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Extreme DNA Content Variation in the Mammalian Central Nervous System


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 effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, brain organization, and neuropathological processes. Analyses of genomic mosaicism in sporadic Alzheimer's disease (AD) provide evidence for potential functional mosaic changes, as dramatic genomic alterations in the AD frontal cortex manifested via a significant increase in DCV. The resulting somatic locus-specific amplification of amyloid precursor protein supports mosaicism as a factor in AD pathogenesis, while microfluidic quantitative (q)PCR analyses of single cortical AD neurons reveal the variability of somatic changes that occur within the brain of a single individual. Given the range of genomic variation that has been observed, understanding of the precise phenotypes and functions produced by genomic mosaicism in either diseased or normal brains is limited. However, the ablation of programmed cell death leading to increased observance of extreme karyotypes in cortical neural progenitor cells supports the functional non- equivalence of varied mosaic forms, as extremely aneuploid cells are targeted for elimination while cells with mild aneuploidies survive. Induction of increased neural mosaic aneuploidy through fetal exposure to substances of abuse demonstrates the fragility of the individual cellular genome and the vulnerability of the brain to induced mosaicism with pathogenic potential, highlighting the consequences of compromised somatic genomic integrity

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