NETWORK FOR LARGE-SCALE SEQUENCING OF THE RAT GENOME

Release Date:  July 17, 2000

RFA:  HG-00-002

National Human Genome Research Institute
  http://www.nhgri.nih.gov/
National Heart, Lung and Blood Institute
  http://www.nhlbi.nih.gov/index.htm

Letter of Intent Receipt Date:  August 15, 2000
Application Receipt Date:       September 21, 2000

PURPOSE

This is a joint initiative between the NHGRI and the NHLBI to expand the current NHGRI 
program for sequencing the rat genome.  The goal of this program is to generate a 
working draft version (3-4 fold sequence coverage) of the rat genome sequence in two 
years or less.  This announcement is intended to solicit proposals to accomplish two 
of the sequencing elements of this program: light sequence coverage of individual BAC 
clones, and whole genome shotgun sequencing.  

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion and 
disease prevention objectives of "Healthy People 2010," a PHS-led national activity 
for setting priority areas.  This Request for Applications (RFA), Network for Large-
Scale Sequencing of the Rat Genome, is related to several of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://health.gov/healthypeople/.

ELIGIBILITY REQUIRMENTS

Applications may be submitted by domestic non-profit and for-profit organizations, 
private and public, such as universities, colleges, private companies, hospitals, 
laboratories, units of state or local governments, and eligible agencies of the 
Federal government. Applications from foreign institutions will not be accepted; 
however subcontracts to foreign institutions will be considered.  Racial/ethnic 
minority individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.

The goals of this RFA can be met in a reasonable time frame only by groups that are 
already sequencing at a significant scale.  Therefore, applications will be accepted 
only from organizations that have attempted at least 1,000,000 lanes of genomic 
sequence data in the 12 months prior to the submission date.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Cooperative Agreement, an 
"assistance" mechanism which is distinguished from a regular research grant in that 
substantial scientific and/or programmatic involvement by NHGRI and NHLBI staff with 
the awardee is anticipated. The cooperative agreement is used when participation by 
NIH staff is warranted to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in a partner 
role; NIH staff will not assume direction, prime responsibility, or a dominant role in 
the activity. Details of the responsibilities, relationships, and governance of the 
studies funded under cooperative agreement(s) are discussed later in this document 
under the section "Terms and Conditions of Award".  Applicants may apply for either a 
new cooperative agreement (U01) or a competing supplement to an existing NHGRI 
cooperative agreement (U01 or U54).  This initiative will be managed by NHGRI staff 
with input and the close cooperation of NHLBI staff.

The length of the project period is two years.   The sizes of the awards will be 
dependent upon the results of the peer review process. The anticipated award date is 
January 1, 2001. 

FUNDS AVAILABLE

It is estimated that up to $32 million (total costs) will be available to support the 
first year of awards made in response to this RFA and up to $26 million (total costs) 
for the second year of support. One to three awards will be made.   In combination 
with the amount of funds that NHGRI has already awarded to two centers to begin work 
on this project, the total amount of funds should be adequate to support the 
generation of the working draft sequence of the rat. The actual level of support will 
be dependent on the receipt of a sufficient number of applications of high scientific 
merit and the availability of funds. The funding level of each of the sequencing 
centers will be subject to an annual evaluation by the Scientific Advisory Panel of 
the Genome Sequencing Network (see below for details). 

RESEARCH OBJECTIVES AND SCOPE

Background 

The NHGRI is currently engaged, along with several other federal, private, and 
international organizations, in a multi-year research program called the Human Genome 
Project (HGP).  Many of the initial goals of the HGP, including genetic and physical 
maps of the mouse and human, and the DNA sequences of E. coli, S. cerevisiae, C. 
elegans and D. melanogaster, have been realized.   Significant progress has also been 
made toward the sequencing of the human genome.  By the end of June 2000, the public 
sequencing effort had released approximately 85% of the genome in at least "working 
draft" form, with more than 20% of the human sequence, including all of chromosomes 21 
and 22, in finished form. The complete high quality human sequence will follow within 
the next two to three years. Mouse genome sequencing has also begun; an intermediate 
version of the mouse sequence will be generated within the next two years and the 
complete sequence will follow no later than 2005 and probably much sooner.

