# High-throughput interrogation of autism risk genes: from molecules to behavior

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $389,757

## Abstract

PROJECT SUMMARY
Over 1,000 genes have been implicated in autism spectrum disorder (ASD) but only a handful have been
confirmed as causing phenotypes related to ASD in animal models. Understanding if and how each gene
contributes to ASD-related phenotypes singly or in combination is not feasible with rodent models, which
require enormous time, expense, and labor to generate and characterize. We have previously leveraged the
nematode C. elegans as a minimum in vivo animal model to quickly characterize genes related to human
neurological conditions. ------ C. elegans displays phenotypes with relevance to ASD including social behaviors
represented by how they tend to clump together in piles while eating. To quickly gain insight into whether 109
SFARI gene orthologs play a role in social behaviors in C. elegans, rather than study one mutant at a time, we
studied a collection of genetically distinct wild-type strains isolated from around the world. Each strain carries a
distinct combination of variants in these 109 ASD risk genes. We discovered that overall, the number and
severity of mutations in ASD risk genes correlated with decreased social behaviors. Moreover, we found that
mutations in certain ASD risk genes appear to cause social deficits, because we could boost social behaviors
by replacing defective ASD risk genes with functional versions. We also found that mutations in orthologs of
genes that cause increased social behavior in C. elegans have already been implicated in positively modifying
social behavior in ASD and Williams syndrome. The central hypothesis is that C. elegans will be a rapid and
inexpensive model organism to determine which combinations of mutations in this vast number of risk genes
cause ASD-related defects. The overall goal is to determine which mutations and combinations of mutations in
ASD risk genes cause ASD-relevant behaviors, and by what mechanisms. The rationale is that there is an
urgent need to understand the in vivo consequences of mutations in genes implicated in autism. The central
hypothesis will be tested with three specific aims: 1) Identify which and how natural variants in ASD risk genes
causally contribute to decreasing social behaviors and sensory integration in C. elegans. 2) Test which and
how variants in ASD risk genes positively modify social behaviors and sensory integration in C. elegans. 3)
Determine the mechanism by which genetic variants of uncertain significance identified in ASD patients
influence social and sensory integration behaviors and neurobiology of C. elegans. ------ The research
proposed in this application is innovative because it uses a minimalist animal model to perform high-throughput
in vivo causal functional analyses of ASD risk genes. The work is significant because it will allow researchers
working with rodents and human patients to focus their efforts on the most promising ASD risk genes. The
results will empower families to understand how patient-specific mutations in unstu...

## Key facts

- **NIH application ID:** 10831533
- **Project number:** 5R01MH133243-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** JONATHAN THOMAS PIERCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,757
- **Award type:** 5
- **Project period:** 2023-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831533

## Citation

> US National Institutes of Health, RePORTER application 10831533, High-throughput interrogation of autism risk genes: from molecules to behavior (5R01MH133243-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10831533. Licensed CC0.

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