Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism

Abstract

Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

“…A link between CNVs and Somatic Copy Number Alterations/Aberrations (SCNAs), which are changes in copy number that have arisen in somatic tissue, has emerged from studies of Iourov and colleagues who examined the frequency of CNVs mapping to the cell cycle pathway within a cohort of patients with intellectual disability, autism, and/or epilepsy (Iourov et al, 2015). The rationale for this study was based on the knowledge that somatic mosaicism is likely the consequence of alterations in cell division and genome maintenance pathways (as described in Section 2).…”

Behavioral Variability and Somatic Mosaicism: A Cytogenomic Hypothesis

“…One should keep in mind that it is impossible to obtain brain samples from a living individual to monitor somatic genome variations for a long period. However, it is possible to correlate the results of behavioral studies with somatic mosaicism evaluations in mitotic tissues and assessment of brain tissue susceptibility to genome instability uncovered by whole-genome scanning technologies (as suggested in [ 28 , 68 ]). In addition, basic research of correlation between somatic mosaicism levels in mitotic and post-mitotic neuronal and non-neuronal (brain) tissues should be pursued.…”

FISH-Based Analysis of Mosaic Aneuploidy and Chromosome Instability for Investigating Molecular and Cellular Mechanisms of Disease

“…CIN presenting as monosomy and trisomy has been confirmed in all of these cases. CIN cases have also exhibited 4-9 copy number variations (CNV) encompassing genes, involved in the pathways to genome instability and somatic mosaicism (genome stability, DNA reparation/replication, mitotic checkpoint, cell cycle regulation and programmed cell death) [35][36][37]. Using bioinformatics for processing molecular karyotypes and addressing previously published data [8,12,18,20,25,[38][39][40][41][42], we have concluded that a proportion of these cases of intellectual disability, autism, epilepsy and/or congenital malformations is likely to be associated with chromosomal instability, which is an element of the pathogenetic cascade and thereby, should be recognized as a contributor to the phenotypic manifestations.…”

“…Molecular karyotyping should be performed with an extended bioinformatics analysis of functional consequences of genomic variations to unveil the impact on molecular pathways involved in maintaining genome stability. It is to note that such genomic variations are indirectly involved in the pathogenesis being, therefore, frequently overlooked [37,39]. Thus, cytogenetic and FISH-based analyses of CIN should be complemented by the aforementioned bioinformatics evaluations.…”