As sequencing technology and efficiency have improved, the capacity of the world-wide 
sequencing enterprise has increased substantially.  Production sequencing capacity has 
reached the point that one or a few large-scale centers can complete the sequencing of 
an entire large genome in a short time.  This presents an opportunity to sequence 
multiple large genomes in parallel.

The availability of the genome sequence from three mammalian genomes would accelerate 
the annotation of the human genome, since regions of evolutionary conservation between 
the three genomes will help to identify protein coding sequences and other important 
sequence features, such as regulatory regions.  The rat genome is a clear choice to be 
sequenced as the third model mammalian sequence as it has served as an important 
physiological model for the human for many years. The NIH has already invested 
significantly in generating genomic resources for the rat.  In recognition of the 
potential of rat models to contribute to the understanding of basic biology and human 
health and disease, the NIH launched the Rat Genome Program in 1995, and the Rat EST 
Program in 1997.  In addition, the Rat Genome Database is now on line 
(http://rgd.mcw.edu/).  These three programs, led collaboratively by the NHLBI and 
NHGRI, were funded by a number of Institutes and Centers at NIH and have produced a 
variety of basic genomic resources for the rat. Obtaining the sequence of the rat 
genome would bring nearly two hundred years of pharmacological, toxicological, and 
physiological data from the rat into genomic context.  The biological relevance and 
wealth of phenotypic data in the rat, when combined with the current and proposed 
genomic resources in mouse and human, would accelerate the development of new 
diagnostic, prevention, and treatment approaches for human medicine.  Recognizing the 
value of obtaining the sequence of three mammalian organisms, the human, mouse and rat 
as soon as possible, NHGRI and NHLBI have initiated the rat genome sequencing 
initiative.  Two NHGRI-supported sequencing centers have already begun a sequencing 
effort to generate one-fold sequence coverage of the rat genome within the next year. 
 
Research Scope 

The initial goal of the Rat Genome Sequencing Project will be to generate a working 
draft sequence (approximately 4-fold average sequence coverage) of 90% of the 
euchromatic portions of the rat genome in two years.  On the basis of lessons learned 
during the sequencing of the human genome, the NHGRI wishes to evaluate a hybrid 
sequencing strategy, involving both map-based and whole genome shotgun components, for 
sequencing the mouse and rat genomes. 

The map-based component of the hybrid strategy will consist of light sequence coverage 
(about 1 fold) of a set of BAC clones covering the genome (the fingerprints and end 
sequences of those clones will be funded separately and made publicly available). The 
whole-genome shotgun sequence component, consisting of sequence derived from members 
of a random shotgun library of the entire rat genome (e.g., paired plasmid-end 
sequence) will represent the majority of the sequence data to be obtained.  The hybrid 
strategy is designed to quickly obtain a useful representation of the rat DNA 
sequence, while facilitating the assembly of the whole genome shotgun sequence data 
and its proper alignment along the chromosomal map.   Applicants should submit 
proposals to participate in the implementation and evaluation of the hybrid sequencing 
strategy for the rat genome 

This strategy requires a tightly focused, large-scale effort, involving no more than 
two or three sequencing centers.  In order to initiate the project rapidly and cost 
effectively, only existing large-scale efforts are eligible to apply (see above). Once 
the awards are made, the groups funded under this RFA, along with the NIH staff 
participants in the cooperative agreements, will develop a collaborative plan to 
produce the rat genome working draft sequence.

Applicants for production sequencing must address the items listed in Application 
Guidance for Production Sequencing under Application Procedures. 

NHGRI POLICIES CONCERNING DNA SEQUENCING

Over the past several years, NHGRI has established a number of policies related to 
large-scale sequencing as described below. These policies will apply to all awards 
made as a result of this RFA. Thus, where applicable, applicants must present plans to 
adhere to the policies: 

Intellectual Property.  In NHGRI's opinion, in the absence of specific biological 
information, genomic DNA sequence information should not be patented but released into 
the public domain where it will be freely available for use by the entire research 
community (see web site: 
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/intellectual_property.html) 
Applicants are 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 (see http://www.iedison.gov/).  NHGRI and NHLBI will 
monitor adherence to this policy through the use of the appropriate existing 
databases, to learn whether or not attempts are being made to patent large blocks of 
primary rat genomic DNA sequence. 

