# Scalable functional analysis of neuropsychiatric risk genes with spatially integrated in vivo Perturb-seq

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $911,929

## Abstract

Although numerous genes and loci associated with autism spectrum disorder and neurodevelopmental delay
(ASD/NDD) have been identified through genome sequencing efforts, the precise mechanisms by which most of
these genetic variants lead to the condition remain largely unknown. We propose to combine high-content in vivo
genetic screening with whole brain cytoarchitecture spatial information from neurons with loss-of-function
mutations in ASD/NDD risk genes to bridge the gap between genetic insights and mechanistic understanding.
This approach, which can be scaled to interrogate large panels of genetic variants in parallel, has the power to
reveal how these diverse gene variants converge to produce ASD/NDD, including identifying the specific brain
regions, cell types, neural circuits, developmental time windows, and molecular networks involved in the
pathogenesis of these disorders.
To achieve this, we propose to use high-resolution and multimodal phenotypic characterizations to
comprehensively map the functions in the neocortex and striatum of a set of 72 high-confidence ASD/NDD risk
genes, many of which encode transcriptional regulators. We will adapt in vivo Perturb-seq to allow high efficiency
screening across multiple developmental time points with both single-nucleus transcriptome and chromatin
accessibility readouts. These rich datasets will enable us to build gene regulatory networks (GRNs) that will
reveal shared and divergent molecular signatures associated with this set of ASD/NDD risk genes. In parallel,
we will explore how perturbation of 5 high-confidence ASD/NDD risk genes impacts cellular migration,
morphology, and long-range connectivity. Here, we will use Perturb-CAST (cytoarchitecture see-through) to
combine sparse genetic perturbations in vivo with whole mount brain clearing and light-sheet imaging to examine
brain-wide changes in cytoarchitecture across developmental time points.
This work will expand two major technologies, in vivo Perturb-seq and Perturb-CAST, which will be broadly
impactful tools for understanding the genetic basis of ASD/NDD and other complex brain disorders. By focusing
on corticostriatal pathways and integrating spatial information, the proposal seeks to uncover commonalities and
shared mechanisms among ASD/NDD risk genes, ultimately contributing to a more comprehensive
understanding of the disorder and potentially guiding future therapeutic approaches.

## Key facts

- **NIH application ID:** 10946605
- **Project number:** 1R01MH137042-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Xin Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $911,929
- **Award type:** 1
- **Project period:** 2024-09-05 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946605

## Citation

> US National Institutes of Health, RePORTER application 10946605, Scalable functional analysis of neuropsychiatric risk genes with spatially integrated in vivo Perturb-seq (1R01MH137042-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10946605. Licensed CC0.

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