METHODS FOR DISCOVERING AND SCORING SINGLE NUCLEOTIDE POLYMORPHISMS

Release Date:  January 9, 1998

RFA:  HG-98-001

P.T.

National Institutes of Health

Letter of Intent Receipt Date:  March 25, 1998
Application Receipt Date:  May 7, 1998

PURPOSE

The purpose of this Request for Applications (RFA) is to solicit applications for
research grants to (1) develop genomic-scale technologies, or (2) implement
pilot-scale or large-scale projects for the discovery and scoring of single
nucleotide polymorphisms (SNPs).  The pilot/large-scale projects may be for SNPs
that are located throughout the genome or that are located in particular genome
regions or in sets of genes related to particular processes, organs, or diseases. 
The availability of a dense collection of SNPs will stimulate many areas of
biological research, including the identification of the genetic components of
disease.

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 Request for Applications (RFA),
"Methods for Discovering and Scoring Single Nucleotide Polymorphisms", is related
to several priority areas, including cancer, heart disease and stroke, diabetes
and chronic disability conditions, maternal and infant health, and others. 
Potential applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-profit
organizations, public and private organizations, such as universities, colleges,
hospitals, laboratories, companies, 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.

MECHANISM OF SUPPORT

All of the institutes participating in this RFA will use the National Institutes
of Health (NIH) individual research project grant (R01).  In addition, several
of the institutes will use the program project grant (P01) or the pilot
project/feasibility study (R21) mechanisms; investigators considering applying
for either an R21 or P01 grant should contact the appropriate program officer
(see below).  The total project period for R01 and P01 applications submitted in
response to the present RFA may not exceed 3 years.  The direct cost per year for
R01 or P01 grants may not exceed $500,000 without prior discussion with the
relevant program officer.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement. 
Future unsolicited competing continuation applications will compete with all
investigator-initiated applications and will be reviewed according to the
customary peer review procedures.

All applications received in response to this solicitation will, for
administrative reasons, be assigned initially to NHGRI.  After discussions among
the participating Institutes and Centers, applications will be reassigned to the
Institute(s) or Center(s) that are programmatically most appropriate.  Because
the scope of the research proposed in response to this RFA encompasses the
interests of several NIH Institutes and Centers, applications may receive dual
assignments based on the established PHS referral guidelines.  Awards will be
made and managed by the NHGRI and/or the other participating Institutes and
Centers.  The earliest anticipated award date is September 30, 1998.

FUNDS AVAILABLE

It is anticipated that $10 million per year will be available for this
initiative.  Awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  The amount of funding for these projects may be
increased if a large number of highly meritorious applications are received and
if funds are available.  Only applications that are found to be of high
scientific merit will be considered for funding and not all of the funds will be
spent if there are not enough highly meritorious applications.  Funding in future
years will be subject to the availability of funds.

RESEARCH OBJECTIVES

Background

Genetic factors appear to contribute to virtually every human disease, conferring
susceptibility or resistance, affecting the severity or progression of disease,
and interacting with environmental influences.  Much of current biomedical
research, in both the public and private sectors, is based upon the expectation
that understanding the genetic contribution to disease will revolutionize
diagnosis, treatment, and prevention.  Defining and understanding the role played
by genetic factors in disease will also allow the non-genetic, environmental
influence(s) on disease to be more clearly identified and understood.

Analysis of DNA sequence variation is becoming an increasingly important source
of information for identifying the genes involved in both disease and in normal
biological processes, such as development, aging, and reproduction.  In trying
to understand disease processes, information about genetic variation is critical
for understanding how genes function or malfunction, and for understanding how
genetic and functional variation are related.  Response to therapies can also be
affected by genetic differences.  Information about DNA sequence variation will
thus have a wide range of application in the analysis of disease and in the
development of diagnostic, therapeutic, and preventative strategies.

