A striking finding from whole-genome sequences is the amount
of information we are missing on gene function. For example,
although Drosophila is arguably the best-understood
multi-cellular organism (and a proven model system for human
diseases), mutations with readily detectable phenotypes have
been isolated for only about 15% of the more than 15,000
annotated fly genes.
Our lack of information on the majority of genes (the
"phenotype gap") does not indicate that the genes have no
functions. Instead, it suggests that we have been unable to
either assay their roles experimentally and/or resolve an issue
of functional redundancy. In addition, our understanding of
many genes for which we have some information is limited by
pleiotropy, whereby the earlier function of a gene prevents
analysis of functions that occur later in development.
How do we systematically learn more information about all
genes? Using transgenic RNAi, it is now possible to disrupt the
activity of single genes with a spatial and temporal resolution
that is impossible or exceedingly difficult to achieve using
classical genetic methods.
With the backing of the NIH/NIGMS, the Drosophila Transgenic
RNAi Project, or TRiP, has the goal to generate 6,250
transgenic RNAi lines designed to fill in the phenotype gap and
help researchers overcome issues associated with pleiotropy.
Specifically, we are using a new approach for transgenic RNAi
that relies on phiC31-targeted integration combined with the
Gal4/UAS system. In this way, conditional and tissue-specific
expression of hairpin constructs in Drosophila will be
generated.
All validated transgenic fly lines will be made available to
the entire community through the Bloomington Drosophila Stock
Center (BDSC). The collection will be invaluable to address a
myriad of questions in biology and medicine, including but not
limited to cell biology, signal transduction and cancer, the
etiology of congenital malformations, neurodegeneration, and
behavior.
A pilot project supported by the HHMI/Janelia Farm Visitor
Program between the laboratories of N. Perrimon, C. Zuker and
G. Rubin has generated nearly 2,300 hairpin lines. See the page
TRiP Stocks to learn target dates
for availability at BDSC. At the same time--and thanks to the
NIH/NIGMS award--the TRiP will continue production and transfer
of RNAi lines to BDSC during the four years of NIH/NIGMS
support.
Genes to be targeted are selected based on the BDSC mandate
of one mutation per gene, the needs of screeners at the
Drosophila RNAi Screening Center (DRSC), and the needs of the
Drosophila community for in vivo phenotypic analyses. The
resource will be housed in the TRiP facility at Harvard Medical
School (production and for screening) and transferred on a
regular schedule to the BDSC (for distribution).
