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.
Highlights
Despite the fact that mechanisms of chromosomal instability (CIN) and somatic chromosomal mosaicism (SCM) remain to be further explored [1,2,3], CIN-associated genome behavior has already been described [4,5,6]
To define these colocalized chromosome abnormalities in an individual and to name the process producing SMC and CIN/genomic instability (GIN) from regular genomic/chromosomal changes (CNV) by a single term, we have introduced the neologism “chromohelkosis”, which literally means “chromosome ulceration or ulcer” (from the Greek words “chromo” designating “chromosome” and “helkosis” derived from helkos, which means “ulceration”, “ulcer”, or “open wound”)
We intentionally composed the word “chromohelkosis” to mimic chromothripsis, chromoanasynthesis, and chromoanagenesis [4,5,6], inasmuch as it seems to be a common mechanism for somatic chromosome rearrangements and CIN
Summary
Despite the fact that mechanisms of chromosomal instability (CIN) and somatic chromosomal mosaicism (SCM) remain to be further explored [1,2,3], CIN-associated genome behavior (chromothripsis, chromoanasynthesis, chromoanagenesis) has already been described [4,5,6]. A large series of studies using a panel of molecular, cytogenomic, and bioinformatic techniques have shown that structural genomic variants (chromosomal rearrangements and CNV) frequently occur through mechanisms involving repeat sequences at the breakpoints as well as DNA recombination-based and replication-based processes [15,16,17,18,19]. Chromosome segregation errors have been indicated to form a wide spectrum of somatic genome rearrangements [20] These results promise the success of forthcoming studies of interplays between genome behavior at chromosomal (subchromosomal) level, CIN and SCM. Whole-genome and bioinformatic analyses of co-occurring non-mosaic and mosaic chromosomal (subchromosomal) variations or CIN in an individual may help to uncover previously unrecognized mechanisms for somatic genome variations at the chromosomal level
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