Completion of the first human DNA sequence, through the efforts of the Human
Genome Project (HGP), is expected by 2005.  While this will be of immense
significance for many reasons, the HGP will actually produce very little
information about DNA sequence variation within the human population.  Although
the DNA sequence that will be produced by the HGP will come from several
individuals, at most positions the sequence will come from only one.  The
exceptions will be regions where overlapping clones from different chromosomes
will be sequenced, but such overlap will be less than 10% of the complete
sequence.  Even in the overlap regions, DNA from only two chromosomes will be
represented at any given site. Thus, additional studies are needed to discover
the amount and distribution of variation in human DNA.

There are several types of DNA sequence variation, including insertions and
deletions, differences in the copy number of repeated sequences, and single base
pair differences.  The latter are the most frequent.  They are termed single
nucleotide polymorphisms (SNPs) when the variant sequence type has a frequency
of at least 1% in the population.  SNPs have many properties that make them
attractive to be the primary analytical reagent for the study of human sequence
variation.  In addition to their frequency, they are stable, having much lower
mutation rates than do repeat sequences.  Detection methods for SNPs are
potentially more amenable to being automated and used for large-scale genetic
analysis.  Most importantly, the nucleotide sequence variations that are
responsible for the functional changes of interest will often be SNPs.

As noted, SNPs are very common in human DNA.  Any two random chromosomes differ
at about 1 in 1000 bases.  For any particular polymorphic base (i.e., a base
where the least common variant has a frequency of at least 1% in the population),
only half or fewer of random pairs of chromosome differ at that site.  Thus,
there are actually more sites that are polymorphic in the human population,
viewed in its entirety, than the number of sites that differ between any
particular pair of chromosomes.  Altogether, there may be anywhere from 6 million
to 30 million nucleotide positions in the genome at which variation can occur in
the human population.  Thus, overall, approximately one in every 100 to 500 bases
in human DNA may be polymorphic.

Information about SNPs will be used in three ways in genetic analysis.  First,
SNPs can be used as genetic markers in mapping studies.  SNPs can be used for
whole-genome scans in pedigree-based linkage analysis of families.  A map of
about 2000 SNPs has the same analytical power for this purpose as a map of 800
microsatellite markers, currently the most frequently used type of marker. 
Second, when the genetics of a disease are studied in individuals in a
population, rather than in families, the haplotype distributions and linkage
disequilibria can be used to map genes by association methods.  For this purpose,
it has been estimated that 30,000 to as many as 300,000 mapped SNPs will be
needed.

Third, genetic analysis can be used in case-control studies to directly identify
functional SNPs contributing to a particular phenotype.  Because only three to
five percent of the human DNA sequence encodes proteins, most SNPs are located
outside of coding sequences.  But SNPs within protein-coding sequences (which
have recently been termed cSNPs) are of particular interest because they are more
likely than a random SNP to have functional significance.  It is also undoubtedly
the case that some of the SNPs in non-coding DNA will also have functional
consequences, such as those in sequences that regulate gene expression. 
Discovery of SNPs that affect biological function will become increasingly
important over the next several years, and will be greatly facilitated by the
availability of a large collection of SNPs, from which candidates for
polymorphisms with functional significance can be identified.  Accordingly,
discovery of a large number of SNPs in human DNA is one objective of this RFA.

SNPs will be particularly important for mapping and discovering the genes
associated with common diseases.  Many processes and diseases are caused or
influenced by complex interactions among multiple genes and environmental
factors.  These include processes involved in development and aging, and common
diseases such as diabetes, cancer, cardiovascular and pulmonary disease,
neurological diseases, autoimmune diseases, psychiatric illnesses, alcoholism,
common birth defects, and susceptibility to infectious diseases, teratogens, and
environmental agents.  Many of the alleles associated with health problems are
likely to have low penetrance, meaning that only a few of the individuals
carrying them will develop disease.  However, because such polymorphisms are
likely to be very common in the population, they make a significant contribution
to the health burden of the population.  Examples of common polymorphisms
associated with an increased risk of disease include the ApoE4 allele and
Alzheimer's disease, and the APC I1307K allele and colon cancer.

