||Drosophila White Paper 2001
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 easy to manipulate 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, immunity, aging, multigenic
inheritance, and development. Indeed, analysis of the Celera-BDGP genomic
sequence of Drosophila melanogaster provided enormous evidence on the
value of the fly as a model for human disease, with about 2/3 of human
disease genes having a clear cognate in Drosophila. Together with the
information on the Drosophila genome and proteome, 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 resources and enabling technologies.
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 disease.
The community gratefully acknowledges the efforts of the BDGP, EDGP and
Celera to produce a high quality genomic sequence of Drosophila
melanogaster, especially on a more rapid timetable than was originally
anticipated. Further, the community is pleased that resources are in place
for the BDGP to bring this sequence to finished quality. In order to take
advantage of the availability of this sequence and to most fully develop the
research potential of the fly in a cost-effective manner, several other
resources and initiatives need to be upgraded or established. In general,
these recommendations focus on additional resources that will further
enrich our understanding of the Drosophila melanogaster genome, and enable
more penetrating investigations of the biology of this model system.
- Support the development of a Drosophila melanogaster cDNA Unigene
set where the cDNAs are sequenced and made available in convenient
cloning vectors. These cDNAs would have a wide range of uses in
functional genomics. The utility of such cDNA collections for all
model organisms was recognized in the last NIH/DOE five-year plan for
the genome project, and the Mammalian Gene Collection (MGC) project
has subsequently been established by the NIH to provide this resource
for human and mouse. We ask that a similar project be carried out for
Drosophila. We understand that there is already a two-year funding
commitment to the BDGP for this Unigene set. We ask for $1,000,000
to fund a third year for the final stages of development of this
- A significant expansion of stock center capacity for Drosophila
melanogaster. This goal will require expansion of the physical space and
personnel at the existing U.S. center or establishment of an additional
melanogaster center to care for and send out the many genetic strains to
the community. We envision that a national capacity in the range of 20,000
different stocks is a necessary minimum to accommodate the anticipated
development of mutants in all genes as well as transgenic strains of broad
community interest. This goal will cost approximately $500,000 per year
beyond current expenditures. Current commitments provide for a collection
of 10,000 stocks by 2003, at a total cost of approximately $615,000 per
In particular, we endorse the commitment of stock center resources to
house another 10,000 unique, characterized P element insertions that will be
generated by the BDGP over the next 2.5 years. These lines will go a long
way toward the goal of having a genetic disruption in every transcription unit
and will be an invaluable resource to the Drosophila research community. It
should be noted that at the Community Resources Workshop, as well as
among Resource Committee members, the need for increased stock center
resources was recognized as one of the key needs of the community.
- 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.
Additional resources to help provide access to functional genomic
information on the fly will also be needed. These needs can be met by
increasing central Drosophila database budgets by about $500,000 per
annum for a total funding commitment of $3,000,000 per year (for the
current year), rising to $3,500,000 per year over a 5 year period.
- Obtain 6X whole genome shotgun coverage of two additional Drosophila
species of sufficient evolutionary distance such that nonconserved
sequences will display substantial divergence. It is our view that having a 3-
way interspecific comparison of the assembled shotgun reads will provide the
most robust view of sequence conservation for the experimental annotation
of the Drosophila melanogaster genome, including the verification of
predicted open reading frames and the identification of conserved regulatory
elements and structural domains within the genome.
The first of the species should be sequenced as quickly as possible, hopefully
beginning within the next year, and the second one should follow shortly
thereafter. The best candidate species should be based upon considerations
of genome size, evolutionary distance and available genetic information.
From these considerations, the case for making Drosophila pseudoobscura
the second species is extremely strong. This species has sufficient
evolutionary distance from D. melanogaster so that sequence conservation
will be indicative of conserved function, and the genome size is smaller than
other candidate species of as great or greater evolutionary distance.
Further, D. pseudoobscura has been a model organism in its own right,
especially for population genetics, and thus having genome-wide sequence for
the species will have some additional benefits.
The choice of the second species will require further investigation and broad
community discussion. Experiments and modeling to identify the most
appropriate second candidate species should be based upon considerations of
genome size, evolutionary distance from both D. melanogaster and D.
pseudoobscura, and on the available genetic information for that species.
Based on current costs, we estimate that 6X whole genome shotgun
sequencing would cost approximately $4,000,000 per species.
- There is a great need for a molecular stock center to house genomic and
cDNA clones, and transgenic constructs of various sorts that are in wide
demand by the community. Such a resource could be housed separately for
Drosophila clones, or could be part of a broader trans-organism facility.
In addition to these major resource needs, we urge NIH to consider program
announcements that encourage innovative technological research or
resource development in the following areas:
- More efficient mutational mapping technologies for gene identification, for example, based on molecular polymorphism markers such as SNPs or microsatellites.
- Homologous gene knockout and gene replacement technology.
- Improving RNAi technology.
- Cryopreservation technology. While "fly freezing" has had a checkered history, it is the only hope for alleviating pressure for more and more national stock center resources, and new avenues of research in this area should be encouraged.
- Techniques for isolating primary cells and establishment of continuous cell lines representing identified cell types, including germ cells, and techniques for organ culture.
- Capture of spatial expression pattern information on all Drosophila genes, including tissue and subcellular localization.
- Improved transgenic technology for inducible spatial or temporal gene expression.
Explanatory Note: This document was originally published as the Drosophila
White Paper 1999 (15January1999). Revisions to this document have
incorporated comments from attendees at the Community Resources
Workshop, chaired by Dr. Laurie Tompkins and which took place on Thursday,
March 23, 2000 at the Drosophila Research Conference in Pittsburgh,
Pennsylvania. As a follow up to this workshop, the Drosophila Community
Resources Committee, a standing committee of the North American
Drosophila Board, met to re-evaluate the community's needs in the context
of the progress of the last two years.
The revision was prepared by the Drosophila Community Resources Committee.
It was then circulated to the Drosophila Board and revised again. It then
circulated to the community at large through FlyBase and through
directed email. The Drosophila Community Resources Committee and the
Drosophila Board were very pleased with the overwhelmingly positive
and thoughtful feedback from about 100 members of the community. While
there were some excellent comments from the community, they covered many
different points and thus, we did not feel that they necessitated revisions
to the White Paper itself. Perhaps the most prevalent theme was a concern
that even at 20,000 stocks, the public stock center needs of the community
might not be met in the not too distant future. While we share this longer
term concern, we feel that the proposal for 20,000 stocks in the public
stock center is reasonable for now, but that this issue may need to be
revisited if and when stock center capacity is exceeded by community needs.