Data Release.  In the case of the sequencing of the human, NHGRI policy encourages 
grantees to release DNA sequence assemblies of 2,000 base pair units or larger within 
24 hours of assembly (see http://www.nhgri.nih.gov/Grant_info/Funding/Statements/). 
Participants in the international human DNA sequencing effort have recommended that 
this policy be applied to sequence data from any organism (Genome Research, Vol. 8, 
Issue 5, 413-413, May 1998).  However, as currently stated, the policy is not 
immediately applicable to sequence data generated from a whole genome shotgun project 
because such data will not, early in the project, fall into the 2 kb contigs to which 
the policy refers.  NHGRI is currently consulting with a number of advisors, including 
sequencers, sequence users, and the National Advisory Council for Human Genome 
Research, to develop an extension of the policy that will continue to ensure the 
public release of hybrid map-based/whole genome shotgun data on a similarly rapid 
basis.

Sequence Quality.  An important component of the HGP's sequencing program has been the 
establishment of quality standards for sequence products, both finished and working 
draft sequence.  Just as important has been the assessment of sequence data produced 
by the HGP participants.  The standards and results of previous quality assessment 
exercises are described at 
http://www.nhgri.nih.gov:80/Grant_info/Funding/Statements/RFA/quality_standard.html.  
NHGRI intends to assess the quality of the sequence data produced by the hybrid 
strategy.  However, the quality standards for a working draft determined by a hybrid 
strategy will necessarily have to be modified from those previously established for 
human working draft. Thus, as in the case of the data release policy, an extension of 
the existing policy is needed and is currently being formulated. The assessment 
criteria are likely to include read quality, data tracking, and assembly quality. 

The quality of genomic data that a center has produced in the last year is likely to 
be a reasonable general indicator of the quality of rat genome sequence that will be 
produced, even if a different strategy (BAC by BAC) was used.   Accordingly, 
applicants should describe their experience in assessing the quality of their sequence 
product  (as described under special application guidance for production sequencing), 
as well as discuss the results of recent NHGRI-conducted quality assessment of their 
sequence data.  If an applicant has not participated in an NHGRI-sponsored quality 
assessment exercise, s/he should be prepared to submit data for independent analysis 
during the review of their applications, if the reviewers request such information.  

SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS

I.  Definitions 

ARBITRATION PANEL: A panel that is formed to review scientific or programmatic 
disagreement (within the scope of the award) that may arise between award recipients 
and NHGRI and NHLBI.  It will be composed of three members: (i) a designee of the 
Steering Committee chosen without the NHGRI and NHLBI staff voting, (ii) one 
NHGRI/NHLBI designee, and (iii) a third designee with relevant expertise who is chosen 
by the other two (in the case of an individual disagreement, the first member may be 
chosen by the individual awardee). The Arbitration Panel will help resolve both 
scientific and programmatic issues that develop during the course of work and that 
restrict progress. 

AWARDEE: The institution to which the cooperative agreement is awarded. 

COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated 
substantial involvement by NHGRI/NHLBI program staff with the recipient organization 
during the performance of the planned activity. 

GENOME SEQUENCING NETWORK: A group of scientists, each funded by a separate 
cooperative agreement, working together to complete the DNA sequences of vertebrate 
genomes.  The Genome Sequencing Network currently is made up of extramural and NIH 
intramural researchers involved in sequencing the human and mouse genomes. 

NHGRI AND NHLBI PROGRAM DIRECTOR(S): Scientists of the NHGRI and NHLBI extramural 
staffs who provide normal stewardship for the awards and who, in addition, have 
substantial scientific/programming involvement during conduct of this activity, as 
defined in the terms and conditions of award. The nature of this involvement is 
described below.

PRINCIPAL INVESTIGATOR (P.I.): The person who assembles the project, is responsible 
for submitting the application in response to this RFA, and is responsible for the 
performance of the project. The Principal Investigator will coordinate project 
activities scientifically and administratively. 