Most of the successes to date in identifying (a) the genes associated with
diseases inherited in a Mendelian fashion, and (b) the genetic contribution to
common diseases, e.g., BRCA1 and 2 for breast cancer, MODY 1, 2, and 3 for type
2 diabetes, and HNPCC for colon cancer, have been of genes with relatively rare,
highly penetrant variant alleles.  These genes are well-suited to discovery by
linkage analysis and positional cloning techniques.  However, the experimental
techniques and strategies useful for finding the low penetrance, high frequency
alleles involved in disease are usually not the same, and are not as well
developed, as those that have been successfully applied in positional cloning. 
For example, pedigree analysis of families often does not have sufficient power
to identify common, weakly contributing loci.  The types of association studies
that do have the power to identify such loci efficiently require new approaches,
techniques, and scientific resources to make them as robust and powerful as
positional cloning.  Among the resources needed is a genetic map of much higher
density than the existing, microsatellite-based map.  Association studies using
a dense map should allow the identification of disease alleles even for complex
diseases.  SNPs are well suited to be the basis of such a map.

Available technologies have been used to discover SNPs with a reasonable degree
of success.  Thus, there is an opportunity to begin to test the feasibility of
applying these methods in a high throughput, large-scale fashion to discover
large numbers of SNPs.  At the same time, there is clearly a need to improve
these methods and to develop new approaches to SNP discovery.  Current methods
for the discovery of SNPs are often not particularly appropriate to score known
SNPs in genotyping assays, and the available scoring techniques leave much to be
desired in terms of throughput, efficiency and cost.  Thus, there is also a
critical need to develop new methods for scoring known SNPs.

Technology development spans a spectrum of stages.  Initially it involves the
development of a new methodology or the significant improvement of an existing
methodology to the point of proof of principle.  The method must then be reduced
to practice.  For such a new method to have a significant impact on genomic
studies, it must also be shown that it can be used efficiently on a large-scale
or genomic basis; this requires another level of technology development.  This
RFA is intended to solicit applications that address any of these phases of
technology development.  Specifically, this RFA is intended to solicit research
projects of two types:  (1) development of new or improved methods, and (2)
pilot-scale or large-scale projects, for SNP discovery and scoring.  Of
particular interest are technologies that can be applied at the "genomic scale"
cost-efficiently, and can be easily exported into other laboratories, or in other
ways made readily accessible to investigators.

Objectives and Scope

The tools needed to discover and score SNPs efficiently are just beginning to
emerge and many more robust technologies are needed.  The Human Genome Project
has been successful in generating information and resources rapidly and
economically, in part, by developing and applying high-throughput and efficient
technologies.  Therefore, the NIH seeks the development of technologies that can
be applied in similar ways to the rapid and efficient discovery of SNPs and the
scoring of SNPs in many samples.  Large-scale projects for SNP discovery will
allow comparison of the various existing technologies, particularly with respect
to scalability, and will begin to generate a large collection of SNPs.

Applications are solicited in these areas:

1. Development of new or improved methods for high throughput, cost-efficient
discovery or scoring (or both) of SNPs.  SNP "discovery" involves finding new
SNPs.  SNP "scoring" involves methods to determine the genotypes of many
individuals for particular SNPs that have already been discovered.  Methods that
involve "wet bench" approaches, computational approaches, or multiplexing are
appropriate.  Proposed methods may focus on obtaining SNPs throughout the genome,
or may focus on cSNPs; they may also target particular types or sets of genes.
Methods that yield additional information (e.g. map location, haplotypes) at the
same time as the SNP itself are appropriate, although the costs and benefits of
obtaining the additional information must be discussed.  Applicants who propose
to develop new methods for SNP discovery or scoring should discuss the potential
advantages of the proposed methods over existing methods.

2. Pilot-scale or large-scale projects for SNP discovery, scoring, or both.

Pilot-scale or large-scale projects may be proposed that target random SNPs or
cSNPs on a genome-wide basis, or all of the SNPs within a defined region of one
to several megabases.  Applications may focus on genes involved in particular
processes or diseases of interest to particular Institutes, as listed below. 
Methods that focus on finding SNPs in coding sequences or regulatory regions, or
on finding SNPs for functional variants of genes, are of particular interest. 
However, the methods must be capable of being applied on a large scale. 
Proposals should include a discussion of error rates, costs, and ease of scale
up.

