scholarly journals A Genome Model Linking Birth Defects to Infections

2019 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Neurodevelopmental Disorders ◽  
Chromosomal Rearrangements ◽  
Lymphatic Drainage ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna ◽  
A Genome ◽  
Foreign Dna

AbstractThe purpose of this study was to test the hypothesis that infections are linked to chromosomal anomalies that cause neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to microbial DNA, including known teratogens. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, epigenetic and chromatin modifications were all found close together in polyfunctional clusters that were deleted or rearranged in neurodevelopmental disorders. In some patients, epigenetic driver mutations also changed access to large chromosome segments. These changes account for immune, circulatory, and structural deficits that accompany neurologic deficits. Specific and repetitive human DNA encompassing large deletions matched infections and passed rigorous artifact tests. Deletions of up to millions of bases accompanied infection-matching sequences and caused massive changes in the homologies to foreign DNAs. In data from three independent studies of private, familial and recurrent chromosomal rearrangements, massive changes in homologous microbiomes were found and may drive rearrangements and encourage pathogens. At least one chromosomal anomaly was found to consist of human DNA fragments with a gap that corresponded to a piece of integrated foreign DNA. Microbial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with the epigenome and highly active recombination during meiosis, driven by massive changes in the homologous microbiome. Abnormal recombination in gametes produces zygotes containing rare chromosome anomalies which cause neurologic disorders and non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA at a critical stage. Some infections may be more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.Abstract Figure

scholarly journals A Genome Model to Explain Major Features of Neurodevelopmental Disorders in Newborns

2019 ◽  
Vol 11 ◽  
pp. 117822261986336 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Lymphatic Drainage ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna ◽  
A Genome ◽  
Foreign Dna

The purpose of this study was to test the hypothesis that infections are linked to chromosomal anomalies that cause neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared with foreign DNAs, including known teratogens. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, epigenetic and chromatin modifications were all found close together in polyfunctional clusters that were deleted or rearranged in neurodevelopmental disorders. In some patients, epigenetic driver mutations also changed access to large chromosome segments. These changes account for immune, circulatory, and structural deficits that accompany neurologic deficits. Specific and repetitive human DNA encompassing large deletions matched infections and passed rigorous artifact tests. Deletions of up to millions of bases accompanied infection-matching sequences and caused massive changes in human homologies to foreign DNAs. In data from 3 independent studies of private, familial, and recurrent chromosomal rearrangements, massive changes in homologous microbiomes were found and may drive rearrangements and encourage pathogens. At least 1 chromosomal anomaly was found to consist of human DNA fragments with a gap that corresponded to a piece of integrated foreign DNA. Microbial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with the epigenome and highly active recombination during meiosis, driven by massive changes in human DNA-foreign DNA homologies. Abnormal recombination in gametes produces zygotes containing rare chromosome anomalies that cause neurologic disorders and nonneurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNAs at a critical stage. Some infections may be more likely tolerated because they resemble human DNA segments. Even rare developmental disorders can be screened for homology to infections within altered epigenomes and chromatin structures. Considering effects of foreign DNAs can assist prenatal and genetic counseling, diagnosis, prevention, and early intervention.

A Genome Model to Explain Major Features of Neurodevelopmental Disorders

2018 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Dna Sequences ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Lymphatic Drainage ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna ◽  
A Genome

Abstract: The purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In patients with neurodevelopmental disorders, DNA’s from viruses and bacteria including known teratogens were tested against chromosome anomalies known to cause the disorders. Results support a theory that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis, and sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.

scholarly journals Parental infections disrupt clustered genes encoding related functions required for nervous system development in newborns

2018 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Dna Sequences ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Gene Clusters ◽  
Nervous System Development ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna

AbstractThe purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to viruses and bacteria including known teratogens. Results support the explanation that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted gene clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis; sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.Graphic Abstract

scholarly journals Chromosomal anomalies that cause male sterility in the mouse also reduce ovary size

