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

2020 ◽  
Vol 21 (21) ◽  
pp. 8328
Author(s):  
Ivan Y. Iourov ◽  
Svetlana G. Vorsanova ◽  
Yuri B. Yurov ◽  
Maria A. Zelenova ◽  
Oxana S. Kurinnaia ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Prenatal Development ◽  
Copy Number Variations ◽  
Brain Diseases ◽  
Molecular Karyotyping ◽  
Chromosomal Mosaicism ◽  
Chromosome Loss ◽  
Chromosomal Imbalances ◽  
Alpha Satellite Dna ◽  
Theory Of Everything

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.

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

2020 ◽  
Author(s):  
Ivan Y Iourov ◽  
Svetlana G Vorsanova ◽  
Yuri B. Yurov ◽  
Maria A Zelenova ◽  
Oxana S Kurinnaia ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Snp Array ◽  
Prenatal Development ◽  
Copy Number Variations ◽  
Brain Diseases ◽  
Molecular Karyotyping ◽  
Chromosomal Mosaicism ◽  
Chromosome Loss ◽  
Chromosomal Imbalances ◽  
Theory Of Everything

Mechanisms for somatic chromosomal mosaicism (SCM) and chromosomal instability (CIN) are incompletely understood. During SNP-array molecular karyotyping and bioinformatic analyses of children with neurodevelopmental disorders and congenital malformations (n=612), we observed colocalizaion 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 chromosome ulceration/open wound). Briefly, structural chromosomal imbalances are likely to cause local instability (“wreckage”) at the breakpoints, which results either to 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” like 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.

scholarly journals Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1071
Author(s):  
Isabel Costantino ◽  
Juliet Nicodemus ◽  
Jerold Chun
Keyword(s):  
Dna Sequence ◽  
Technology Development ◽  
Copy Number Variations ◽  
Brain Cell ◽  
Brain Diseases ◽  
Multiple Forms ◽  
Somatic Variation ◽  
Dna Content Variation ◽  
Effects Of Aging ◽  
The Brain

Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell’s genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.

scholarly journals Lessons Learned from CNV Analysis of Major Birth Defects

2020 ◽  
Vol 21 (21) ◽  
pp. 8247
Author(s):  
Alina Christine Hilger ◽  
Gabriel Clemens Dworschak ◽  
Heiko Martin Reutter
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
De Novo ◽  
Copy Number Variations ◽  
Lessons Learned ◽  
Organ System ◽  
Molecular Karyotyping ◽  
The Past ◽  
Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

scholarly journals Chromosomal abnormalities and copy number variations in children with idiopathic mental illness

2019 ◽  
pp. 80-81
Author(s):  
O. S. Kurinnaia ◽  
I. Y. Iourov ◽  
S. G. Vorsanova
Keyword(s):  
Mental Illness ◽  
Mental Disorders ◽  
Copy Number ◽  
Genetic Factors ◽  
Chromosomal Abnormalities ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Correct Data

Genetic factors of mental illness are generally recognized. Here, it is shown that molecular karyotyping in combination with original bioinformatics methods offers the opportunity for effective uncovering genomic pathology, which may provide correct data on genetic factors for mental disorders in children.

scholarly journals CNVs and Chromosomal Aneuploidy in Patients With Early-Onset Schizophrenia and Bipolar Disorder: Genotype-Phenotype Associations

2021 ◽  
Vol 11 ◽  
Author(s):  
Hojka Gregoric Kumperscak ◽  
Danijela Krgovic ◽  
Maja Drobnic Radobuljac ◽  
Nina Senica ◽  
Andreja Zagorac ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Early Onset ◽  
Late Onset ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Early Onset Schizophrenia ◽  
Chromosomal Aneuploidy ◽  
Standards And Guidelines ◽  
Genetic Loading ◽  
Or Genes