STEERING COMMITTEE (SC): A committee that is the main governing board of the Genome 
Sequencing Network. Membership includes the NHGRI and NHLBI Program Directors, the 
P.I. of each awarded sequencing project, as well as the projects to characterize the 
BAC libraries.  Each cooperative agreement will have one vote. If needed, 
subcommittees may be established to discuss issues that arise in the genome sequencing 
of a specific organism.  

SCIENTIFIC ADVISORY PANEL (SAP): A panel that evaluates the progress of the Genome 
Sequencing Network and provides recommendations to the Director, NHGRI, about 
continued support of the components of the Genome Sequencing Network. The Advisory 
Panel is composed of four to six senior scientists with relevant expertise who are not 
P.I.s of a cooperative agreement involved in the Genome Sequencing Network. A new 
member will be jointly appointed to the SAP by the Directors, NHGRI and NHLBI, to 
provide further advice on the rat genome sequencing project. If it is deemed 
necessary, a subcommittee to the SAP may be appointed to deal with any specific issues 
that might arise with the rat genome sequencing project.  This subcommittee will be 
appointed by the Directors, NHGRI and NHLBI.  

II.  Terms and Conditions of Award 

The following terms and conditions will be incorporated into the award statement and 
will be provided to the Principal Investigator, as well as the appropriate 
institutional official, at the time of award.  The following special terms of award 
are in addition to, and not in lieu of, otherwise applicable OMB administrative 
guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 [Part 92 is 
applicable when State and local Governments are eligible to apply], and other HHS, 
NIH, and NIH grant administration policies: 

1.  The administrative and funding instrument used for this program will be the 
Cooperative Agreement (U01, U54).  The cooperative agreement is an "assistance" 
mechanism (rather than an "acquisition" mechanism), in which substantial NIH 
scientific and/or programmatic involvement with the awardee is anticipated during the 
performance of the activity. Under the Cooperative Agreement, the NIH purpose is to 
support and/or stimulate the recipient's activity by involvement in and otherwise 
working jointly with the award recipient in a partner role, but it is not to assume 
direction, prime responsibility, or a dominant role in the activity. Consistent with 
this concept, the dominant role and prime responsibility for the activity resides with 
the awardee(s) for the project as a whole, although specific tasks and activities in 
carrying out the study will be shared among the awardee(s) and the NHGRI and NHLBI 
Program Directors.

2. P.I. Rights and Responsibilities: 

The P.I. will have the primary responsibility for defining the details for the project 
within the guidelines of the RFA and for performing the scientific activity. The P.I. 
will agree to accept close coordination, cooperation, and participation of NHGRI and 
NHLBI staff in those aspects of scientific and technical management of the project as 
described under "NHGRI and NHLBI Program Staff Responsibilities." 

The P.I. of a sequence production center will: 

o  Determine experimental approaches, design protocols, set project milestones and 
conduct experiments
o  Ensure that the genomic sequence produced meets a quality standard and cost agreed 
upon at the time of award 
o  Ensure that data resources developed as part of this project are released according 
to NHGRI policies and that results are published and submitted to a public database 
o  Adhere to the NHGRI policies regarding intellectual property, data release and 
other policies that might be established during the course of this activity 
o  Submit data for quality assessment in any manner specified by the Steering 
Committee or the Scientific Advisory Panel. 
o  Submit periodic progress reports in a standard format, as agreed upon by the 
Steering Committee and the Scientific Advisory Panel 
o  Accept and implement the common guidelines and procedures approved by the Steering 
Committee 
o  Accept and participate in the cooperative nature of the group 
o  Attend Steering Committee meetings 
o Coordinate and collaborate with other U.S. and international groups sequencing the 
rat genome 

