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

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms21218328 ◽

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.

Download Full-text

Laundering CNV data for candidate process prioritization in brain disorders

Molecular Cytogenetics ◽

10.1186/s13039-019-0468-7 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 3

Author(s):

Maria A. Zelenova ◽

Yuri B. Yurov ◽

Svetlana G. Vorsanova ◽

Ivan Y. Iourov

Keyword(s):

Snp Array ◽

Autism Spectrum ◽

Copy Number Variations ◽

Genomic Research ◽

Molecular Karyotyping ◽

Molecular Pathways ◽

Data Sets ◽

Brain Disorders ◽

Disease Mechanisms ◽

Neuropsychiatric Diseases

Abstract Background Prioritization of genomic data has become a useful tool for uncovering the phenotypic effect of genetic variations (e.g. copy number variations or CNV) and disease mechanisms. Due to the complexity, brain disorders represent a major focus of genomic research aimed at revealing pathologic significance of genomic changes leading to brain dysfunction. Here, we propose a “CNV data laundering” algorithm based on filtering and prioritizing of genomic pathways retrieved from available databases for uncovering altered molecular pathways in brain disorders. The algorithm comprises seven consecutive steps of processing individual CNV data sets. First, the data are compared to in-house and web databases to discriminate recurrent non-pathogenic variants. Second, the CNV pool is confined to the genes predominantly expressed in the brain. Third, intergenic interactions are used for filtering causative CNV. Fourth, a network of interconnected elements specific for an individual genome variation set is created. Fifth, ontologic data (pathways/functions) are attributed to clusters of network elements. Sixth, the pathways are prioritized according to the significance of elements affected by CNV. Seventh, prioritized pathways are clustered according to the ontologies. Results The algorithm was applied to 191 CNV data sets obtained from children with brain disorders (intellectual disability and autism spectrum disorders) by SNP array molecular karyotyping. “CNV data laundering” has identified 13 pathway clusters (39 processes/475 genes) implicated in the phenotypic manifestations. Conclusions Elucidating altered molecular pathways in brain disorders, the algorithm may be used for uncovering disease mechanisms and genotype-phenotype correlations. These opportunities are strongly required for developing therapeutic strategies in devastating neuropsychiatric diseases.

Download Full-text

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

Genes ◽

10.3390/genes12071071 ◽

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.

Download Full-text

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

BMC Medical Genomics ◽

10.1186/s12920-021-00899-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Na Ma ◽

Hui Xi ◽

Jing Chen ◽

Ying Peng ◽

Zhengjun Jia ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Sex Chromosome ◽

Snp Array ◽

Genomic Rearrangements ◽

Chromosomal Mosaicism ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Low Level ◽

Autosomal Aneuploidy ◽

Number Variation

Abstract Background Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. Methods A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. Results Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. Conclusion In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

Download Full-text

Lessons Learned from CNV Analysis of Major Birth Defects

International Journal of Molecular Sciences ◽

10.3390/ijms21218247 ◽

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.

Download Full-text

Integrating genomic correlation structure improves copy number variations detection

Bioinformatics ◽

10.1093/bioinformatics/btaa737 ◽

2020 ◽

Author(s):

Xizhi Luo ◽

Fei Qin ◽

Guoshuai Cai ◽

Feifei Xiao

Keyword(s):