Introduction: Early-onset schizophrenia (EOS) and bipolar disorder (EOB) start before the age of 18 years and have a more severe clinical course, a worse prognosis, and a greater genetic loading compared to the late-onset forms. Copy number variations (CNVs) are an important genetic factor in the etiology of psychiatric disorders. Therefore, this study aimed to analyze CNVs in patients with EOS and EOB and to establish genotype-phenotype relationships for contiguous gene syndromes or genes affected by identified CNVs.Methods: Molecular karyotyping was performed in 45 patients, 38 with EOS and seven with EOB hospitalized between 2010 and 2017. The exclusion criteria were medical or neurological disorders or IQ under 70. Detected CNVs were analyzed according to the standards and guidelines of the American College of Medical Genetics.Result: Molecular karyotyping showed CNVs in four patients with EOS (encompassing the PAK2, ADAMTS3, and ADAMTSL1 genes, and the 16p11.2 microduplication syndrome) and in two patients with EOB (encompassing the ARHGAP11B and PRODH genes). In one patient with EOB, a chromosomal aneuploidy 47, XYY was found.Discussion: Our study is the first study of CNVs in EOS and EOB patients in Slovenia. Our findings support the association of the PAK2, ARHGAP11B, and PRODH genes with schizophrenia and/or bipolar disorder. To our knowledge, this is also the first report of a multiplication of the ADAMTSL1 gene and the smallest deletion of the PAK2 gene in a patient with EOS, and one of the few reports of the 47, XYY karyotype in a patient with EOB.

Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations

2017 ◽  
Vol 109 (13) ◽  
pp. 1063-1069 ◽  
Author(s):  
Rong Zhang ◽  
Florian Marsch ◽  
Franziska Kause ◽  
Franziska Degenhardt ◽  
Eeberhard Schmiedeke ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Molecular Karyotyping

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

2013 ◽  
Vol 16 (4) ◽  
pp. 802-807 ◽  
Author(s):  
Friederike Baudisch ◽  
Markus Draaken ◽  
Enrika Bartels ◽  
Eberhard Schmiedeke ◽  
Soyhan Bagci ◽  
...  
Keyword(s):  
De Novo ◽  
Bladder Exstrophy ◽  
Anorectal Malformations ◽  
Monozygotic Twin ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Genetic Changes ◽  
Coding Regions ◽  
Whole Exome

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

scholarly journals Illegitimate and Repeated Genomic Integration of Cell-Free Chromatin in the Aetiology of Somatic Mosaicism, Ageing, Chronic Diseases and Cancer

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 407 ◽  
Author(s):  
Gorantla V. Raghuram ◽  
Shahid Chaudhary ◽  
Shweta Johari ◽  
Indraneel Mittra
Keyword(s):  
Dna Damage ◽  
High Throughput Sequencing ◽  
Somatic Mosaicism ◽  
Copy Number Variations ◽  
The Body ◽  
Chromosomal Mosaicism ◽  
Common Mechanism ◽  
Genomic Integration ◽  
Age Related ◽  
Degenerative Disorders

Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal variations and footprints of transposable elements. High-throughput sequencing has led to increasing detection of mosaicism in healthy individuals which is related to ageing, neuro-degenerative disorders, diabetes mellitus, cardiovascular diseases and cancer. These age-related disorders are also known to be associated with significant increase in DNA damage and inflammation. Herein, we discuss a newly described phenomenon wherein the genome is under constant assault by illegitimate integration of cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body every day. We propose that such repeated genomic integration of cfCh followed by dsDNA breaks and repair by non-homologous-end-joining as well as physical damage to chromosomes occurring throughout life may lead to somatic/chromosomal mosaicism which would increase with age. We also discuss the recent finding that genomic integration of cfCh and the accompanying DNA damage is associated with marked activation of inflammatory cytokines. Thus, the triple pathologies of somatic mosaicism, DNA/chromosomal damage and inflammation brought about by a common mechanism of genomic integration of cfCh may help to provide an unifying model for the understanding of aetiologies of the inter-related conditions of ageing, degenerative disorders and cancer.

scholarly journals Aneugenic Activity of Op18/Stathmin Is Potentiated by the Somatic Q18→E Mutation in Leukemic Cells

2006 ◽  
Vol 17 (7) ◽  
pp. 2921-2930 ◽  
Author(s):  
Per Holmfeldt ◽  
Kristoffer Brännström ◽  
Sonja Stenmark ◽  
Martin Gullberg
Keyword(s):  
Chromosomal Instability ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Chromosome Loss ◽  
Significant Finding ◽  
Mitotic Spindles ◽  
Wild Type ◽  
Apparent Effect ◽  
Hairpin Rna ◽  
Functional Consequences

