Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons

Bos, Hilda van den; Spierings, Diana C.J.; Taudt, Aaron; Bakker, Björn; Porubský, David; Falconer, Ester; Novoa, Carolina; Halsema, Nancy; Kazemier, Hinke G.; Hoekstra-Wakker, Karina; Guryev, Victor; Dunnen, Wilfred F. A. den; Foijer, Floris; Colomé-Tatché, Maria; Boddeke, Hendrikus; Landsdorp, Peter M.

doi:10.1186/s13059-016-0976-2

Cited by 124 publications

(141 citation statements)

References 26 publications

(46 reference statements)

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“…These studies suggest that the level of aneuploidy in brain and liver is much lower than previously reported, with aneuploidy only affecting $2-5% of the cells, similar to the low rates of aneuploidy which were reported for epidermis. [62][63][64] Together these data suggest that many human tissues, including brain, skin and liver, contain a low level of aneuploidy. However, the exact contribution of aneuploid cells to in vivo tissues still needs to be more accurately quantified.…”

Section: How Well Is Aneuploidy Tolerated In Vivo?mentioning

confidence: 76%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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Section: How Well Is Aneuploidy Tolerated In Vivo?mentioning

confidence: 76%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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“…On the other hand, in a recent study, a twofold increase in X chromosome aneuploidy was found in AD neurons when compared to age matched controls [65]. To summarize, although again the rates of aneuploidy and which chromosomes are afected difer between studies, the overall trends suggest that aneuploidy might be increased in AD [66].…”

Section: Origin Of Aneuploid Cells In the Brainmentioning

confidence: 77%

“…All of these single cell sequencing studies use cells of which the chromosome copy numbers are known as validation of the method: human male trisomy 21 ibroblasts [82], human male trisomy 18 neurons [81], mouse trisomy 16 brain cells [87] and human female trisomy 21 neurons [66]. In each case, the known aneuploidy as well as the correct number of X chromosomes, male or female, was detected with 100% accuracy, conirming the sensitivity of single cell sequencing.…”

Section: Low Levels Of Aneuploidy Found In the Brain Using Single Celmentioning

confidence: 82%

“…After sequencing, the individual reads are split into libraries for each individual cell based on the cellular barcode (demultiplexing), and the copy numbers of individual chromosomes can be determined by comparing the read density on each chromosome. An extra copy of a chromosome is expected to result in 50% increase in read density, while loss of a chromosome leads to a 50% reduction of the read density on that chromosome [66,85,86]. Depending on the sequencing depth, single cell sequencing can, in addition to whole chromosome aneuploidies, also reveal smaller copy number changes.…”

Section: Low Levels Of Aneuploidy Found In the Brain Using Single Celmentioning

confidence: 99%

“…aneuploidy both in controls and AD [66]. All of these single cell sequencing studies use cells of which the chromosome copy numbers are known as validation of the method: human male trisomy 21 ibroblasts [82], human male trisomy 18 neurons [81], mouse trisomy 16 brain cells [87] and human female trisomy 21 neurons [66].…”

Section: Low Levels Of Aneuploidy Found In the Brain Using Single Celmentioning

confidence: 99%

See 2 more Smart Citations

Does Aneuploidy in the Brain Play a Role in Neurodegenerative Disease?

Bos¹,

Spierings²,

Foijer³

et al. 2017

Chromosomal Abnormalities - A Hallmark Manifestation of Genomic Instability

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Aneuploidy, a state in which cells exhibit copy number changes of (parts of) chromosomes, is a hallmark of cancer cells and, when present in all cells, leads to miscarriages and congenital disorders, such as Down syndrome. In addition to these well-known roles of aneuploidy, chromosome copy number changes have also been reported in some studies to occur in neurons in healthy human brain and possibly even more in Alzheimer's disease (AD). However, the studies of aneuploidy in the human brain are currently under debate as earlier indings, mostly based on in situ hybridization approaches, could not be reproduced by more recent single cell sequencing studies with a much higher resolution. Here, we review the various studies on the occurrence of aneuploidy in brain cells from normal individuals and Alzheimer's patients. We discuss possible mechanisms for the origin of aneuploidy and the pros and cons of diferent techniques used to study aneuploidy in the brain, and we provide a future perspective.

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