Copy number variations (CNVs) - is there a biological difference between submicroscopic and microscopically visible ones?

Liehr, Thomas

doi:10.13172/2054-197x-1-1-852

Cited by 4 publications

(5 citation statements)

References 22 publications

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“…Thus, it has been postulated that MG-CNVs and euchromatic CG-CNVs are biologically the same [ 15 ]. The latter may also partly explain the event of rare UBCAs, which, similar to MG-CNVs can be dispersed throughout all the genome (for localization of most frequent MG-CNVs see [ 23 ] Fig. 3 ).…”

Section: Introductionmentioning

confidence: 99%

“…It is also known that each human being carries about thousand MG-CNVs ranging from only a few hundred basepairs to over 1 Mb. The major determinant for the clinical impact of a CNV seems to be, if dosage sensitive genes are present in the corresponding DNA-stretch” [ 23 ]. Besides, it was recently found that more than one MG-CNV (larger than 500 kb) can contribute to phenotypic variability associated with genomic disorders and may be the reason for developmental impairment; this phenomenon is called “two-hit”-model [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Cytogenetically visible copy number variations (CG-CNVs) in banding and molecular cytogenetics of human; about heteromorphisms and euchromatic variants

Liehr

2016

Mol Cytogenet

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BackgroundCopy number variations (CNVs) having no (obvious) clinical effects were rediscovered as major part of human genome in 2004. However, for every cytogeneticist microscopically visible harmless CNVs (CG-CNVs) are well known since decades. Harmless CG-CNVs can be present as heterochromatic or even as euchromatic variants in clinically healthy persons.ResultsHere I provide a review on what is known today on the still too little studied harmless human CG-CNVs, point out which can be mixed up with clinically relevant pathological CG-CNVs and shortly discuss that the artificial separation of euchromatic submicroscopic CNVs (MG-CNVs) and euchromatic CG-CNVs is no longer timely.ConclusionOverall, neither so-called harmless heterochromatic nor so-called harmless euchromatic CG-CNVs are considered enough in evaluation of routine cytogenetic analysis and reporting. This holds especially true when bearing in mind the so-called two-hit model suggesting that combination of per se harmless CNVs may lead to clinical aberrations if they are present together in one patient.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytogenetically visible copy number variations (CG-CNVs) in banding and molecular cytogenetics of human; about heteromorphisms and euchromatic variants

Liehr

2016

Mol Cytogenet

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“…The two-hit model for euchromatic CNVs, as suggested in 2010 [ 12 ], has already been supported as potentially valid, and maybe at a lower efficiency, is valid also for heterochromatic CNVs—especially for heterochromatic CG-CNVs [ 7 ]. The majority of constitutional syndromes in humans are suggested to result from multigenic traits [ 81 ].…”

Section: Chromosomal Heteromorphisms (Chs) and Cancermentioning

confidence: 99%

“…Euchromatic regions include dosage-independent genes that may vary in copy numbers without (yet known or identified) influence on the phenotype or health of an individual; these were identified in 2004 and are referred to as copy number variants (CNVs) in the current literature [ 5 , 6 ]. These CNVs are generally only detectable by chromosomal microarray (CMA) studies and the majority of these findings are considered “CNVs detectable by molecular genetics” (MG-CNVs) [ 7 , 8 ]. MG-CNVs can be so sufficiently large that they become visible in banding cytogenetics and termed “cytogenetically visible copy number variations” (CG-CNVs) [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…These CNVs are generally only detectable by chromosomal microarray (CMA) studies and the majority of these findings are considered “CNVs detectable by molecular genetics” (MG-CNVs) [ 7 , 8 ]. MG-CNVs can be so sufficiently large that they become visible in banding cytogenetics and termed “cytogenetically visible copy number variations” (CG-CNVs) [ 7 , 8 ]. At present, euchromatic CG-CNVs and MG-CNVs are the focus of intense research [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal Heteromorphisms and Cancer Susceptibility Revisited

Liehr

2022

Cells

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Chromosomal heteromorphisms (CHs) are a part of genetic variation in man. The past literature largely posited whether CHs could be correlated with the development of malignancies. While this possibility seemed closed by end of the 1990s, recent data have raised the question again on the potential influences of repetitive DNA elements, the main components of CHs, in cancer susceptibility. Such new evidence for a potential role of CHs in cancer can be found in the following observations: (i) amplification and/or epigenetic alterations of CHs are routinely reported in tumors; (ii) the expression of CH-derived RNA in embryonal and other cells under stress, including cancer cells; (iii) the expression of parts of CH-DNA as long noncoding RNAs; plus (iv) theories that suggest a possible application of the “two-hit model” for euchromatic copy number variants (CNVs). Herein, these points are discussed in detail, which leads to the conclusion that CHs are by far not given sufficient consideration in routine cytogenetic analysis, e.g., leukemias and lymphomas, and need more attention in future research settings including solid tumors. This heightened focus may only be achieved by approaches other than standard sequencing or chromosomal microarrays, as these techniques are at a minimum impaired in their ability to detect, if not blind to, (highly) repetitive DNA sequences.

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Discovery of 33mer in chromosome 21 – the largest alpha satellite higher order repeat unit among all human somatic chromosomes

Glunčić

Vlahović

Paar

2019

Sci Rep

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The centromere is important for segregation of chromosomes during cell division in eukaryotes. Its destabilization results in chromosomal missegregation, aneuploidy, hallmarks of cancers and birth defects. In primate genomes centromeres contain tandem repeats of ~171 bp alpha satellite DNA, commonly organized into higher order repeats (HORs). In spite of crucial importance, satellites have been understudied because of gaps in sequencing - genomic “black holes”. Bioinformatical studies of genomic sequences open possibilities to revolutionize understanding of repetitive DNA datasets. Here, using robust (Global Repeat Map) algorithm we identified in hg38 sequence of human chromosome 21 complete ensemble of alpha satellite HORs with six long repeat units (≥20 mers), five of them novel. Novel 33mer HOR has the longest HOR unit identified so far among all somatic chromosomes and novel 23mer reverse HOR is distant far from the centromere. Also, we discovered that for hg38 assembly the 33mer sequences in chromosomes 21, 13, 14, and 22 are 100% identical but nearby gaps are present; that seems to require an additional more precise sequencing. Chromosome 21 is of significant interest for deciphering the molecular base of Down syndrome and of aneuploidies in general. Since the chromosome identifier probes are largely based on the detection of higher order alpha satellite repeats, distinctions between alpha satellite HORs in chromosomes 21 and 13 here identified might lead to a unique chromosome 21 probe in molecular cytogenetics, which would find utility in diagnostics. It is expected that its complete sequence analysis will have profound implications for understanding pathogenesis of diseases and development of new therapeutic approaches.

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Copy number variations (CNVs) - is there a biological difference between submicroscopic and microscopically visible ones?

Abstract: For citation purposes: Liehr T. Copy number variations-is there a biological difference between submicroscopic and microscopically visible ones? OA Genetics 2013 Apr 01;1(1):2.

Cited by 4 publications

References 22 publications

Cytogenetically visible copy number variations (CG-CNVs) in banding and molecular cytogenetics of human; about heteromorphisms and euchromatic variants

Cytogenetically visible copy number variations (CG-CNVs) in banding and molecular cytogenetics of human; about heteromorphisms and euchromatic variants

Chromosomal Heteromorphisms and Cancer Susceptibility Revisited

Discovery of 33mer in chromosome 21 – the largest alpha satellite higher order repeat unit among all human somatic chromosomes

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