Most of the Institutes and Centers participating in this RFA have interests in
genes that are related to particular processes, organs, or diseases, as listed
below.  In addition, some are interested in supporting development of methods
that are either general or specific to genes in which they are interested, as
noted below.  Applications that propose to identify SNPs in or around genes of
particular interest to a participating Institute are particularly welcome.

NCI - Genes involved in cancer.

NCRR - Genes and non-coding regions anywhere in the genome.

NEI - Genes involved in the development, function, and diseases of the eye.

NHGRI - Genes and non-coding regions anywhere in the genome.

NHLBI - Genes involved in the development, function, regulation, and diseases of
the cardiovascular, pulmonary, and hematological systems.

NIA - Genes for repair enzymes for DNA, proteins, and lipids; antioxidant
enzymes; apoptosis-related proteins; receptors; stress response proteins;
transcription factors and neurodegenerative diseases of aging.  Specific gene
region: the WRN gene for Werner's syndrome.

NIAAA - Genes involved in function of the central nervous system, e.g., those
encoding neurotransmitter receptors, transporters, and biosynthetic enzymes,
neurotrophic factors and their receptors, ion channels, signal transducing
proteins, and transcription factors.  Genes whose products mediate the toxic
effects of alcohol.

NIAID - Genes involved in susceptibility to infectious diseases, allergy, and
autoimmunity.

NIAMS - Genes involved in arthritis and musculoskeletal and skin diseases.

NICHD - Genes involved in developmental biology, gametogenesis, fertilization,
embryogenesis, organogenesis, and reproductive endocrinology; genes associated
with the formation of birth defects; genes involved in mental retardation, autism
and other developmental disabilities; genes associated with learning, behavior,
and temperament; and genes affecting drug metabolizing enzymes in children.

NIDA - Genes involved in drug abuse and addiction.

NIDCD - Genes related to normal and disordered mechanisms of communication,
including hearing, balance, voice, speech, language, taste and smell.

NIDDK - Genes involved in diabetes and digestive and kidney diseases.

NIDR - Genes involved in the development, function, and diseases of craniofacial,
oral, and dental tissues.

NIEHS - Genes controlling the distribution and metabolism of toxicants; genes for
DNA repair pathways; genes for the cell cycle control system; genes for cell
death and differentiation; and genes for the signal transduction systems
controlling expression of the genes in the other categories.  For NIEHS,
participation in this RFA is the first phase of the Environmental Genome Project;
see http://dir.niehs.nih.gov/dirosd/policy/.

NIGMS - Genes and non-coding regions not targeted to disease.

NIMH - Genes involved in behavior, mental disorders, and the development,
function, and regulation of the central nervous system.

NINDS - Genes involved in neurological processes, in particular those genes or
chromosomal regions identified as related to neurological disorders or stroke.

The following Institutes and Centers are interested in supporting the development
of methods that are either general or specific to genes in which they are
interested - NCI, NCRR, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIDA, NIDDK, NIDR,
NIEHS, NIGMS, and NIMH.

Population Resources.  Most genetic variation occurs within rather than between
ethnic groups; this means that sequence variants that are common in one group are
likely to be found in other groups as well.  Efforts are currently under way to
establish a central repository of anonymous DNA samples as a resource for the
discovery of SNPs. This resource may be available by the time applications are
funded under this RFA.  However, applicants should propose one or more
alternative sources of appropriate samples in case the planned resource is not
available by that time.  Applicants for SNP discovery projects should provide
plans that will allow the detection of SNPs that are common in the U.S.
population.  In most populations studied, the minimum frequency should be 1% for
cSNPs and 10% for SNPs that are not in coding regions.