Copy Number ◽

Snp Array ◽

Copy Number Variations ◽

Correlation Structure ◽

Supplementary Information ◽

Dependence Structure ◽

Random Pattern ◽

Genomic Correlation ◽

Equal Chance ◽

Cnv Detection

Abstract Motivation Copy number variation plays important roles in human complex diseases. The detection of copy number variants (CNVs) is identifying mean shift in genetic intensities to locate chromosomal breakpoints, the step of which is referred to as chromosomal segmentation. Many segmentation algorithms have been developed with a strong assumption of independent observations in the genetic loci, and they assume each locus has an equal chance to be a breakpoint (i.e. boundary of CNVs). However, this assumption is violated in the genetics perspective due to the existence of correlation among genomic positions, such as linkage disequilibrium (LD). Our study showed that the LD structure is related to the location distribution of CNVs, which indeed presents a non-random pattern on the genome. To generate more accurate CNVs, we proposed a novel algorithm, LDcnv, that models the CNV data with its biological characteristics relating to genetic dependence structure (i.e. LD). Results We theoretically demonstrated the correlation structure of CNV data in SNP array, which further supports the necessity of integrating biological structure in statistical methods for CNV detection. Therefore, we developed the LDcnv that integrated the genomic correlation structure with a local search strategy into statistical modeling of the CNV intensities. To evaluate the performance of LDcnv, we conducted extensive simulations and analyzed large-scale HapMap datasets. We showed that LDcnv presented high accuracy, stability and robustness in CNV detection and higher precision in detecting short CNVs compared to existing methods. This new segmentation algorithm has a wide scope of potential application with data from various high-throughput technology platforms. Availability and implementation https://github.com/FeifeiXiaoUSC/LDcnv. Supplementary information Supplementary data are available at Bioinformatics online.

Download Full-text

High-Resolution Genomic Profiling of Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukaemia (ALL) Identified Novel Recurrent Copy Number Variations Involved in Both Pathogenesis and Resistance to Tyrosine Kinase Inhibitors.

Blood ◽

10.1182/blood.v110.11.230.230 ◽

2007 ◽

Vol 110 (11) ◽

pp. 230-230

Author(s):

Ilaria Iacobucci ◽

E. Ottaviani ◽

A. Astolfi ◽

S. Soverini ◽

N. Testoni ◽

...

Keyword(s):

High Resolution ◽

Copy Number ◽

Complex Disease ◽

B Lymphocyte ◽

Philadelphia Chromosome ◽

Snp Array ◽

Copy Number Variations ◽

Imatinib Resistance ◽

Copy Number State ◽

Monosomy 7

Abstract The Ph chromosome is the most frequent cytogenetic aberration associated with ALL and it represents the single most significant adverse prognostic marker. Despite the encouraging results achieved with imatinib, resistance develops rapidly and is quickly followed by disease progression. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors driving both the disease and resistance remains to be defined. In order to identify at submicroscopic level genetic lesions driving leukemogenesis and resistance, we profiled until now the genomes of 18 patients, out of 55 Ph+ ALL patients treated in our institute, at diagnosis (n=11) or at the time of haematological relapse (n=7) during therapy with imatinib or dasatinib. 250 ng of genomic DNA were processed on 500K single nucleotide polymorphism (SNP) array according to protocols provided by the manufacturer (Affymetrix Inc., Santa Clara, CA, USA). The median SNP call rate of analysed samples was 96%. Raw signal data were analyzed by BRLMM algorithm and copy number state was calculated with respect to a set of 48 Hapmap normal individuals and a diploid reference set of samples obtained from acute leukaemia cases in remission. Regions of amplification and deletion were visualized by Integrated Genome Browser and mapped to RefSeq to identify the specific genes involved in the lesion. Our analysis identified multiple copy number alterations per case, with deletions outnumbering amplification almost 3:1. Lesions varied from loss or gain of complete chromosome arms (trisomy 4, monosomy 7, loss of 9p, 10q, 14q, 16q and gain of 1q and 17q) to microdeletions and microduplications targeting genomic intervals. The recurring microdeletions that we detected in at least 50% of patients (both at diagnosis and at relapse) included 1p36.21 (PRAMEF), 3q29 (TFCR), 7p14.1 (AMPH), 8p23 (DEFB105A), 14q11.2 (DAD1), 16p13.11 (PDXDC1, NTAN1, RRN3), 16p11.2 (SNP) and 19p13.2 (CARM1, SMARCA4). A common microamplification was 4q13.2 (TMPRSS11E) and 17q21.31. Some genomic alterations were identified in genes regulating B-lymphocyte differentiation, such as PAX5 (n=3), BLNK (n=1) and VPREB1 (n=6) and in genes with an established role in leukemogenesis, such as MDS, BTG1, MLLT3 and RUNX1. Furthermore, many of the deletions detected included genes encoded for phosphatase proteins (e.g. PTPRD, PPP1R9B, PTPN18) and for zinc-finger proteins without any difference between diagnosis and resistance. It is noteworthy that some lesions felt in regions lacking annotated genes (loss: 2p11.2, 3p12.3, 7q11.21 and 14q32.33; gain: 8q23.3 and 13q21.1). Using high-resolution genome wide approach we showed that Ph+ ALL is a more complex disease characterized by multiple genomic anomalies which may provide new insights into the mechanisms underlying leukemogenesis and may be used as targets for existing or novel drugs. Supported by: European LeukemiaNet, COFIN 2003, Novartis Oncology Clinical Development, AIL.