3. NHGRI and NHLBI Program Staff Responsibilities: 

The NHGRI and NHLBI Program Directors will have substantial scientific/programmatic 
involvement during the conduct of this activity through technical assistance, advice 
and coordination.  However, the role of NHGRI and NHLBI will be to facilitate and not 
to direct the activities. It is anticipated that decisions in all activities will be 
reached by consensus of the Genome Sequencing Network and that NHGRI and NHLBI staff 
will be given the opportunity to offer input to this process. One NHGRI and one NHLBI 
Program Director shall participate as a member of the Steering Committee.  Together, 
NHGRI and NHLBI staff will have two votes.  The Program Directors will: 

o  Participate (with the other Steering Committee members) in the group process of 
setting research priorities, deciding optimal research approaches and protocol 
designs, and contributing to the adjustment of research protocols or approaches as 
warranted. The Program Directors will assist and facilitate the group process and not 
direct it. 
o  Serve as liaison, helping to coordinate activities among and for the awardees, 
including acting as a liaison to the NHGRI and NHLBI and the other Institutes and 
Centers of the NIH, and as an information resource about extramural genome research 
activities. The Program Directors will also coordinate the efforts of the Genome 
Sequencing Network with other U.S. large-scale sequencing efforts and with the 
international sequencing community.
o  Attend all Steering Committee meetings as a voting member and assist in developing 
operating guidelines, quality control procedures, and consistent policies for dealing 
with recurrent situations that require coordinated action. The Program Directors must 
be informed of all major interactions of members of the Steering Committee. The NHGRI 
and NHLBI Program Directors will be responsible for scheduling the time and preparing 
concise (3 to 4 pages) minutes or a summary of the Steering Committee meetings, which 
will be delivered to members of the group within 30 days after each meeting.  The 
Program Directors will report progress to the NHGRI and NHLBI Directors, and other NIH 
Institutes and Centers periodically. 
o  Lend relevant expertise and overall knowledge of NHGRI- and NHLBI- sponsored 
research to facilitate the selection of scientists not affiliated with the awardee 
institutions who are to serve on the Advisory Panel and the Steering Committee. 
o  Serve as liaison between the Steering Committee and the Advisory Panel, attending 
Advisory Panel meetings in a non-voting liaison member role. 
o  Serve on subcommittees of the Steering Committee and the Advisory Panel, as 
appropriate. 
o  Provide advice in the management and technical performance of the investigation. 
o  Assist in promoting the availability of the rat genome sequence and related 
resources developed in the course of this project to the scientific community at 
large. 
o  Retain the option to recommend the withholding or reduction of support from any 
project within the Genome Sequencing Network that substantially fails to achieve its 
sequencing goals at the quality and cost agreed to at the time of award, fails to 
remain state of the art in its production sequencing capabilities, or fails to comply 
with the Terms and Conditions of the award. 
o Participate in data analyses, interpretations, and where warranted, co-authorship of 
the publication of results of studies conducted through the Genome Sequencing Network. 

4. Collaborative Responsibilities

The Steering Committee will serve as the main governing board of the Genome Sequencing 
Network. The Steering Committee membership will include the NHGRI and NHLBI Program 
Director(s), and the P.I. from each awarded cooperative agreement and intramural 
project.  Additional members may be added by action of the Steering Committee. Other 
government staff may attend the Steering Committee meetings, if their expertise is 
required for specific discussions. The National Center for Biotechnology Information 
will maintain a central server to coordinate this project and will attend the Steering 
Committee meetings. It will not be a member of the committee or have a vote. 
 
The Steering Committee will be responsible for discussing progress within the Genome 
Sequencing Network, and for advising NHGRI and NHLBI as to how the Genome Sequencing 
Network can complete the working draft rat DNA sequence within the stated goals of 
time and accuracy, and within budget. The Steering Committee will help to develop 
uniform procedures for data quality assessment. Members of the Steering Committee will 
be required to accept and implement the common guidelines and procedures approved by 
the Steering Committee. 

5. Scientific Advisory Panel 

The Scientific Advisory Panel will be responsible for reviewing and evaluating the 
progress of the Rat Genome Sequencing Network toward producing a working draft 
sequence of the rat DNA sequence by 2002. The membership of the Scientific Advisory 
Panel is described in the Definitions section, above. The membership of the Advisory 
Panel may be enlarged permanently, or on an ad hoc basis, as needed.  

The Scientific Advisory Panel will meet at least once a year. The first part of this 
meeting will be a joint meeting with the Steering Committee to allow the Advisory 
Panel members to interact directly with the members of the Genome Sequencing Network. 
Annually, the Advisory Panel will make recommendations regarding progress of the 
Genome Sequencing Network and present advice about changes, if any, which may be 
necessary in the Genome Sequencing Network program to the Directors, NHGRI and NHLBI. 

