Research

The Zhou Lab studies somatic mosaicism and age-associated mutagenesis as drivers of selective vulnerability in the aging human brain. We focus on major neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD).

A central goal of the lab is to determine whether rare genetic lesions arising in small subsets of brain cells initiate focal neurodegeneration and influence its subsequent spread, and to define how age-associated mutational processes create vulnerability to disease.

Current Projects

Pathogenic Clonal Somatic Mutations in ALS and FTD

We identify pathogenic clonal somatic mutations in ALS and FTD brains. Using high-depth duplex sequencing, we investigate whether somatic mutations arising during development or expanding clonally in postnatal life contribute to focal vulnerability in neurodegenerative disease.

Somatic Repeat Expansions in ALS and FTD

We investigate somatic repeat expansions in ALS and FTD, including expansions that may be undetectable in peripheral tissues. By applying targeted long-read sequencing to postmortem brain tissue, we aim to uncover mosaic repeat expansions that may initiate or modify disease onset.

Private Somatic Mutations Across Cell Types in Neurodegeneration

We profile private somatic mutations across neuronal and glial cell types in ALS, FTD, and AD brains. Using single-cell whole-genome sequencing and mutational signature analysis, we examine how postnatal mutagenesis accumulates with aging and whether disease-specific mutational processes shape cellular vulnerability.

Somatic Genetics of Cerebral Cavernous Malformations

Extending developmental mosaicism frameworks, we investigate both clonal and private somatic mutations in cerebral cavernous malformations. In collaboration with Dr. Issam Awad, we aim to define how somatic genetic events drive lesion formation and vascular pathology.