# Systematic Analysis of 21st Chromosome Ortholog Overexpression in C. elegans

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2022 · $43,677

## Abstract

PROJECT SUMMARY
Down syndrome (DS) is the most common genetic cause of intellectual disability. While societal improvements
have enhanced the quality of life for those with DS, which 21st chromosome (Hsa21) genes are responsible for
the multitude of characteristic phenotypes that accompany DS remains unknown. These include intellectual
disability, motor incoordination, low muscle tone, and craniofacial abnormalities, which are consistent across
people with DS, as well as other variably-occurring co-morbid conditions such as congenital heart disease and
autism, to name just a few. Although mouse models have shed light on the role some Hsa21 genes play in
some phenotypes, such as Alzheimer’s pathology (APP) and leukemia (GATA1), most Hsa21 genes have not
been studied in detail. This study will circumvent the time-consuming and costly use of mouse models for the
study of individual Hsa21 genes by systematically investigating which Hsa21 genes cause behavioral deficits
when overexpressed in the efficient model Caenorhabditis elegans. Our lab found that C. elegans shares 51
highly-conserved genes with the human 21st chromosome. Through the study of mutants for these genes, we
found that in worm 14 Hsa21 orthologs are essential genes and 10 Hsa21 orthologs are required for neural or
muscular function, 3 of which had not previously been studied. This study will use epistasis analysis to further
functionally characterize one of those novel genes, mtq-2, which appears to be an important novel modifier of
synaptic G-protein signaling. Additionally, to probe how overexpression (OE) of individual Hsa21 genes
contributes to DS phenotypes, a set of 51 C. elegans transgenic strains that each overexpresses a different
conserved Hsa21 ortholog will be generated. This set will be assessed one-by-one using high-throughput,
quantitative behavioral analyses to deduce which genes cause neural or muscular dysfunction when
overexpressed. This research will be conducted through the University of Texas’s highly supportive and
well-resourced Institute for Neuroscience graduate program, under the direction of a PI who has ample
experience mentoring successful PhD students. The trainee has demonstrated leadership by founding a large
women’s STEM professional organization. Inspired by a sister with DS, the trainee plans to apply her
leadership, scientific expertise, and personal insights to run a DS lab following postdoctoral training. By
identifying Hsa21 genes that cause phenotypes when overexpressed in C. elegans, this study will spotlight
genes to prioritize for further study by her and others in mouse and human stem-cell models of DS. The set of
Hsa21 OE strains produced will be shared freely around the world to establish C. elegans as the first
mechanistic in vivo model to conveniently study consequences of individual Hsa21 gene OE. This will promote
DS research by additional worm labs and allow other DS labs to expand their repertoire of model systems for
studying spec...

## Key facts

- **NIH application ID:** 10488058
- **Project number:** 5F31HD105424-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Sophia M Sanchez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,677
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488058

## Citation

> US National Institutes of Health, RePORTER application 10488058, Systematic Analysis of 21st Chromosome Ortholog Overexpression in C. elegans (5F31HD105424-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10488058. Licensed CC0.

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