6. Arbitration Process 

Any disagreement that may arise on scientific/programmatic matters (within the scope 
of the award), between award recipients and the NHGRI and NHLBI may be brought to 
arbitration.  An Arbitration Panel, whose composition is described in the Definitions 
(above) will be convened.  This special arbitration procedure in no way affects the 
awardee's right to appeal an adverse action that is otherwise appealable in accordance 
with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 
 
7. Yearly Milestones 

All Awardees participating in the Genome Sequencing Network will be asked to define 
yearly milestones at the time of the award and to update these milestones annually at 
the anniversary date. These will be made a condition of the award.  In accord with the 
procedures described above, NHGRI and NHLBI may withhold or reduce funds for projects 
that substantially fail to meet their milestones or to maintain the state of the art. 

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within specified 
page limitations.  Unless otherwise specified in an NIH solicitation, internet 
addresses (URLs) should not be used to provide information necessary to the review 
because reviewers are under no obligation to view the Internet sites.  Reviewers are 
cautioned that their anonymity may be compromised when they directly access an 
Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone number of 
the Principal Investigator, the identities of other key personnel and participating 
institutions, and the number and title of the RFA in response to which the application 
may be submitted. Although a letter of intent is not required, is not binding, and 
does not enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan the 
review.

The letter of intent should be sent by August 15, 2000 to:
 
Dr. Jane L. Peterson
Program  /Director, Large Scale Sequencing
National Human Genome Research Institute 
National Institutes of Health 
Building 31, Room B2B07, MSC2033
Bethesda, MD 20892-2033 

APPLICATION PROCEDURES

The research grant application form NIH 398 (rev. 4/98) is to be used in applying for 
these grants. These forms 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 301/435-0714, E-mail:GrantsInfo@nih.gov. 

The RFA label available in the NIH 398 (Rev 4/98) application form must be affixed to 
the bottom of the face page of the application.  Type the RFA number on the label.   
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.   

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change. Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the Checklist, and 
three signed photocopies, in one package to: 

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

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

Dr. Ken Nakamura
Scientific Review Administrator 
Office of Scientific Review 
Building 31, Room B2B37, MSC 2032
National Human Genome Research Institute 
National Institutes of Health 
Bethesda, MD 20982-2032
Telephone: (301) 402-0838 

Applications must be received by September 21, 2000.  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 that is essentially the same 
as one currently pending initial review, unless the applicant withdraws the pending 
application. The CSR will not accept any application that is essentially the same as 
one already reviewed.

SPECIAL APPLICATION GUIDANCE FOR PRODUCTION SEQUENCING

Applicants must consider and address the following in preparing applications for 
sequence production projects called for in this RFA: 

I. Progress Report

The NHGRI has conducted several competitions for large-scale sequencing projects 
during the past few years.  In so doing, it has been our experience that there are 
specific information items that are central to the review of large-scale sequencing 
proposals, and that the applications that have been most highly rated have provided 
that information clearly and succinctly. 

For the purposes of this RFA, completed data is defined as any genomic sequence data 
produced in your center. 

Section A. Text.  The total length for this section should not exceed 10-15 pages 
(5000-7500 words). Brief, concise answers are encouraged. Please focus these answers 
on your past accomplishments, rather than future plans, unless specifically asked for. 

1. Sequence production. How does your group's past effort support its ability to 
successfully accommodate the rat sequencing project? Discussion should include, but is 
not limited to: 

Prior experience in sequencing and increasing throughput. What is the amount of 
genomic sequence produced in the last year by your center? How much of that, if any, 
was deposited in a public database? Based on an average of the last three months of 
sequencing, what is the total current capacity of your group (include the number of 
attempted lanes per month, the number of successful lanes per month, and the number of 
base pairs per lane at of least phred 20--or equivalent--quality)? Please include 
capacity from sequencing genomic DNA of other organisms and capacity due to funding 
from all sources. If you have produced paired end reads from cloned inserts, describe 
your experience in tracking the paired ends as well as your success in retrieving the 
data. Applicant's experience, if any, in whole genome shotgun sequencing should be 
described.

