Constitutional Aneuploidy in the Normal Human Brain

Rehen, Stevens K.; Yung, Yun C.; McCreight, Matthew P.; Kaushal, Dhruv; Yang, Amy H.; Almeida, Beatriz S. V.; Kingsbury, Marcy A.; Cabral, Katia M. S.; McConnell, Michael J.; Anliker, Brigitte; Fontanoz, Marisa; Chun, Jerold

doi:10.1523/jneurosci.4560-04.2005

Cited by 286 publications

(266 citation statements)

References 28 publications

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“…This observation is in agreement with a recent single-neuron sequencing study that, despite identifying a high frequency of subchromosome copy number variants, did not observe high levels of whole-chromosome aneuploidy in neurons (30). Prior reports used SKY and FISH to assess the prevalence of aneuploidy and found it to exceed 50% and 20% in the liver and brain, respectively (13,14,(16)(17)(18)(19)(20). We attribute this difference to drawbacks associated with using FISH to detect somatic aneuploidy.…”

Section: Discussionsupporting

confidence: 91%

“…We conclude that the prevalence of aneuploidy in the adult human brain is 2.2% (95% CI 0.3%-7.9%; Fig. 2B and Table S1), significantly less than the more than 20% aneuploidy reported by prior studies (16)(17)(18)(19)(20).…”

Section: Resultsmentioning

confidence: 53%

“…Using spectral karyotyping (SKY), they reported that 33% of embryonic mouse neural progenitor cells harbored loss or gain of one or more chromosomes. Subsequent studies using FISH indicated that approximately 20% of adult mouse and human brain cells were aneuploid (16)(17)(18)(19)(20). These aneuploid cells were believed to arise from chromosome mis-segregation events in neural progenitor cells and were shown to integrate into brain circuitry (21,22).…”

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confidence: 99%

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Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

291

253

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Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 53%

mentioning

confidence: 99%

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Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

291

253

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“…In the literature, there are contrasting data on chromosomal stability of nonimmortalized NSC lines and some data indicate that, at least for adult mouse SVZ stem cells in vivo, chromosomal abnormalities might actually be somehow expected. [28][29][30][31][32][33] Although preliminary, these results indicate that the chromosomal instability described by a number of authors for both adult mouse SVZ-derived neurosphere 8,20 and adult rat hippocampal progenitor 17 cultures is also present in aNS-1 cells. Further analyses are required to better define when these aberrations arise in the aNS cultures and how they evolve with time.…”

Section: Discussionsupporting

confidence: 51%

Setting the conditions for efficient, robust and reproducible generation of functionally active neurons from adult subventricular zone-derived neural stem cells

et al. 2008

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Although new culture conditions enable homogeneous and long-term propagation of radial glia-like neural stem (NS) cells in monolayer and serum-free conditions, the efficiency of the conversion of NS cells into terminally differentiated, functionally mature neurons is relatively limited and poorly characterized. We demonstrate that NS cells derived from adult mouse subventricular zone robustly develop properties of mature neurons when exposed to an optimized neuronal differentiation protocol. A high degree of cell viability was preserved. At 22 days in vitro, most cells (65%) were microtubule-associated protein 2 þ and coexpressed c-aminobutyric acid (GABA), GAD67, calbindin and parvalbumin. Nearly all neurons exhibited sodium, potassium and calcium currents, and 70% of them fired action potentials. These neurons expressed functional GABA A receptors, whereas activable kainate, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartic acid receptors were present in approximately 80, 30 and 2% of cells, respectively. Antigenic and functional properties were efficiently and reliably reproduced across experiments and cell passages (up to 68). This is the first report showing a consistent and reproducible generation of large amounts of neurons from long-term passaged adult neural stem cells. Remarkably, the neuronal progeny carries a defined set of antigenic, biochemical and functional characteristics that make this system suitable for studies of NS cell biology as well as for genetic and chemical screenings.

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“…For somatic tissues, an important part of the knowledge on mosaicism has been obtained from studies using cytogenetic banding techniques, which provide information on whole chromosome copy number or large aberrations, and fluorescent in situ hybridization (FISH), studying a single locus. These studies have shown that the grade of mosaicism varies from tissue to tissue and the percentage of aneuploid cells increases with age, but provide limited insight on the occurrence of small genetic imbalances [2][3][4][5] . More recently, the group of Abyzov et al 6 made use of the clonal nature of humaninduced pluripotent stem cells (hiPSCs) to show that human skin fibroblasts are highly mosaic, with up to 30% of cells carrying copy number variants (CNVs).…”

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confidence: 99%

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations

et al. 2014

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Current knowledge on chromosomal mosaicism in human cell cultures is mostly based on cytogenetic banding methods. The recent development of high-resolution full-genome analysis methods applicable to single cells is providing new insights into genetic and cellular diversity. Here we study the genetic content of 92 individual human cells, including fibroblasts, amniocytes and embryonic stem cells (hESCs), using single-cell array-based comparative genomic hybridization (aCGH). We find that human somatic and embryonic stem cell cultures show significant fractions of cells carrying unique megabase-scale chromosomal abnormalities, forming genetic mosaics that could not have been detected by conventional cytogenetic methods. These findings are confirmed by studying seven clonal hESC sub-lines by aCGH. Furthermore, fluorescent in situ hybridisation reveals an increased instability of the subtelomeric regions in hESC as compared to somatic cells. This genetic heterogeneity may have an impact on experimental results and, in the case of hESC, on their potential clinical use.

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Constitutional Aneuploidy in the Normal Human Brain

Abstract: Together, these data demonstrate that human brain cells (both neurons and non-neuronal cells) can be aneuploid and that the resulting genetic mosaicism is a normal feature of the human CNS.

Cited by 286 publications

References 28 publications

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Setting the conditions for efficient, robust and reproducible generation of functionally active neurons from adult subventricular zone-derived neural stem cells

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations

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