The genomically mosaic brain: aneuploidy and more in neural diversity and disease - PubMed (original) (raw)

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The genomically mosaic brain: aneuploidy and more in neural diversity and disease

Diane M Bushman et al. Semin Cell Dev Biol. 2013 Apr.

Abstract

Genomically identical cells have long been assumed to comprise the human brain, with post-genomic mechanisms giving rise to its enormous diversity, complexity, and disease susceptibility. However, the identification of neural cells containing somatically generated mosaic aneuploidy - loss and/or gain of chromosomes from a euploid complement - and other genomic variations including LINE1 retrotransposons and regional patterns of DNA content variation (DCV), demonstrate that the brain is genomically heterogeneous. The precise phenotypes and functions produced by genomic mosaicism are not well understood, although the effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, and brain organization. Here we discuss genomic mosaicism as a feature of the normal brain as well as a possible factor in the weak or complex genetic linkages observed for many of the most common forms of neurological and psychiatric diseases.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Schematic of genomic mosaicism analysis techniques. A, Cells from cycling populations may be arrested in metaphase for either chromosome spread enumeration by counting DAPI-stained chromosomes (bottom left), or full karyotype analysis by SKY (bottom right). B, Non-cycling or interphase cells are hybridized with chromosome-specific FISH probes (e.g., the chromosome 8 and 16 point probes shown here in red and green, respectively). Euploid cells, disomic for both chromosomes, would display 2 dots of each; here, both nuclei are disomic for chromosome 8, while the nucleus on the left is monosomic for chromosome 16 and the nucleus on the right is trisomic for chromosome 16. C, Isolated cells and nuclei are stained to saturation with dyes like the DNA-intercalating dye Propidium Iodide or DRAQ5 for flow cytometric analysis. The prominent peak of the resulting DNA content histogram contains cells in the G0/G1 phase of the cell cycle (2N DNA content); S phase (2

<n<4) and="" g2="" m="" (4n)="" phase="" are="" distinguishable="" on="" the="" linear="" scale="" of="" x-axis.="" <b="">D, Hetergeneous DNA content histogram from human frontal cortical nuclei (green, red and blue are separate individuals) stained with propidium iodide, showing broad bases and right-hand shoulders. Chicken erythrocyte nuclei (CEN) were included as an internal reference standard and control. E, Overlay of representative lymphocyte (green), cerebellar (red) and cortical (blue) histograms displaying an area of increased DCV unique to the cortical sample. (Adapted with permission from Peterson et al., 2012; Westra et al., 2010.)</n<4)>

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