OPPORTUNITY FOR OBTAINING THE SEQUENCE OF MOUSE DNA OF PARTICULARLY HIGH 
BIOMEDICAL INTEREST 

Release Date:  January 12, 2000

NOTICE:  HG-00-001

National Human Genome Research Institute

Submission dates for 2000: February 1, April 1, June 1, August 1, October 1, and 
December 1.

BACKGROUND AND PURPOSE

The National Institutes of Health (NIH), through the National Human Genome 
Research Institute (NHGRI), has funded a research network of large-scale 
sequencing centers to sequence the mouse genome.  The mouse sequence is a 
critical resource that will provide a rich trove of information for mouse and 
human geneticists and for annotating the human DNA sequence.  A draft sequence 
of the mouse genome will be produced first, with a target date of 2003.  
According to the current strategy, the draft sequence will then be finished to a 
high quality standard.  While the initial emphasis of the research network will 
be on producing large amounts of draft sequence, some of the early sequencing 
capacity will be devoted to particular regions which have special significance 
for advancing biomedical research. 

Through the program described in this Notice, the NIH intends to accommodate the 
needs of the scientific community to obtain sequence for specific regions of 
biomedical interest sooner than would otherwise be possible.  However, as the 
entire mouse genome sequence is also of very high interest, the complementary 
components of sequencing specific regions and generating a draft sequence of the 
whole genome will have to be balanced.  Initially, about 10% of the sequencing 
capacity devoted to mouse genomic sequencing will be available for the activity 
described in this Notice.  If the demand to sequence specific regions far 
exceeds the capacity, NHGRI will re-evaluate the program.

As with all sequence data generated by the Human Genome Project, all of the 
sequence data generated by the NIH-supported Mouse Genome Sequencing Network 
will be subject to the "Bermuda Rules."  The data will be rapidly released into 
GenBank; unfinished data will be submitted within 24 hours of generation of 2kb 
assemblies, and finished data as soon as completed.  In particular, under this 
program of sequencing regions of high biomedical significance, no sequence data 
will be made available to the requestor prior to public release.   All 
publications using this data must acknowledge the publicly funded effort.  There 
will be no cost to investigators seeking this sequencing service; the sequencing 
will be done by centers that have already been funded through the NIH Mouse 
Genome Sequencing Network.

PROGRAM DESCRIPTION

In collaboration with the large-scale sequencing centers and representatives of 
the mouse research community, the NHGRI and its advisors have established a 
program to allow the international biomedical research community to identify, 
request and prioritize regions of the mouse genome of special interest for 
focused genomic sequencing. This program is intended to address the interest of 
the biomedical research community in obtaining sequence information about 
specific regions of the mouse genome in parallel with the generation of the 
draft sequence of the mouse and the completion of the human genomic sequence 
which is expected by 2003. The  program will make this opportunity available to 
the community at large and, at the same time, will assist the NIH Mouse Genome 
Sequence Network in managing requests for access to its limited sequencing 
capacity.  

The program will allow any investigator interested in obtaining the sequence of 
a specific region to submit a short, Web-based application describing the 
region, its importance, and its readiness to be sequenced.   A panel of peer 
reviewers is being established to consider the applications and advise the NHGRI 
on the priority of the requests. Those requests judged to be sufficiently 
important to warrant priority sequencing will be listed for the centers engaged 
in mouse genomic sequencing to choose and sequence, up to the maximum capacity 
available for this activity.  

Requests must be submitted via the website starting January 5, 2000.   The NHGRI 
expects there to be a considerable demand for this service in the short term, 
but for the program to have a limited lifetime.  The program will be evaluated 
periodically to confirm its usefulness to the community and its effect on the 
efficiency of production sequencing. 

In addition to the NHGRI program, the Department of Energy, the Medical  
Research Council in the United Kingdom and Genoscope in France have similar 
programs.  Every effort will be made to coordinate with these agencies to avoid 
unnecessary duplication of effort.

ELIGIBILITY REQUIREMENTS

Any investigator may submit a request to sequence a BAC clone or BAC contig 
identified in the RPCI-23 library. 

SCOPE OF REQUEST

BAC clones are the sequencing substrate used by the research network.   Requests 
will be accepted to sequence either a single BAC clone or a single BAC contig.  
Only clones from the RPCI-23 BAC library (constructed from the C57 BL6/J mouse 
strain) will be considered. This strain  was chosen in consultation with members 
of the mouse research community. The requestor must provide information about 
the biological importance of the region to be sequenced, relevant mapping 
information, and other pertinent information that is available about the 
requested clone(s). Clones must be identified using the naming convention found 
at http://www.ncbi.nlm.nih.gov/genome/clone/nomenclature.shtml.  There will be 
no limit to the number of requests that an investigator may submit.  However, 
each request must be submitted as a separate application.  If the clone (or 
contig) requested to be sequenced in one application is related to one in 
another application (such as in the case of gene families, etc), the 
relationship should be noted. 

Investigators may submit requests for either draft or finished sequence.  The 
current working definition of draft sequence is at least 4-fold coverage of a 
region in Phred 20-quality bases.   This will contain on the order of 10 gaps 
per BAC and the numerous contigs may not be ordered or oriented within the BAC 
clone.  Finished sequence is defined as sequence that is at least 99.99% 
accurate and contains no gaps. Because less work is involved, draft sequence 
projects will typically be finished more rapidly than finished sequence 
projects.
 
