# The Role of Chromosome Y in Human Microglia and Neurodevelopment

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $42,188

## Abstract

PROJECT SUMMARY
Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders, diagnosed in one
in 44 children in the United States. Sex is among the most significant risk factors for ASD, with males being three
to five times more likely than females to manifest the disorder. While epidemiological data documenting these
sex differences in autism are abundant, there is currently little understanding of the fundamental differences
between male and female biology that contribute to the sex biases in autism prevalence, severity, and clinical
presentation. Based on mounting evidence implicating i) important microglial contributions to neurodevelopment,
ii) sex-biased microglial activation in individuals with ASD, and iii) our preliminary findings regarding microglia-
specific sex-linked gene expression, this proposal is built around the central hypothesis that genetic sex
differences in microglia contribute the male bias in ASD.
Sex chromosomes may be especially important drivers of sexual dimorphism in human brain development. For
one, ASD manifests at an early age, before the puberty-associated increase in sex hormone production. Further,
progressive chromosome Y aneuploidy (e.g. XY, XYY, XYYY, XYYY) leads to incrementally increased incidence
of ASD. These observations suggest a significant role for chromosome Y for presenting ASD-related behaviors.
Yet, there is a gap in knowledge about Y-linked genes and their contribution to sex dimorphism outside the
reproductive tract and to ASD pathophysiology. Therefore, the project goal is to test the hypothesis that
increasing chromosome Y dose in human microglia in vitro (Aim 1) and in a xenotransplantation model (Aim 3)
results in microglial pathology, neuropathological defects, and ASD-associated behavioral deficits. Delineating
genome wide transcriptional disruption and genome wide reorganization (Aim 2) will further uncover how
chromosome Y-linked genes contribute to microglia-specific gene networks and expand our knowledge on Y-
linked genes associated with ASD. The long-term goal is to generate a framework for studying genetic sex
differences in microglia and their contributions to sex-biased brain development. A deeper understanding of the
contribution and molecular regulation of microglia in ASD will lay the groundwork to ultimately identify novel
potential sex-specific interventions to improve the outcomes for individuals with ASD.
The proposed research will take place in the Coufal and Glass laboratories at UC San Diego. The Coufal lab
expertise is in human induced pluripotent stem cell models of neuroimmunology, and the Glass lab has expertise
in tissue-resident macrophage gene regulation and epigenetics. Through graduate coursework, mentorship, and
hands-on learning, Celina will gain experience in stem cell modeling systems for human brain cell types and for
approaching large datasets from a quantitative perspective. These skills will be valuable for the completion of
th...

## Key facts

- **NIH application ID:** 10814790
- **Project number:** 5F30HD112148-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Celina Tien Nguyen
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,188
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814790

## Citation

> US National Institutes of Health, RePORTER application 10814790, The Role of Chromosome Y in Human Microglia and Neurodevelopment (5F30HD112148-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814790. Licensed CC0.

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