1984 ◽  
Vol 44 (2) ◽  
pp. 219-224 ◽  
Author(s):  
Ursula Mittwoch ◽  
Shantha Mahadevaiah ◽  
Leslie A. Setterfield
Keyword(s):  
Male Sterility ◽  
Germ Cells ◽  
Reciprocal Translocation ◽  
Chromosomal Anomalies ◽  
Male Sterile ◽  
Chromosome Anomalies ◽  
Ovarian Size ◽  
Males And Females ◽  
The Difference ◽  
Ovarian Involvement

SUMMARYTwo male-sterile chromosome anomalies, the insertion Is(7; 1)40H and the tertiary trisomy, Ts(512)31H, were found to be associated with reduced ovarian volumes in immature females. Together with the reciprocal translocation, T(11; 19)42H, in which this effect was described previously, reduced ovaries have been found in all three male-sterile chromosome anomalies investigated so far, suggesting that ovarian involvement is likely to be common in these conditions. Assuming that the smaller ovarian size reflects a reduction in the number of oocytes, it is suggested that male-sterile chromosome anomalies may exert basically similar deleterious effects on meiotic germ cells in males and females, the difference in outcome being due to cell-physiological differences between spermatocytes and oocytes and to the small number of surviving oocytes required for fertility in females.

Patterns of genome duplication within the Brassica napus genome

Genome ◽  
2003 ◽  
Vol 46 (2) ◽  
pp. 291-303 ◽  
Author(s):  
I A.P Parkin ◽  
A G Sharpe ◽  
D J Lydiate
Keyword(s):  
Brassica Napus ◽  
Genome Duplication ◽  
Chromosomal Rearrangements ◽  
Centric Fusion ◽  
Linkage Groups ◽  
Gross Chromosomal Rearrangements ◽  
A Genome ◽  
C Genome ◽  
Homologous Locus ◽  
Duplicate Loci

The progenitor diploid genomes (A and C) of the amphidiploid Brassica napus are extensively duplicated with 73% of genomic clones detecting two or more duplicate sequences within each of the diploid genomes. This comprehensive duplication of loci is to be expected in a species that has evolved through a polyploid ancestor. The majority of the duplicate loci within each of the diploid genomes were found in distinct linkage groups as collinear blocks of linked loci, some of which had undergone a variety of rearrangements subsequent to duplication, including inversions and translocations. A number of identical rearrangements were observed in the two diploid genomes, suggesting they had occurred before the divergence of the two species. A number of linkage groups displayed an organization consistent with centric fusion and (or) fission, suggesting this mechanism may have played a role in the evolution of Brassica genomes. For almost every genetically mapped locus detected in the A genome a homologous locus was found in the C genome; the collinear arrangement of these homologous markers allowed the primary regions of homoeology between the two genomes to be identified. At least 16 gross chromosomal rearrangements differentiated the two diploid genomes during their divergence from a common ancestor.Key words: genome evolution, Brassicaeae, polyploidy, homoeologous linkage groups.

scholarly journals Insight into origins, mechanisms, and utility of DNA methylation in B-cell malignancies

Blood ◽  
2018 ◽  
Vol 132 (10) ◽  
pp. 999-1006 ◽  
Author(s):  
Christopher C. Oakes ◽  
Jose I. Martin-Subero
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Driver Mutations ◽  
Detailed Knowledge ◽  
B Cell Differentiation ◽  
B Cell Malignancies ◽  
Essential Information ◽  
A Genome ◽  
Cytidine Deaminase Activity ◽  
Insight Into