Prior experience in attaining milestones. What example(s) can you provide that you
have proposed milestones for a sequencing project and then met them on schedule? What
internal metrics have you used to evaluate progress in the past and what internal
metrics (for example, reads/month, failed lanes, base pairs per lane in GenBank, etc.)
do you believe will be the most useful to you in managing your project's sequencing 
performance? 

Cost analysis.  What is your current cost per lane for shotgun sequence?  Do you 
anticipate being able to reduce that further in the next year?  In the next two years? 
If so, please explain how.  You should express cost analyses in terms of total costs, 
which include all equipment and indirect costs, as well as direct costs. How do you 
monitor costs internally? 
     
Integration.  Do you anticipate that there will be any issues associated with 
expanding your center's program to include sequencing the genome of a new organism? If 
not, please explain why.  If so, please discuss how those integration problems will be 
addressed.

2. Discuss how your center checks the quality of the sequence it produces. 

3. How do you expect your management plan to accommodate the needs of this project? 

4. State your data release policy. 

Section B. Graphical and Tabular Material

Please provide the following material. 

1. A graph indicating, for the past year, the number of lanes attempted per week, the 
number of successful lanes per week, and the weekly success rate. 

2. Please provide a graph showing shotgun sequence output per month for at least the 
last 12 months.  (This should be a non-cumulative monthly total.) 

II. Research Proposal

Sequence Production Plan. The applicant must present a plan to implement and evaluate 
the hybrid map-based/whole genome shotgun strategy for sequencing the rat genome, and 
propose milestones for achieving the proposed sequence production.  This must 
thoroughly discuss and justify the applicant's specific choices pertinent to all 
phases of the sequence pipeline, starting with subcloning of BAC clones (for the map-
based arm) or production of a whole genome shotgun library (for the other arm) through 
release of the sequence data to GenBank.  The applicant should also discuss how the 
data to be generated could be used to produce the finished rat sequence if such an 
outcome were to be called for by the NHGRI and NHLBI.  It will be important to discuss 
potential bottlenecks or other problems that may be anticipated and how they will be 
addressed.  Finally a plan for assembly (including a description of computational 
issues) of the whole genome shotgun and individual BAC data must be provided.

Sequence Cost. Both past (monthly costs for the first six months of 2000) sequencing 
costs and projected costs for rat sequence production must be included.  Costs should 
reflect the production only of working draft quality sequence; it is not necessary to 
include finishing costs.  The calculated costs of sequencing (both prior and projected 
sequencing costs) must take into account all of the expenses associated with working 
draft sequence production, beginning with construction of a BAC subclone library or 
whole genome shotgun library, through assembly of the working draft sequence to the 
depth proposed and data submission.  The total cost of sequencing must also include 
any production-related technology development (see below) that has been or will be 
supported by the project. However, the applicant must also provide a breakdown of 
costs so that the reviewers can evaluate the contribution of different cost elements, 
such as production-related technology development, to the reported total cost. 

Sequence Quality: Applicants should describe existing quality assessment protocols and 
an analysis of the quality of sequence produced in the period January through June 
2000. Internal quality control programs should be described, including quality 
assessment criteria.  Evidence of the usefulness of such programs should be included, 
as well as any changes being proposed for the rat sequencing project.  Applicants must 
also be prepared to submit sequence data produced in the last six months, including 
sequence traces, success rates, and information about data tracking, prior to review 
if NHGRI and the reviewers decide that data quality needs to be assessed in more 
detail.   This decision will be made after the application has been seen by the 
reviewers.  If an applicant's data have been evaluated by an NHGRI quality assessment 
exercise in the past six months, this may be sufficient to fulfill this requirement.  

Management Plan. The management of a sequencing center requires a significant 
commitment by the P.I. of the project.  A P.I. for a large-scale project is expected 
to devote at least 30% effort to the project.  If a P.I. is already devoting more than 
30% effort to the existing center, an additional 10% effort should be committed to the 
rat sequencing project.  A description of how the rat sequencing project will be 
integrated into the other sequencing activities of the center should be provided.