Human Subjects Issues Associated with SNP Discovery.  Recently it has become
evident that human subjects issues are raised by the large-scale sequencing of
human genomic DNA because large amounts of DNA sequence information from single
individuals will be generated.  These issues are discussed in "Guidance on Human
Subjects Issues in Large-Scale DNA Sequencing," which can be found on the NHGRI
Home Page at 
http://www.NHGRI.nih.gov/Grant_info/Funding/Statements/large_scale.html.  As a
result of the research supported under this RFA, it is possible that an analogous
situation might exist, i.e., that enough information might be developed about the
genotypes of the individuals whose DNA was used to discover SNPs to allow them
to be identified and, consequently, become subject to any risk(s) that might
arise as a result of that identification.  Applicants should address any special
human subjects issues that arise as a result of their proposed research.

Data and Materials Dissemination. The sharing of materials, data, and software
in a timely manner has been an essential element in the rapid progress that has
been made in genome research.  While Public Health Service (PHS) policy requires
that investigators make unique research resources, including DNA sequences and
mapping information, readily available when they have been published (PHS Grants
Policy Statement, April 1, 1994, pp. 8-25 to 8-26), the advisors to the NIH and
the Department of Energy (DOE) genome programs have encouraged more rapid
sharing.  This has, in fact, become the norm in the genome community.

NIH is interested in ensuring that the information about SNPs that is developed
through this RFA becomes readily available to the research community for further
research and development, in the expectation that this will eventually lead to
products of benefit to the public.  For this reason, NIH is concerned that patent
applications on large numbers of SNPs, in the absence of such demonstrated
utility, might have a chilling effect on the future development of products that
can improve the public health.  At the same time, NIH recognizes the rights of
grantees to elect and retain title to subject inventions developed under Federal
funding under the provisions of the Bayh-Dole Act.  Indeed, for inventions
developed in its intramural program, NIH does file patent applications, in accord
with a set of policies that are described at
http://www.nih.gov/od/ott/200po6.htm.

To address the joint interests of the government in the availability of, and
access to, the results of publicly funded research and in the opportunity for
economic development based on those results, NIH requires applicants who respond
to this RFA to develop and propose specific plans for sharing the data,
materials, and software generated through the grant.  For this purpose, it is the
opinion of the NIH that dissemination of such developments via individual
laboratory web sites is not sufficient, as it would force interested
investigators to have to search several different data collections to make use
of the results of this initiative.  It is preferable that data pertaining to all
SNPs discovered or scored should be placed in a common, public database.  Any
additional information known, such as map location, should similarly be deposited
in that database.  A specific database suitable for this purpose will be
identified when the awards are made.

The initial review group will comment on the proposed plan for sharing and data
release.  The adequacy of the plan will also be considered by NIH staff as one
of the criteria for award.  The proposed sharing plan, after negotiation with the
applicant when necessary, will be made a condition of the award.  Evaluation of
renewal applications will include assessment of the effectiveness of data,
material, and software release.

Applicants are also reminded that the grantee institution is required to disclose
each subject invention to the Federal Agency providing research funds within two
months after the inventor discloses it in writing to grantee institution
personnel responsible for patent matters.  The awarding Institute or Center
reserves the right to monitor grantee activity in this area to ascertain if
patents on large numbers of SNPs of ill-defined functionality are being filed.

Where appropriate, grantees may work with the private sector to make unique
resources available to the larger biomedical research community at a reasonable
cost.  Applicants may request funds to defray the costs of sharing materials or
submitting data, with adequate justification.

POST-AWARD MANAGEMENT

During the course of the grant period, it is anticipated that technologies will
improve and the rate of progress and focus of work supported by the grant(s) may
change.  During the course of the award period, the principal investigators may
be invited to meet with NIH program staff in Bethesda, MD, to review scientific
progress.  Other scientists external to and knowledgeable about these studies may
also be invited to participate.  Budget requests should include travel funds for
the PI to meet annually in the Washington DC area, should such meetings be
advisable.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 104-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18,
1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from program staff or
contact person listed under INQUIRIES.  Program staff may also provide additional
relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are encouraged to discuss their research objectives and
the appropriate grant mechanism with NIH staff in the relevant Institute or
Center early in their planning process.  Prospective applicants are asked to
submit, by March 25, 1998, a letter of intent that includes a descriptive title
of the proposed research, the name, address, email address, and telephone number
of the principal investigator, the identities of other key personnel and
participating institutions; and the number and title of this RFA.  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 will allow
NIH 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:

Lisa D. Brooks, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 614, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Lisa_Brooks@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  Applications kits are available at most institutional offices
of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: 
ASKNIH@od.nih.gov.

