MEMP PhD Thesis Defense: Yifan Zhao

Decoding Brain Somatic Mosaicism with New Single-Cell Copy Number Analysis Methods

Copy number variants (CNVs) represent a significant but understudied form of somatic variation in the human brain, with potential implications for neurodevelopment, aging and disease. While single-cell whole-genome sequencing (scWGS) enables genome-wide profiling at single-cell resolution, existing computational methods struggle to accurately detect non-clonal CNVs, limiting our understanding of genomic mosaicism in the brain. In this thesis, I present two novel and complementary computational approaches for high-resolution CNV analysis in single cells. The first, HiScanner, is a CNV detection method that integrates single-cell assay-specific characteristics and introduces innovations in bin size optimization, read depth normalization, and joint segmentation across cells. Through extensive benchmarking experiments, I demonstrate HiScanner's superior performance compared to existing tools. The second is a validation method that leverages unique molecular patterns from tagmentation-based scWGS, representing the first tool that exploits fragment overlap patterns to corroborate CNV predictions. I then apply these tools to investigate CNVs in three biological contexts: tumor evolution in paired initial and recurrent meningiomas, age-related genomic changes in neurotypical human brains, and developmental patterns in fetal and postnatal brain tissues. By analyzing both scWGS and multimodal single-cell data (paired RNA-seq and ATAC-seq), I characterize cell-type-specific CNV patterns and their potential functional implications. This work establishes a robust framework for studying somatic CNVs at single-cell resolution and provides insights into genomic instability in brain development, aging, and disease.

Thesis Supervisor:
Peter J. Park, PhD
Professor of Biomedical Informatics, Harvard Medical School
Director, Bioinformatics and Integrative Genomics PhD program, Harvard Medical School

Thesis Committee Chair:
Alex K. Shalek, PhD
Director, Institute for Medical Engineering & Science and Health Innovation Hub, MIT
J. W. Kieckhefer Professor, Institute for Medical Engineering & Science, Department of Chemistry, and Koch Institute, MIT

Thesis Readers:
Christopher A. Walsh, MD, PhD
Bullard Professor of Pediatrics and Neurology, Harvard Medical School
Chief, Division of Genetics, Boston Children’s Hospital
Investigator of the Howard Hughes Medical Institute

Po-Ru Loh, PhD
Associate Professor of Medicine, Harvard Medical School 
Associate Member, Broad Institute of MIT and Harvard

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Yifan Zhao is inviting you to a scheduled Zoom meeting

Topic: Yifan Zhao MEMP PhD Thesis Defense
Time: Tuesday, April 15, 2025, 10:00 AM Eastern Time (US and Canada)

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