REVIEW CONSIDERATIONS

General Considerations 

Upon receipt, applications will be reviewed for completeness by CSR and for 
responsiveness by the NHGRI and NHLBI. Incomplete applications will be returned to the 
applicant without further consideration. If NHGRI and NHLBI staff find that the 
application is not responsive to the RFA, it will be returned without further 
consideration. 

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by the 
NHGRI and NHLBI in accordance with the review criteria stated below. As part of the 
initial merit review, a process will be used by the initial review group in which 
applications receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the top half of 
the applications under review, will be discussed, assigned a priority score, and 
receive a second level review by the National Advisory Council for Human Genome 
Research and by the National Heart Lung and Blood Advisory Council.  

All applications will be judged on the basis of the scientific and technical merit of 
the proposed projects and the documented ability of the investigators to meet the 
RESEARCH OBJECTIVES of the RFA. 

Review Criteria 

The application must be directed toward attaining the programmatic goals as stated 
under RESEARCH OBJECTIVES AND SCOPE. The following criteria will be used by peer 
review groups to evaluate these applications: 

o  Likelihood that the project will produce a significant fraction of the rat genome 
working draft sequence
o  Prior experience and quality of the proposed plan for: 
a) Producing high quality sequence data 
b) Increasing sequence throughput
c) Decreasing sequencing costs
o  Quality of the proposed plan for sequence production and identifying and solving 
critical integration problems, including adequacy of the informatics activities. 
o  Sequence quality: 
a) Merit of sequence quality assessment plans, including  monitoring and minimizing
sequencing errors, and other QA/QC plans 
b) Results from NHGRI sequence quality assessment exercises
o  Track Record of the P.I. and other key personnel 
o  Quality of the center's existing management, including workflow, plans for further 
scale-up to accommodate rat genomic sequencing, divisions of labor/responsibility 
among components, coordination between components, appropriate staffing, training, 
etc.
o  Plans for release of data and resources developed through this project. 
o  Plans to coordinate efforts with other U.S. and international large-scale 
sequencing groups and mapping efforts
o  Availability of the facilities, resources, expertise and technology necessary to 
perform the research, and the level of institutional commitment. 
o  Appropriateness of the proposed budget and time-line in relation to the proposed 
research. 

AWARD CRITERIA

Awards will be made on the basis of scientific and technical merit as determined by 
peer review, including the significance of the projected contribution toward meeting 
the NHGRI program goal of contributing to the completion of the rat genome working 
draft DNA sequence by the year 2003, program needs and balance, data release and 
intellectual property, and the availability of funds. 

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged. The opportunity to 
clarify issues or questions about the RFA from potential applicants is welcome.   
Direct inquiries regarding programmatic issues to:

Dr. Jane L. Peterson (for sequencing)
Division of Extramural Research 
National Human Genome Research Institute 
National Institutes of Health 
Building 31, Room B2B07 MSC 2033
Bethesda, MD 20892-2033
Telephone: (301) 496-7531 
FAX: (301) 480-2770 
E-mail:Jane_Peterson@nih.gov 

Dr. Ken Nakamura (for review)
Scientific Review Administrator 
Office of Scientific Review 
National Human Genome Research Institute 
National Institutes of Health 
Building 31, Room B2B37, MSC 2032
Bethesda, MD 20982-2032
Telephone: (301) 402-0838
E-mail:  Ken_Nakamura@nih.gov

Direct inquiries regarding fiscal matters to:
Ms. Jean Cahill 
Grants Administration Branch 
National Human Genome Research Institute 
Building 31, Room B2B34, MSC 2031
Bethesda, MD 20892-2031
Telephone: (301) 402-0733 
FAX: (301) 402-1951 
E-mail:Jean_Cahill@nih.gov 

Schedule 
Letter of Intent Receipt Date: August 15, 2000
Application Receipt Date: September 21, 2000
Scientific Review Date: October/November, 2000
Advisory Council Date: December, 2000
Anticipated Award Date: January 1, 2001

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic Assistance No. 93.172. 
Awards are made under the authority 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 NIH grants policies and Federal Regulations 42 CFR Part 52 and 45 
CFR Parts 74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 122372 or Health Systems Agency review. 

The NIH 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 NIH mission to protect and advance the physical 
and mental health of the American people. 

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