph.D.

Assistant to the Director for Scientific Data Management

National Center for Human Genome Research

Building 38A, Room 610

Bethesda, MD  20892

Telephone:  (301) 496-7531

E-mail:  BENTON@BIO.NLM.NIH.GOV



PHS Grants Policy



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



AUTHORITY AND REGULATION



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, Section 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 requirements of Executive Order

12372 or to Health Systems Agency review.



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