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 and three signed
photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application, including
appendices, must also be sent to:

Dr. Rudy Pozzatti
Office of Scientific Review
National Human Genome Research Institute
Building 38A, Room 613
38 Library Drive, MSC 6050
Bethesda, MD  20892-6050

Applications must be received by May 7, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) 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 CSR will also 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.  The applicants should also ensure that their revised
applications respond to the review criteria by which the applications in response
to this RFA will be evaluated.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for
responsiveness to the RFA by NIH program staff.  Incomplete applications will be
returned to the applicant without further consideration.  If the application is
not responsive to the RFA, NIH 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 for
scientific and technical merit in accordance with the criteria stated below by
an appropriate peer review group convened by the NHGRI.  As part of the initial
merit review, all applications will receive a written critique and may undergo
a process in which only those applications deemed to have the highest scientific
merit will be discussed and assigned a priority score.  All applications will
receive a second level of review by the appropriate National Advisory Council.

Review criteria are:

o  Significance: For technology development proposals, does this application
address the development of  a promising technology that can be usefully applied
to the rapid and efficient discovery or scoring of SNPs?  If the aims of the
application are achieved, how will it improve the capabilities of researchers to
discover SNPs or use SNPs in the genetic analysis of complex traits?

o  For pilot-scale/large scale SNP discovery proposals, does this application
address the efficient and rapid development of a useful resource of SNPs?  If the
aims of the application are achieved, how much will the SNP collection that is
available to the research community be improved?

o  Approach: Are the conceptual framework, design, methods, and analyses
appropriate and adequate to accomplish the aims of the project?  For pilot-
scale/large-scale projects, are the methods adequate to allow the rapid,
efficient detection of SNPs?  Does the applicant acknowledge potential problem
areas and consider alternate approaches? Is the scientific and technical merit
of the proposed research sufficient to advance the objectives of the RFA?

o  Innovation: Does the project employ novel concepts, approaches or method? Are
the aims original and innovative?  Does the project propose to develop new or
significantly improved methodologies or technologies for SNP discovery or
scoring?

o  Investigator: Are the Principal Investigator and staff appropriately trained
and well suited to carry out this work?  Is the work proposed appropriate to the
experience level of the principal investigator and other researchers (if any)?

o  Scalability:  For technology development or pilot-scale SNP production
projects, what is the likelihood that the technology or approach will be able to
be used efficiently at a full production level in a timely manner?

o  Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

o Budget and duration: Are the proposed budget and duration appropriate in
relation to the proposed research?

The availability of special opportunities for furthering research programs
through the use of unusual talent resources, populations, or environmental
conditions in other countries which are not readily available in the United
States or which provide augmentation of existing U.S. resources will be
considered in the review.

The initial review group also will examine the provisions for the protection of
human and animal subjects, and the safety of the research environment.  For R21
applications, preliminary data are not required.  However, the applicant does
have the responsibility to develop a sound research plan and to present any other
information that can be considered as evidence of feasibility.

The initial review group will also be asked to comment on the plans for making
the data and materials developed under the proposed project accessible to the
biomedical research community: Will the forthcoming methodologies, resources,
software, and collections of SNPs be usable by, and accessible to, the broad
scientific community of biomedical researchers who are discovering and using SNPs
in a wide range of research investigations?  Any opinions expressed by the
reviewers about this aspect of the proposal will be recorded as an administrative
note.