Op18/stathmin (Op18) is a phosphorylation-regulated microtubule destabilizer that is frequently overexpressed in tumors. The importance of Op18 in malignancy was recently suggested by identification of a somatic Q18→E mutation of Op18 in an adenocarcinoma. We addressed the functional consequences of aberrant Op18 expression in leukemias by analyzing the cell cycle of K562 cells either depleted of Op18 by expression of interfering hairpin RNA or induced to express wild-type or Q18E substituted Op18. We show here that although Op18 depletion increases microtubule density during interphase, the density of mitotic spindles is essentially unaltered and cells divide normally. This is consistent with phosphorylation-inactivation of Op18 during mitosis. Overexpression of wild-type Op18 results in aneugenic activities, manifest as aberrant mitosis, polyploidization, and chromosome loss. One particularly significant finding was that the aneugenic activity of Op18 was dramatically increased by the Q18→E mutation. The hyperactivity of mutant Op18 is apparent in its unphosphorylated state, and this mutation also suppresses phosphorylation-inactivation of the microtubule-destabilizing activity of Op18 without any apparent effect on its phosphorylation status. Thus, although Op18 is dispensable for mitosis, the hyperactive Q18→E mutant, or overexpressed wild-type Op18, exerts aneugenic effects that are likely to contribute to chromosomal instability in tumors.

P-523 Whole-chromosome aneuploidies revealed by transcriptome of trophectoderm biopsied from human pre-implantation blastocyst

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
L Song ◽  
X Yanwen ◽  
C Bing ◽  
X Yan ◽  
Y Xiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
R Package ◽  
Copy Number Variations ◽  
Next Generation Sequencing Data ◽  
Chromosomal Mosaicism ◽  
Rna Seq ◽  
Sequencing Data ◽  
Registration Number ◽  
Mrna Transcriptome

Abstract Study question Whether mRNA transcriptome of biopsied trophectoderm (TE) in human pre-implantation blastocyst can predict embryo karyotype? Summary answer mRNA transcriptome of biopsied TE can precisely predict whole-chromosome aneuploidies but not mosaicism or segmental aneuploidies. What is known already Karyotype of human pre-implantation blastocyst is well recognized by PGT-A. However, genome can’t demonstrate gene expression level which might infer the development potential of euploidy. Transcriptome of blastocyst by singe-cell RNA-seq has revealed the lineage segregation of human pre-implantation blastocyst. It is not known whether transcriptome of biopsied TE used in PGT-A can infer the karyotype of human pre-implantation blastocyst. Study design, size, duration A total of 74 TE samples were biopsied from 26 blastocysts which were donated from patients who underwent PGT at our Reproductive Medicine Center. All of these embryos have been previously diagnosed as aneuploidies (n = 19) or euploidies (n = 7) with monogenic disorder. Participants/materials, setting, methods The DNA and mRNA of all biopsied TEs were separated independently using a modified oligo-dT bead capture, followed by PGT-A of DNA and smart2-sequencing of mRNA (G&T-seq). Karyotype of biopsied TEs were confirmed with PGT-A performed in MiSeq system (Illumina) in our PGT laboratory with the use of next-generation sequencing. Data of transcriptome was analyzed using Rstudio and R package InferCNV to predict aneuploidies by referring to euploidies which were inferred with corresponding PGT-A results. Main results and the role of chance In human pre-implantation blastocyst, all whole-chromosome aneuploidies could be inferred by transcriptome of biopsied TE, which were consistent with PGT-A result. But chromosomal mosaicism or segmental aneuploidies were hard to be predicted precisely by transcriptome of TE. Limitations, reasons for caution The main limitation of this study lies in the inability to retrieve the exact copy number variations from mRNA transcription. Gene expression is in a great imbalance in such an early development of human pre-implantation blastocyst. Wider implications of the findings Our data suggest that mRNA transcriptome is enough for prediction of whole-chromosome aneuploidies. The method and value for predicting mosaicism and segmental aneuploidies by transcriptome should be further investigated. Trial registration number not applicable

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