# Human gene duplications in neurodevelopment and disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $691,844

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite significant efforts to identify genes important in human neurodevelopment and disease, a large
proportion of genes and variants remain undiscovered. Duplicated parts of the genome are largely
understudied due to historical errors in the reference and bioinformatic pipelines that filter reads mapping to
multiple locations in the genome. With the recent publication of a complete telomere-to-telomere human
genome, genes and variants can be more effectively assayed across complex loci, but modified computational
approaches are necessary. The proposed study will leverage diverse expertise in functional genomics
and human genetics to test the hypothesis that a subset of human duplicated genes both contribute to
neurological features and cause disorders exclusive to modern-day humans. Duplicated genes have
previously been shown to play a role in early brain development and are enriched at genomic hotspots where
recurrent copy-number variants are associated with neurodevelopmental disorders. Starting with a
comprehensive list of thousands of human duplicated genes, functions of a subset of genes expressed during
human corticogenesis will be tested using CRISPR knockout of orthologs and expression of human paralogs in
zebrafish to determine their effects on general morphology, synaptic function, and brain development. The
ability to test tens to hundreds of genes in parallel and conservation of basic developmental processes—such
as neural proliferation, axonal guidance, and synaptogenesis—make zebrafish an ideal model to test these
genes. Second, a genetic screen will be performed in human population cohorts to identify conserved
duplicated genes. Since standard methods filter variants across many complex genomic loci, an improved
bioinformatics approach leveraging short-read data will be devised and optimized using available sequencing
benchmarks. Further, conserved genes will be screened for de novo and rare variants in autistic individuals
using published datasets. Leveraging this multifaceted approach will enable systematic assessment of
duplicated genes and their putative roles in human neurological traits and disorders. The zebrafish toolkit will
be generally applicable to assaying functions of additional (non-duplicated) genes important in brain
development, while the improved bioinformatics approach will enable additional screens of duplicated genes in
other disease cohorts. This project will not only provide important insights into what it means to be human, but
also it has the capability to discover missing genetic risk and elucidate the etiology of complex genetic neural
traits and disorders.

## Key facts

- **NIH application ID:** 10932392
- **Project number:** 5R01MH132818-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Megan Y Dennis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $691,844
- **Award type:** 5
- **Project period:** 2023-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932392

## Citation

> US National Institutes of Health, RePORTER application 10932392, Human gene duplications in neurodevelopment and disease (5R01MH132818-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932392. Licensed CC0.

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