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

Turan, Zeliha Gözde ; Richter, Vincent ; Bochmann, Jana ; Parvizi, Poorya ; Yapar, Etka LU orcid ; Işıldak, Ulas ; Waterholter, Sarah Kristin ; Leclere-Turbant, Sabrina ; Son, Çağdaş Devrim and Duyckaerts, Charles , et al. (2022) In Acta Neuropathologica Communications 10(1).
Abstract

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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Brain, Copy number variation, Denoising, Fluorescence-activated cell sorting, Laser capture microdissection, Single-cell whole-genome sequencing
in
Acta Neuropathologica Communications
volume
10
issue
1
article number
175
publisher
BioMed Central (BMC)
external identifiers
  • pmid:36451207
  • scopus:85143098789
ISSN
2051-5960
DOI
10.1186/s40478-022-01452-2
language
English
LU publication?
yes
id
c02ceadc-8595-4658-8f0d-e3f19cf642bc
date added to LUP
2022-12-23 11:12:38
date last changed
2024-04-16 18:41:10
@article{c02ceadc-8595-4658-8f0d-e3f19cf642bc,
  abstract     = {{<p>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.</p>}},
  author       = {{Turan, Zeliha Gözde and Richter, Vincent and Bochmann, Jana and Parvizi, Poorya and Yapar, Etka and Işıldak, Ulas and Waterholter, Sarah Kristin and Leclere-Turbant, Sabrina and Son, Çağdaş Devrim and Duyckaerts, Charles and Yet, İdil and Arendt, Thomas and Somel, Mehmet and Ueberham, Uwe}},
  issn         = {{2051-5960}},
  keywords     = {{Alzheimer’s disease; Brain; Copy number variation; Denoising; Fluorescence-activated cell sorting; Laser capture microdissection; Single-cell whole-genome sequencing}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Acta Neuropathologica Communications}},
  title        = {{Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients}},
  url          = {{http://dx.doi.org/10.1186/s40478-022-01452-2}},
  doi          = {{10.1186/s40478-022-01452-2}},
  volume       = {{10}},
  year         = {{2022}},
}