# The role of autism susceptibility genes in the 16p11.2 locus on the development and function of human stem cell-derived neural cells

> **NIH NIH K99** · BROAD INSTITUTE, INC. · 2021 · $22,590

## Abstract

PROJECT SUMMARY/ABSTRACT
Recent reports estimate that 1 out of every 6 children in the United States meet the diagnostic criteria for
neurodevelopmental disorders such as autism spectrum disorders (ASD), attention-deficit hyperactivity disorder
(ADHD), and intellectual disability (ID). The prevalence of ASDs, which are characterized by persistent social
impairments, language deficits, and repetitive behaviors, has increased by 120% over the past 15 years, a
problem further exacerbated by the fact that the disease mechanisms underlying ASDs are largely unknown and
no targeted therapeutic interventions exist. Recent progress in human genome sequencing has begun to
illuminate pathways to disease through the identification of several genetic risk factors, the most common of
which is the deletion of 16p11.2 locus (16p11.2del). Initial studies have nominated specific genes in the 16p11.2
locus in neuronal dysfunction, though these findings are built on mouse and zebrafish models rather than human
neural cell types. This proposal aims to elucidate the disease mechanisms underlying 16p11.2del phenotypes
using in vitro induced pluripotent stem cell (iPSC)-derived human brain cells. In Aim 1 (K99), human iPSC-
derived neural progenitor cells and neurons generated using novel protocols will be compared to human fetal
brain tissue using single-cell RNA sequencing (scRNA-seq) techniques to validate these in vitro cellular models
for future studies. Aim 2 of this proposal (K99) will employ an innovative “population-in-a-dish” strategy in which
stem cell lines from many different neurotypical and 16p11.2del patients will be pooled into one culture flask to
interrogate phenotypic differences. Aim 3 (R00) will leverage these scRNA-seq techniques to decipher the role
of 16p11.2 genes in specific pathways important for neurodevelopment. The successful completion of these aims
could lead to the identification of genetic targets for therapeutic intervention, while also dramatically changing
the way the field conducts in vitro modeling of human brain disorders. These experiments will provide new
training for the principal investigator (PI) of this proposal in scRNA-seq and bioinformatics methods that will serve
as the foundation of an independent research laboratory that will use stem cell-derived neural cells and large
transcriptome datasets, combined with animal models, to elucidate the cellular and molecular mechanisms
governing neurodevelopmental disorders. This work will be completed at the Broad Institute and Harvard
University, where the opportunities for technical and intellectual growth are innumerable. The PI will attend
regular meetings with mentors and collaborators to receive feedback on experimental design and career
decisions. The PI will attend grant writing and project management courses at Harvard, while also improving his
communication skills by presenting data at international scientific conferences. As a whole, this career
development plan will he...

## Key facts

- **NIH application ID:** 10334934
- **Project number:** 3K99MH119327-02S1
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Michael Frederick Wells
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $22,590
- **Award type:** 3
- **Project period:** 2021-02-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334934

## Citation

> US National Institutes of Health, RePORTER application 10334934, The role of autism susceptibility genes in the 16p11.2 locus on the development and function of human stem cell-derived neural cells (3K99MH119327-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10334934. Licensed CC0.

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