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.
Somatic mosaicism (somatic genome variations) has long been considered as a source for human genomic diversity and pathology [
In the present study, we have performed an analysis of genomic CNV affecting genes implicated in the cell cycle pathway (hsa04110 from the Kyoto Encyclopedia of Genes and Genomes or KEGG) by high-resolution molecular karyotyping (SNP-microarray analysis) in a cohort of 225 children with intellectual disability, autism, epilepsy, and/or congenital malformations. Genomes of these individuals were addressed inasmuch as their phenotypes had resulted from genomic rearrangements (chromosome abnormalities), which had not affected genes implicated in this specific pathway.
Genomes of 225 children with intellectual disability, autism, epilepsy, and/or congenital malformations from a cohort (~2500 patients) that has been partially described in a previous study [
Genomic CNVs were analyzed using CytoScan HD Arrays (Affymetrix, Santa Clara, CA) consisting of approximately 2.7 million markers for CNV evaluation and approximately 750,000 SNPs. CNVs were addressed by the Affymetrix Chromosome Analysis Suite (ChAS) software (ChAS analysis files for CytoScan HD Array version NA32.3). Genomic localization and gene content of detected CNVs were defined using NCBI Build GRCh37/hg19 reference sequence. The procedures have been previously described in detail [
Data analysis was performed using a bioinformatic workflow described recently [
CNVs affecting genes implicated in the cell cycle pathway according to the KEGG (
Distribution of genomic CNVs (numbers correspond to amount of individuals demonstrating CNV affecting a gene) across genes implicated in the cell cycle pathway (hsa04110).
Recurrent CNVs (apart from four copies of
Single CNVs affecting a gene implicated in the cell cycle pathway were found in 99 individuals. In the remainder, the incidence of the CNVs was as shown in Figure
Individual incidence of CNV affecting genes implicated in the cell cycle pathway.
There is a line of evidence that somatic mosaicism is common in humans. Although somatic genome variations manifesting as structural chromosomal or genomic rearrangements are occasionally reported in unaffected population [
Somatic genome variations are considered to have prenatal origin. Developmental chromosome and genome instability hallmarks human prenatal development at cellular and tissular levels [
CNV burden is a clinically valuable parameter that is important for assessing disease mechanisms and phenotypic significance of genomic variations [
Here, we have used KEGG for addressing contribution of CNVs to possible susceptibility to chromosome instability and to origin of somatic mosaicism.
The present data demonstrates that there do exist more-or-less common recurrent CNVs affecting 5 genes (
Our study provides a preliminary support for a hypothesis suggesting zygotic (sporadic and heritable) genomic variation to form a susceptibility to cellular genome instability or somatic genome variations (mosaicism) through genetic variability affecting genes implicated in cell cycle genome maintenance regulation pathways. Since this hypothesis appears to be valid at least in case of the cell cycle pathway (hsa04110), one may speculate that future studies targeted at evaluating related pathways (i.e., mitotic chromosome segregation, DNA reparation/replication, genome stability maintenance, etc.) are able to clarify whether zygotic genomic variation can generate somatic genome variation in health and disease.
Our preliminary study has shown that natural CNV affecting genes implicated in the cell cycle pathway is relatively common. It is noteworthy that a significant proportion of individuals with these CNVs carry a kind of CNV burden across genes implicated in the cell cycle pathway. These data provide an experimental support for the hypothesis suggesting natural zygotic genomic variation (heritable and sporadic) predisposing to nonheritable/postzygotic genomic changes (aneuploidy) affecting genes implicated in cell cycle regulation or related pathways acquired during the lifetime. Since an analysis of a single pathway, alterations in which result in somatic mosaicism (aneuploidy), could support the hypothesis, one may assume that increasing the numbers of pathways analyzed in this context would certainly give further insights into origins of somatic mosaicism and determine intrinsic interactions between zygotic and postzygotic genome variation.
Written consent was obtained from patients for publishing the results of this study.
The authors declare no conflict of interests.
The paper is dedicated to Ilya V. Soloviev. The study was supported by the Russian Science Foundation (Project no.14-15-00411).