AWARD CRITERIA

The earliest anticipated date of award is September 30, 1998.  Subject to the
availability of funds, and consonant with the priorities of this RFA, the
participating Institutes and Centers will provide funds for a project period of
up to three years.  Factors that will be used to make award decisions are:

o  quality of the proposed project as determined by peer review;
o  balance among the projects in addressing different experimental approaches and
their complementarity to other ongoing efforts;
o  adequacy of plans to make data and material developed as a result of the
proposed research accessible to the biomedical research community in a timely
manner; and
o  availability of funds.

INQUIRIES

Written, telephone, and email inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues and mechanisms of support to the
following NIH staff.

Lisa D. Brooks, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 614, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Lisa_Brooks@nih.gov

Grace L. Shen, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 501
Rockville, MD  20892-7381
Telephone:  (301) 496-5226
FAX:  (301) 496-8656
Email:  gs35r@nih.gov

Marjorie Tingle, Ph.D
Health Science Administrator
National Center for Research Resources
6705 Rockledge Drive, Room 6154
Bethesda, MD  20892
Telephone:  (301) 435-0772
FAX:  (301) 480-3659
Email:  marjoriet@ep.ncrr.nih.gov

Maria Y. Giovanni, Ph.D
National Eye Institute
Executive Plaza South, Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  myg@ nei.nih.gov

Stephen C. Mockrin, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
TWO Rockledge Centre
6701 Rockledge Drive, Suite 9044, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0477
FAX:  (301) 480-1336
Email:  mockrins@gwgate.nhlbi.nih.gov

Huber R. Warner, PhD
Biology of Aging Program
National Institute on Aging
Gateway Building, Room 2C231
Bethesda, MD  20892
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  warnerh@exmur.nia.nih.gov

Robert W.Karp, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
Division of Basic Research
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov

Vicki Seyfert, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A21
Bethesda, MD  20852
Telephone:  (301) 496-7551
FAX:  (301) 402-2571
Email:  vs62y@nih.gov

Steven J. Hausman, Ph.D.
Extramural Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 45, Room 5AS-13F, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-2463
FAX:  (301) 480-4543
Email:  sh41g@nih.gov

A. Tyl Hewitt, Ph.D.
Genetics and Teratology Branch
National Institute of Child Health and Human Development
Executive Building, Room 4B01
6100 Executive Blvd., MSC 7510
Bethesda, MD  20892
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  HewittT@hd01.nichd.nih.gov

Theresa Lee, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A19
Rockville, MD  20857
Telephone:  (301) 443-6300
FAX:  (301) 594-6043
Email:  tl37h@nih.gov

Catherine McKeon, Ph.D.
Metabolic Diseases and Gene Therapy Research Program
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN.18B
Bethesda, MD  20892-6600
Telephone:  (301) 594-8810
FAX:  (301) 480-3505
Email:  Catherine_McKeon@nih.gov

Rochelle K. Small, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400C, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3464
FAX:  (301) 402-6251
Email:  rochelle_small@nih.gov

Linda Thomas, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-24J
Bethesda, MD  20892-6402
Telephone:  (301) 594-2425
(301) 480-8318
Email:  ThomasL@de45.nidr.nih.gov

Jose M. Velazquez, Ph.D.
Program Administrator
National Institute of Environmental Health Sciences
P.O.Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 541-2843
Email:  Velazqu1@niehs.nih.gov

Irene Eckstrand, Ph.D.
Program Director
Developmental and Cellular Processes Branch
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.25K
Bethesda, MD 20892-6200
(301) 594-0943
(301) 480-2228 (fax)
Email:  irene_eckstrand@nih.gov

Steven O. Moldin, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD 20857
(301) 443-2037
(301) 443-9890
Email:  smoldin@nih.gov

Judy Small, Ph.D.
Division of Fundamental Neurosciences and Developmental Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8C04
Bethesda, MD  20892
Telephone:  (301) 496-5821
FAX:  (301) 402-0887
Email:  js134h@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jean Cahill
Grants Management Officer
National Human Genome Research Institute
Building 38A, Room 613, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 402-0733
FAX:  (301) 402-1951
Email:  Jean_Cahill@nih.gov

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 PHS strongly encourages all grant and contract 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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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