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.
Highlights
Somatic mosaicism has long been considered as a source for human genomic diversity and pathology [1,2,3]
Our study provides a preliminary support for a hypothesis suggesting zygotic genomic variation to form a susceptibility to cellular genome instability or somatic genome variations through genetic variability affecting genes implicated in cell cycle genome maintenance regulation pathways
Our preliminary study has shown that natural copy number variation (CNV) affecting genes implicated in the cell cycle pathway is relatively common
Summary
Somatic mosaicism (somatic genome variations) has long been considered as a source for human genomic diversity and pathology [1,2,3]. Causes and consequences of postzygotic genomic variation (i.e., loss/gain of chromosomes in a cell or aneuploidy) remain largely unknown. The latter is probably the reason for mosaicism underappreciation in current genomic research [2,3,4]. Since common types of somatic mosaicism (mainly postzygotic aneuploidy) are likely to result from alterations in cell division (mitotic) regulation and genome maintenance pathways [4, 13,14,15], it has been hypothesized that zygotic (heritable and sporadic) genomic variation across genes implicated in pathways related to cell cycle regulation is the most likely cause of intercellular genome diversification [14]. A simple analysis of genomic copy number variation (CNV) in genes implicated in these pathways is able to answer the question whether this hypothesis is worth further testing
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