Project Details
Description
Project Summary/Abstract
The objective of this project is to extend the C. elegans genetic toolkit available to researchers by providing
publicly available gene knockout (KO) mutations in genes of high value to those interested in human biology
and disease. C. elegans is a proven model for discovery of gene function and for embedding genes into
functional pathways, many of which were discovered in this transparent animal and are conserved in humans.
Loss-of-function mutations are the gold-standard for genetic analysis and allow inferences of gene function and
interaction. A relatively recent trend is that large-scale screens (e.g., RNA-seq, proteomics, natural variation
studies) generate long candidate gene lists for researchers to sort through and functionally validate, requiring
loss of function mutants in many genes to be examined. Having a community-driven resource generate KOs in
such genes provides reproducibility and an economy of scale that benefits all. We have developed an efficient
and high throughput CRISPR-Cas9 based gene knockout (KO) project to provide a set of precisely edited gene
knockout strains to the communities of C. elegans researchers and human geneticists. We seek to continue
the production phase of this project, thereby transformatively increasing the efficiency and impact of C. elegans
molecular genetics. We employ a highly coordinated three-site production strategy to generate KOs. Each
gene edit is carefully confirmed, and validated strains are grossly phenotyped and deposited into the
Caenorhabditis Genetics Center (CGC) strain collection along with detailed strain information for distribution to
the community. Strains are advertised through both the CGC and WormBase websites. We have generated
over 1,000 KOs to date; these KOs have supported a variety of research projects – spanning from mechanistic
studies of human variants to metabolomics – funded by at least 14 NIH Institutes and Centers, demonstrating
the high impact of our resource. We propose to continue to use our established pipelines to target an additional
2500 C. elegans orthologs of human genes. We will prioritize known or suspected human disease genes,
druggable gene classes, as well as understudied genes that are conserved to humans but that have no
actionable information. This is a multi-PI project which includes the lead-PIs of the CGC and of WormBase and
a subcontractor who maintains multiple community-centered databases, including a CRISPR guide RNA
selection site.
Status | Finished |
---|---|
Effective start/end date | 4/1/17 → 4/30/24 |
Funding
- NIH Office of the Director: $581,760.00
- NIH Office of the Director: $605,202.00
- NIH Office of the Director: $558,767.00
- NIH Office of the Director: $544,679.00
- NIH Office of the Director: $605,202.00
- NIH Office of the Director: $587,575.00
- NIH Office of the Director: $354,096.00
- NIH Office of the Director: $566,208.00
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