Download Full-text

Clinical Utility and the Yield of Single Nucleotide Polymorphism Array in Prenatal Diagnosis of Fetal Central Nervous System Abnormalities

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.666115 ◽

2021 ◽

Vol 8 ◽

Author(s):

Meiying Cai ◽

Hailong Huang ◽

Liangpu Xu ◽

Na Lin

Keyword(s):

Central Nervous System ◽

Single Nucleotide Polymorphism ◽

Copy Number ◽

Chromosomal Abnormalities ◽

Karyotype Analysis ◽

Snp Array ◽

Copy Number Variations ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Pathogenic Cnvs

Applying single nucleotide polymorphism (SNP) array to identify the etiology of fetal central nervous system (CNS) abnormality, and exploring its association with chromosomal abnormalities, copy number variations, and obstetrical outcome. 535 fetuses with CNS abnormalities were analyzed using karyotype analysis and SNP array. Among the 535 fetuses with CNS abnormalities, chromosomal abnormalities were detected in 36 (6.7%) of the fetuses, which were consistent with karyotype analysis. Further, additional 41 fetuses with abnormal copy number variations (CNVs) were detected using SNP array (the detection rate of additional abnormal CNVs was 7.7%). The rate of chromosomal abnormalities, but not that of pathogenic CNVs in CNS abnormalities with other ultrasound abnormalities was significantly higher than that in isolated CNS abnormalities. The rates of chromosomal abnormalities and pathogenic CNVs in fetuses with spine malformation (50%), encephalocele (50%), subependymal cyst (20%), and microcephaly (16.7%) were higher than those with other isolated CNS abnormalities. The pregnancies for 36 cases with chromosomal abnormalities, 18 cases with pathogenic CNVs, and three cases with VUS CNVs were terminated. SNP array should be used in the prenatal diagnosis of fetuses with CNS abnormalities, which can enable better prenatal assessment and genetic counseling, and affect obstetrical outcomes.

Download Full-text

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

V M BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY ◽

10.31363/2313-7053-2019-4-1-80-81 ◽

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.

Download Full-text

Evaluation of Chromosomal Abnormalities and Copy Number Variations in Fetuses with Ultrasonic Soft Markers

10.21203/rs.3.rs-66062/v1 ◽

2020 ◽

Author(s):

Meiying Cai ◽

Na Lin ◽

Liangpu Xu ◽

hailong huang

Keyword(s):

Copy Number ◽

Chromosomal Abnormalities ◽

Snp Array ◽

Copy Number Variations ◽

Clinical Value ◽

Obstetrical Outcomes ◽

Genetic Abnormalities ◽

Significant Difference ◽

Snp Array Analysis ◽

Soft Marker

Abstract Background: Some ultrasonic soft markers can be found during ultrasound examination. However, the etiology of the fetuses with ultrasonic soft markers is still unknown. This study aimed to evaluate the genetic etiology and clinical value of chromosomal abnormalities and copy number variations (CNVs) in fetuses with ultrasonic soft markers.Methods: Among 1131 fetuses, 729 had single ultrasonic soft marker, 322 had two ultrasonic soft markers, and 80 had three or more ultrasonic soft markers. All fetuses underwent conventional karyotyping, followed by single nucleotide polymorphism (SNP) array analysis. Results: Among 1131 fetuses with ultrasonic soft markers, 46 had chromosomal abnormalities. In addition to the 46 fetuses with chromosomal abnormalities consistent with the results of the karyotyping analysis, the SNP array identified additional 6.1% (69/1131) abnormal CNVs. The rate of abnormal CNVs in fetuses with ultrasonic soft marker, two ultrasonic soft markers, three or more ultrasonic soft markers were 6.2%, 6.2%, and 5.0%, respectively. No significant difference was found in the rate of abnormal CNVs among the groups.Conclusions: Genetic abnormalities affect obstetrical outcomes. The SNP array can fully complement conventional karyotyping in fetuses with ultrasonic soft markers, improve detection rate of chromosomal abnormalities, and affect obstetrical outcomes.

Download Full-text