Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients

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2022-12-01

Author

Turan, Zeliha Gözde
Richter, Vincent
Bochmann, Jana
Parvizi, Poorya
Yapar, Etka
Işıldak, Ulas
Waterholter, Sarah-Kristin
Leclere-Turbant, Sabrina
Son, Çağdaş Devrim
Duyckaerts, Charles
Yet, İdil
Arendt, Thomas
Somel, Mehmet
Ueberham, Uwe

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The possible role of somatic copy number variations (CNVs) in Alzheimer’s disease (AD) aetiology has been controversial. Although cytogenetic studies suggested increased CNV loads in AD brains, a recent single-cell whole-genome sequencing (scWGS) experiment, studying frontal cortex brain samples, found no such evidence. Here we readdressed this issue using low-coverage scWGS on pyramidal neurons dissected via both laser capture microdissection (LCM) and fluorescence activated cell sorting (FACS) across five brain regions: entorhinal cortex, temporal cortex, hippocampal CA1, hippocampal CA3, and the cerebellum. Among reliably detected somatic CNVs identified in 1301 cells obtained from the brains of 13 AD patients and 7 healthy controls, deletions were more frequent compared to duplications. Interestingly, we observed slightly higher frequencies of CNV events in cells from AD compared to similar numbers of cells from controls (4.1% vs. 1.4%, or 0.9% vs. 0.7%, using different filtering approaches), although the differences were not statistically significant. On the technical aspects, we observed that LCM-isolated cells show higher within-cell read depth variation compared to cells isolated with FACS. To reduce within-cell read depth variation, we proposed a principal component analysis-based denoising approach that significantly improves signal-to-noise ratios. Lastly, we showed that LCM-isolated neurons in AD harbour slightly more read depth variability than neurons of controls, which might be related to the reported hyperploid profiles of some AD-affected neurons.

Subject Keywords

Alzheimer’s disease, Brain, Copy number variation, Denoising, Fluorescence-activated cell sorting, Laser capture microdissection, Single-cell whole-genome sequencing

URI

https://hdl.handle.net/11511/101791

Journal

Acta Neuropathologica Communications

DOI

https://doi.org/10.1186/s40478-022-01452-2

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Department of Biology, Article

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Citation Formats

Z. G. Turan et al., “Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients,” Acta Neuropathologica Communications, vol. 10, no. 1, pp. 0–0, 2022, Accessed: 00, 2023. [Online]. Available: https://hdl.handle.net/11511/101791.