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White Paper

T. Kaufman kaufman at bio.indiana.edu
Mon Jan 18 15:56:15 EST 1999

I am posting this announcement for Larry Goldstein, the current President
of the Drosophila Board.  If you wish to respond to his request do so
directly to him [ lgoldstein at ucsd.edu ] or to the Drosophila board [
flyboard at morgan.harvard.edu ] and not to me.



Dear Fly Friends and Colleagues,

As some of you may know, there will be a Model Organisms Workshop at the
NIH on February 16 and 17, 1999.  The purpose of this workshop is to "help
the NIH develop a process by which it can set priorities for the support of
genetic and genomic resources needed to facilitate the structural and
functional analysis of non-mammalian models.  This workshop is being
organized at the request of Dr. Varmus, Director, NIH.  It is anticipated
that there will be significant participation by Dr. Varmus as well as by a
number of Institute and Center Directors.  Dr. Raju Kucherlapti, Albert
Einstein College of Medicine, and Dr. David Valle, Johns Hopkins University
School of Medicine, will serve as co-chairs of the workshop." (from the
invitation I received).

In preparation for this meeting, I have spent the past few months working
with the FlyBoard and a small ad hoc group (Gelbart, Duyk, Hartl, Kaufman,
Karpen, Rubin, and Spradling), to develop a list of recommended resources
needed by the general Drosophila community.  The intent has been to develop
a set of proposed resources that would accelerate all of our research
efforts and would effectively capitalize upon the flood of genomic data and
materials becoming available.  I have appended below a "white paper" that
emerged from this process.

At this point, we would welcome any additional input from you and the
community at large.  For these suggestions to have some impact, I must have
them by February 5, 1999.  Please email suggestions or comments directly to
me at lgoldstein at ucsd.edu or to the flyboard at
flyboard at morgan.harvard.edu.

Thank you for helping with this important community endeavor.

Larry Goldstein, President, Drosophila Board
lgoldstein at ucsd.edu

Drosophila White Paper-1/15/99

The advent of complete genomic sequences from many complex organisms has
posed an important set of problems.  What are all these genes doing, how do
their functions interact, and how may we take advantage of the sequences to
advance understanding and cure human disease?  An important piece of the
solution is complete genetic analysis in model organisms where the full
array of genetic technologies may be brought to bear on such issues.
Drosophila melanogaster is an extraordinarily attractive model organism
owing to a combination of its unusually manipulable genetic system,
relatively low cost, and biological complexity comparable to that of a
mammal.  Many organ systems in mammals have well-conserved homologues in
Drosophila, and Drosophila research has already led the way in providing
new insights into cancer, neurodegenerative diseases, behavior, aging,
multigenic inheritance, and development.  In addition, the past years of
investment in Drosophila research, and the anticipated completion of the
genomic sequence will catalyze an explosion in outstanding research and
insights into normal and disease mechanisms if harnessed properly.

While there is no question that the investigator-initiated RO1 program in
Drosophila is as strong and vital as ever, there are clearly identifiable
bottlenecks to more rapid research progress.  Thus, our community agrees
that to seriously meet the opportunities and challenges in Drosophila
genomics and genetics, there must be targeted development of shared genetic
resources such as libraries of transposon mutants in all genes, adequate
databases, stock centers, complete genomic expression analyses,
polymorphism databases, and related goals.  We believe that the successful
development of these resources will benefit both the Drosophila and
non-Drosophila biomedical research communities alike and catalyze a rapid
wave of discovery with significant applications to human biology and

Specifically, our community has come together and agreed that the following
initiatives would be valuable and cost-effective to the research

1)  Finish the Drosophila genome sequence by the end of 2001.  Achieving
this crucial goal is consistent with the Five Year Plan for the Genome
Project and will require full funding of the already approved grant for
sequencing the Drosophila genome ($44,000,000 for the three year period
from 12/1/98-11/30/01).  Finishing sooner would greatly accelerate
important biomedical research progress and avoid lost opportunity costs.

2)  A significant expansion of the capacity of the stock centers.  This
goal will require expansion of the physical space and personnel to care for
and send out the many genetic strains to the community.  We envision that a
national capacity in the range of 30,000 different stocks is a necessary
minimum to accommodate the anticipated development of mutants in all genes.
This goal will cost approximately $1,000,000 per year beyond current

3)  The database capacities available to the community must be
significantly expanded.  The current torrent of sequences requires
annotation, linkage to the genetic maps and phenotypes, and links to
databases of diversity.  This objective can be accomplished for $3,000,000
per year rising to $3,500,000 per year over a 5 year period.

4)  Completion of the sequences of cDNA clones corresponding to all genes
in the genomic sequence and their major alternative splice forms.  This
"rosetta stone" will be crucial to fully comprehend the range of proteins
encoded in the Drosophila genome.  This goal can likely be accomplished for

5)  Generation of a collection of P-element insertions in all genes.  We
estimate that 20,000 different lines will result and could be generated
using P-elements that generate controlled misexpression.  This library of
mutants in all genes will be an indispensable resource to all workers in
the community and can be generated for $2,000,000.

6)  Determination of expression patterns of all genes and coding sequences.
These patterns would be determined at different developmental stages, in
different tissues, and under different environmental conditions.  This work
could be done for $1,500,000.

7)  Determination of the sequence of Drosophila virilis.  The sequence of
this related species will be crucial for the interpretation of the
Drosophila melanogaster sequence and for helping to infer function and
identify those characteristics of the Drosophila genome that are conserved
and therefore likely to be important.  Determining this sequence once the
D. melanogaster sequence is near complete can be done relatively
economically since the D. melanogaster sequence can help guide D. Virilis
sequence determination and interpretation.  This goal can be achieved by
starting with an investment of $2,000,000 per year to sequence regions of
greatest interest in BAC clones, rising to $4,000,000 per year as the
effort picks up speed.  The ultimate cost will be on the order of
$20,000,000 over several years.

8)  Creation of a standard set of cell culture models derived from various
Drosophila tissues and developmental stages.  A crucial resource for
elucidating function for the various genes will be to have high quality
cell culture models in which to conduct biochemical and cell biological
analysis of mutants.  This goal will require both the establishment of new
permanent cell lines and the development of methods for readily preparing
primary cultures from Drosophila organs and tissues.  The most
cost-effective method to achieve these goals would be to establish an RO1
or RFA mechanism with an initial investment of $500,000-$1,000,000 per

9)  Development and application of high resolution, high sensitivity
measures of protein expression and covalent modification in normal and
mutant organisms.  The availability of a complete Drosophila sequence
coupled to rapid improvements in mass spec protein sequencing and
separation technologies will allow unparalleled insights into cellular and
biochemical changes that will occur in various mutants.  This emerging
technology is poised to be applied to a model genome prior to attempting
such efforts on vertebrates.  Depending upon rates of technology
development, this goal could be achieved for $1,000,000-$2,000,000.

Larry Goldstein
UCSD School of Medicine
9500 Gilman Drive
La Jolla, CA  92093-0683
phone:  619 534 9702
fax:  619 534 9701

Thom Kaufman   	     	       kaufman at sunflower.bio.indiana.edu
--- Biology Dept.,  Indiana University, Bloomington, IN 47405 ---

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