Normal Human Pluripotent Stem Cell Lines Exhibit Pervasive Mosaic Aneuploidy

Human pluripotent stem cell (hPSC) lines have been considered to be homogeneously euploid. Here we report that normal hPSC – including induced pluripotent - lines are karyotypic mosaics of euploid cells intermixed with many cells showing non-clonal aneuploidies as identified by chromosome counting, spectral karyotyping (SKY) and fluorescent in situ hybridization (FISH) of interphase/non-mitotic cells. This mosaic aneuploidy resembles that observed in progenitor cells of the developing brain and preimplantation embryos, suggesting that it is a normal, rather than pathological, feature of stem cell lines. The karyotypic heterogeneity generated by mosaic aneuploidy may contribute to the reported functional and phenotypic heterogeneity of hPSCs lines, as well as their therapeutic efficacy and safety following transplantation

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 integrit

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 integrit