Single-cell mosaicism analysis reveals cell-type-specific somatic mutational burden in Alzheimer’s Dementia
Open accessAbstract
Despite significant advances in identifying genetic drivers of neurodegenerative disorders, the majority of affected individuals lack molecular genetic diagnosis, with somatic mutations proposed as one potential contributor to increased risk. Here, we report the first cell-type-specific map of somatic mosaicism in Alzheimer’s Dementia (AlzD), using 4,014 cells from prefrontal cortex samples of 19 AlzD and 17 non-AlzD individuals. We integrate full-transcript single-nucleus RNA-seq (SMART-Seq) with matched individual-level whole-genome sequencing to jointly infer mutational events and the cell-type in which they occurred. AlzD individuals show increased mutational burden, localized in excitatory neurons, oligodendrocytes, astrocytes and disease-associated “senescent” cells. High-mutational-burden cells showed mutational enrichment and similar single-cell expression profiles in AlzD cases versus non-AlzD individuals, indicating cellular-level genotype-to-phenotype correlation. Somatic mutations are specifically enriched for known AlzD genes, and implicate biologically meaningful cell-type specific processes, including: neuronal energy regulation, endocytic trafficking ( NEFM ), lipid metabolism ( CNP, CRYAB ), proteostasis ( USP34 ), cytoskeleton, and microtubule dynamics ( MACF1 ).
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Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions) in neurodegeneration.
“Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions in neurodegeneration)124–128.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [127]
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References 86 · Cited by 7
- Authors
- Kousi, M., Boix, C., Park, Y. P., Mathys, H., Sledzieski, S., Peng, Z., Bennett, D. A., Tsai, L.-H., & Kellis, M.
- Affiliations
- Broad Institute (US)
- Rush University Medical Center (US)
- Corresponding author
- Kellis, Manolis
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2022-04-22
- OpenAlex
- W4280530684
- Cited by
- 7
- References
- 86
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG058002, R01AG062335, RF1AG054012, RF1AG062377)
- National Institute of Mental Health (U01MH119509, R01MH109978)
- National Human Genome Research Institute (R01HG008155)
- National Institute of Neurological Disorders and Stroke (U01NS110453)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's dementia, somatic mosaicism, somatic mutations, mutational burden, single-nucleus RNA sequencing, prefrontal cortex, excitatory neurons, oligodendrocytes, astrocytes, senescent cells, endosomal trafficking, lipid metabolism, proteostasis, microtubule dynamics, MACF1, USP34, alphaB-crystallin, CNP
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