The Cytogenomic “Theory of Everything”: Chromohelkosis May Underlie Chromosomal Instability and Mosaicism in Disease and Aging

Abstract

Mechanisms for somatic chromosomal mosaicism (SCM) and chromosomal instability (CIN) are not completely understood. During molecular karyotyping and bioinformatic analyses of children with neurodevelopmental disorders and congenital malformations (n = 612), we observed colocalization of regular chromosomal imbalances or copy number variations (CNV) with mosaic ones (n = 47 or 7.7%). Analyzing molecular karyotyping data and pathways affected by CNV burdens, we proposed a mechanism for SCM/CIN, which had been designated as “chromohelkosis” (from the Greek words chromosome ulceration/open wound). Briefly, structural chromosomal imbalances are likely to cause local instability (“wreckage”) at the breakpoints, which results either in partial/whole chromosome loss (e.g., aneuploidy) or elongation of duplicated regions. Accordingly, a function for classical/alpha satellite DNA (protection from the wreckage towards the centromere) has been hypothesized. Since SCM and CIN are ubiquitously involved in development, homeostasis and disease (e.g., prenatal development, cancer, brain diseases, aging), we have metaphorically (ironically) designate the system explaining chromohelkosis contribution to SCM/CIN as the cytogenomic “theory of everything”, similar to the homonymous theory in physics inasmuch as it might explain numerous phenomena in chromosome biology. Recognizing possible empirical and theoretical weaknesses of this “theory”, we nevertheless believe that studies of chromohelkosis-like processes are required to understand structural variability and flexibility of the genome.

Turner’s syndrome mosaicism in girls with neurodevelopmental disorders: a cohort study and hypothesis

“…It is import to note that somatic chromosome abnormalities (aneuploidy and structural rearrangements) are ontogenetically instable. In other words, the rates of mosaicism may increase with age mediating agingrelated diseases and adverse aging effects [23,[40][41][42][43][44]. More importantly, X chromosome loss progresses during aging and is considered as a cytogenetic biomarker of aging [45][46][47].…”

“…Therefore, unapparent phenotypic manifestations of TSM [57], should not be considered as a limitation for defining TSM as a biomarker for multifactorial diseases mediated by X chromosome aneuploidy. Furthermore, aging-related exhausting of molecular pathways guaranteeing chromosome stability and genetic-environmental interactions predispose to an increase in genome instability levels throughout ontogeny [23,34,[58][59][60][61][62]. Moreover, chromosome abnormalities may initiate chromosome instability per se [23].…”

“…Furthermore, aging-related exhausting of molecular pathways guaranteeing chromosome stability and genetic-environmental interactions predispose to an increase in genome instability levels throughout ontogeny [ 23 , 34 , 58 – 62 ]. Moreover, chromosome abnormalities may initiate chromosome instability per se [ 23 ]. These observations allowed us to propose a hypothesis described below.…”

“…SNP-array-analysis (molecular karyotyping) using CytoScan HD Arrays (Affymetrix, Santa Clara, CA, USA) consisting of about 2.7 million markers was performed as described earlier [ 22 , 23 ]. Data were visualized using the Affymetrix ChAS (Chromosome Analysis Suite) software CytoScan® HD Array Version 4.1.0.90/r29400 (reference sequence—GRCh37/hg19).…”

40-Hz Auditory Steady-State Response (ASSR) as a Biomarker of Genetic Defects in the SHANK3 Gene: A Case Report of 15-Year-Old Girl with a Rare Partial SHANK3 Duplication

“…The results were visualized by the Affymetrix ChAS (Chromosome Analysis Suite) CytoScan ® HD Array software (reference sequence GRCh37/hg19). The procedures were earlier described in detail [ 105 , 106 ]. All the genomic variations uncovered by the molecular genetic analysis were analyzed using a panel of bioinformatic techniques targeting the phenotypic outcome of each variation.…”