PROCEDURE FOR SUBMITTING A REQUEST

The request form that must be used is available at http://mouse.info.nih.gov.  
The completed form must be submitted electronically following the instructions 
given.  The Web-based request must include: 

1. A short description of the biomedical importance of the region contained 
within the BAC clone or BAC clone contig that is to be sequenced. 

2.  Evidence that the region described lies within the requested clone(s).  

3.   Evidence, e.g., restriction digest, that the clone(s) picked using the 
library address specified is the requested clone. 

4.  Evidence that confirms that the requested region has not already been 
sequenced, and that the requested BAC is not already in the sequencing pipeline. 
Information on the status of individual BACs within the research network 
sequencing pipeline can be found at: http://www.ncbi.nlm.nih.gov/genome/clone/.

5.  In the case of a single BAC, all known underlying and overlapping clones 
must be identified. 

In the case of a BAC contig where significant map building may have been 
done, all known underlying and overlapping clones must be identified and 
evidence for the structure of the BAC contig described. 

6.  Any other additional information about the clone(s),  if available, such as: 
the size of the region to be sequenced; genomic map location, available marker 
information; sequence information; restriction digest fingerprint pattern; clone 
instability, repeats, deletions, and problems growing the clone(s) and the 
conditions used to overcome them.

7.  The sequence coverage required (draft or complete).  If complete sequence is 
required, a strong justification must be presented.

All requestors must agree to the following terms and conditions:

(a) Data will be released according to the "Bermuda Rules"(All sequence 
data generated by the publicly funded effort will be rapidly released into 
the public domain.  Unfinished data will be released within 24 hours of 
generation of 2 kb assemblies and finished data will be released as soon 
as completed.).  No sequence data will be made available to the requestor 
prior to public release.

(b) All publications using this data must acknowledge the publicly 
funded effort using the following statement:  "The sequence data were 
generated through the NIH-funded Mouse Genome Sequencing Network."

REVIEW FOR DESIGNATION AS A PRIORITY REGION

The reviews will be conducted by a panel of biologists with a broad range of 
biomedical interests. Requests will be reviewed approximately one month after 
the submission dates listed above.  Because of the accelerated review and 
frequent deadlines, the submission dates will not be waived for any reason.

The criteria for determining the relative priority of the requests will be:

-    biomedical significance of the region contained in the clones identified 
for sequencing.  Why is this region of particular importance to the rapid 
advancement of biomedicine?  Is the genetic information in this region of 
particularly widespread relevance?;  and

-   evidence that this region(s) is contained in those clones.  

Requests will receive one of three designations: highest priority; moderate 
priority; and declined. 

In the case where the review panel decides that an application is of moderate 
priority or should be declined, NHGRI program staff will provide the 
investigator with written comments indicating which of the review criteria were 
not adequately addressed.  Because of the rapid review cycle, resubmission will 
be the only means for re-consideration of a request. There will be no limit on 
the number of times a request for a specific region can be resubmitted, but each 
iteration will be required to contain additional significant information.

POST-REVIEW AND PROGRAMMATIC CONSIDERATIONS 

NHGRI staff will inform all requestors of the results of the review, 
approximately two weeks after the review meeting.  NHGRI program staff listed 
below will act as the contact point for the investigator during the remainder of 
the sequencing process.  Program staff will provide information about the 
expected timing for the sequencing of a particular project.  Requestors SHOULD 
NOT contact the sequencing centers directly unless program staff advises them to 
do so.  The sequencing centers will be focused on high throughput production of 
sequence data and should therefore be shielded from any unnecessary 
distractions. 

The identity of clones (using standard nomenclature) that have been designated 
as highest or moderate priority will be listed on a public Web site with an 
indication of the priority recommended.  The name of the investigator who 
requested that the clone(s) be sequenced and the significance of the region(s) 
contained in the clones will not be given.  Once a sequencing center has chosen 
a BAC clone or contig for sequencing, that change in status will be indicated on 
the public Web site.  Clones to be sequenced will then be entered into the 
sequencing pipeline: http://www.ncbi.nlm.nih.gov/genome/clone/.   

This is a new program and the exact work flow cannot be entirely predicted.  
Every effort will be made to sequence the clones that are designated highest or 
moderate priority.  Some BACs may be finished within two months of entering the 
sequencing pipeline but some BACs may require  longer periods of time.  There 
may be regions that are found to be so difficult to sequence that it will be 
necessary to archive the clone until new methods for sequencing are available.  
It is expected that such clones will be rare, but in such a case, NHGRI staff 
will notify the investigator who submitted the request.   It is also possible 
that a BAC with significant overlap to the one requested, containing the 
requested sequence, will be in the sequencing pipeline prior to the request 
entering the sequencing pipeline.  In this case, NHGRI staff will discuss with 
the submitting investigator how to proceed. 

INQUIRIES

Telephone, electronic and/or written inquiries are welcomed. 

To discuss programmatic issues related to this program, please contact:

Bettie J. Graham, Ph.D.
National Human Genome Research Institute
Building 31, Room B2B07
National Institutes of Health
Bethesda, MD 20892-2033
Telephone: (301) 496-7531
Fax: (301) 480-2770
E-mail: bettie_graham@nih.gov

To discuss review issues related to this program, please contact:

Jerry Roberts, Ph.D.  
National Human Genome Research Institute
National Institutes of Health 
Building 31, Room B2B37 
Bethesda, MD 20892-2032 
Phone: (301) 402-0838                                    
Fax: (301) 435-1580
E-mail:  jerry_roberts@nhgri.nih.gov 

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