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

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.

S‐phase duration is the main target of cell cycle regulation in neural progenitors of developing ferret neocortex

“…This could in turn be related to the genomic heterogeneity of the mature brain, thought to be a source of neural diversity (Bushman and Chun, 2013). In the ferret, the extent of S‐phase shortening is greater than in the mouse (Arai et al, 2011); this could be a consequence of the greater progenitor number and neuron output of a gyrencephalic brain, especially during the generation of supragranular layers, compared with a lissencephalic one.…”

Programmed Cell Death in Neurodevelopment

“…It has been proposed that PCD plays an important role in buffering error or noise in several aspects of neural development. Indeed, it has been reported that many aneuploid cells are generated in mouse embryonic cerebral cortex development and that this phenomenon is greatly increased by inhibition of apoptosis during development (Bushman and Chun, 2013;Peterson et al, 2012;Rehen et al, 2001). Although how and why neural aneuploidy originates spontaneously in mammalian brain development remains unclear, these results suggest that endogenous PCD in the cerebral cortex, if not all of the nervous system, may arise from somatic genomic alterations.…”

“…Although how and why neural aneuploidy originates spontaneously in mammalian brain development remains unclear, these results suggest that endogenous PCD in the cerebral cortex, if not all of the nervous system, may arise from somatic genomic alterations. PCD may thus serve as a quality control mechanism to eliminate cells that have undesirable genomic alterations ( Figure 4D) (Bushman and Chun, 2013;Peterson et al, 2012). Hereafter, we will further discuss the quality control function, in other words, buffering action, of PCD by considering the potential triggers of PCD, namely developmental error, noise, or intrinsic developmental programs.…”

Aneuploidy in Lewy body diseases

“…Aneuploidy is an abnormal number of copies of a genomic region, which is often observed not only in tumor cells but also in human brain, particularly during development (Bushman and Chun, 2013;Iourov et al, 2012). However, hyperploid neurons are not only just a feature of the developing brain but also exist in the healthy adult at an estimated frequency of about 10% (Bushman and Chun, 2013;Iourov et al, 2012).…”