# C. elegans Resource Core

> **NIH NIH U54** · WASHINGTON UNIVERSITY · 2021 · $110,098

## Abstract

The Washington University (WU) Model Organism Screening Center (wuMOSC) will utilize four model
organisms, C. elegans, Drosophila, zebrafish and hPSC, for functional analysis of gene-variants nominated by
Undiagnosed Disease Network (UDN). C. elegans is a major model organism for studies of animal cell and
developmental biology, excelling at gene function discovery and elaboration of pathways in which gene
products act. A number of features make C. elegans appropriate for being the first line organism for
experimental assessment of UDN variant on gene product function. These include short generation time (4
days), small size, inexpensive maintenance, self-fertile hermaphroditism, and optical transparency that permits
detailed phenotypic analysis at all stages of the life cycle. About 60% of human genes have an ortholog in the
C. elegans genome, indicating that a substantial portion of potential disease genes can be experimentally
examined in the worm. C. elegans research has advanced our understanding of disease. For example,
published work has demonstrated that variant knock-in can recapitulate the effect on gene product function for
known diseases, provide support for phenotypic expansion and provide support for molecular diagnosis of a
UDP gene. In a project paralleling the activities of Phase I UDN MOSC, we have been collaborating with the
WU Pediatric Genetics Clinic to examine candidate gene-variants of uncertain significance found in patients
that did not receive a molecular diagnosis, by CRISPR/Cas9 variant knock-in into the C. elegans ortholog and
assessing if there is a change in function. This work indicated that ~1/3 of patient variants can be assessed by
knock-in with the worm, given conservation of both the gene and variant residues. Importantly, CRISPR/Cas9
mediated homology directed knock-in of variants occurs at very high frequency, allowing us to obtain variant
knock-in strains, out-crossed twice, in ~3 weeks. The wuMOSC Leadership Project, working in conjunction
with the C. elegans Resource Core, will assign ~60 UDN gene-variants for function analysis in the worm. The
variants will be knocked into the orthologous worm gene. To assess function, a prioritized phenotyping
pipeline will be employed that includes 7 different phenotyping platforms, from simple morphological analysis,
to high-throughput assays for viability, growth, reproduction, to assessment of movement/behavior and custom
assays that are derived from published phenotypes for the gene of interest. The pipeline allows focusing on
known phenotypes or broad searches for unknown phenotypes, increasing the likelihood of detecting a
phenotype. High-throughput phenotypic assays are important because of the large number of genes and
genotypes that will be analyzed. Results from phenotypic analysis will inform on the functional effect of the
variant, which will be communicated to the UDN, providing information that can contribute to a diagnosis.

## Key facts

- **NIH application ID:** 10213225
- **Project number:** 5U54NS108251-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** TIM SCHEDL
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $110,098
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213225

## Citation

> US National Institutes of Health, RePORTER application 10213225, C. elegans Resource Core (5U54NS108251-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213225. Licensed CC0.

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