AbstractUnderstanding how tumor cells fundamentally alter their identity is critical to identify specific vulnerabilities for use in precision medicine. In B-cell malignancy, knowledge of genetic changes has resulted in great gains in our understanding of the biology of tumor cells, impacting diagnosis, prognosis, and treatment. Despite this knowledge, much remains to be explained as genetic events do not completely explain clinical behavior and outcomes. Many patients lack recurrent driver mutations, and said drivers can persist in nonmalignant cells of healthy individuals remaining cancer-free for decades. Epigenetics has emerged as a valuable avenue to further explain tumor phenotypes. The epigenetic landscape is the software that powers and stabilizes cellular identity by abridging a broad genome into the essential information required per cell. A genome-level view of B-cell malignancies reveals complex but recurrent epigenetic patterns that define tumor types and subtypes, permitting high-resolution classification and novel insight into tumor-specific mechanisms. Epigenetic alterations are guided by distinct cellular processes, such as polycomb-based silencing, transcription, signaling pathways, and transcription factor activity, and involve B-cell-specific aspects, such as activation-induced cytidine deaminase activity and germinal center–specific events. Armed with a detailed knowledge of the epigenetic events that occur across the spectrum of B-cell differentiation, B-cell tumor–specific aberrations can be detected with improved accuracy and serve as a model for identification of tumor-specific events in cancer. Insight gained through recent efforts may prove valuable in guiding the use of both epigenetic- and nonepigenetic-based therapies.

Two Rare Variants of Down Syndrome: Down-Turner Syndrome and Down Syndrome with Translocation (13;14): A Case Report

2020 ◽  
Author(s):  
Evren GUMUS
Keyword(s):  
Down Syndrome ◽  
Case Report ◽  
Turner Syndrome ◽  
Rare Variants ◽  
Chromosomal Anomalies ◽  
Phenotypic Characteristics ◽  
Phenotypic Effect ◽  
Chromosome Anomalies ◽  
Structural Chromosome

In the present paper, we report two rare cases of Down syndrome (DS); mosaic Down-Turner syndrome and DS with rob (13;14). Patient 1 karyotype is mos 45,X[41] / 47, XX,+21[59] and patient 2 karyotype is 46, XY, rob (13;14)(q10;q10),+21. With these two unusual cases, we aimed to look at the most common numerical and structural chromosome anomalies from a different window and evaluate the phenotypic effect in the presence of different chromosomal anomalies. Our main goal is to evaluate the phenotypic characteristics of these two rare variants in the light of literature.

scholarly journals Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening inSaccharomyces cerevisiae

2004 ◽  
Vol 101 (24) ◽  
pp. 9039-9044 ◽  
Author(s):  
Stephanie Smith ◽  
Ji-Young Hwang ◽  
Soma Banerjee ◽  
Anju Majeed ◽  
Amitabha Gupta ◽  
...  
Keyword(s):  
Chromosomal Rearrangements ◽  
Gross Chromosomal Rearrangements ◽  
Genome Wide ◽  
A Genome ◽  
Mutator Genes

scholarly journals High Prevalence and Genetic Diversity of Large phiCD211 (phiCDIF1296T)-Like Prophages inClostridioides difficile

2017 ◽  
Vol 84 (3) ◽  
Author(s):  
Julian R. Garneau ◽  
Ognjen Sekulovic ◽  
Bruno Dupuy ◽  
Olga Soutourina ◽  
Marc Monot ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mobile Genetic Elements ◽  
Large Chromosome ◽  
Comparative Genomic ◽  
Content Type ◽  
Genetic Elements ◽  
Clostridioides Difficile ◽  
A Genome ◽  
Depth Analysis ◽  
High Prevalence

ABSTRACTClostridioides difficile(formerlyClostridium difficile) is a pathogenic bacterium displaying great genetic diversity. A significant proportion of this diversity is due to the presence of integrated prophages. Here, we provide an in-depth analysis of phiCD211, also known as phiCDIF1296T, the largest phage identified inC. difficileso far, with a genome of 131 kbp. It shares morphological and genomic similarity with other large siphophages, like phage 949, infectingLactococcus lactis, and phage c-st, infectingClostridium botulinum. A PhageTerm analysis indicated the presence of 378-bp direct terminal repeats at the phiCD211 genome termini. Among striking features of phiCD211, the presence of several transposase and integrase genes suggests past recombination events with other mobile genetic elements. Several gene products potentially influence the bacterial lifestyle and fitness, including a putative AcrB/AcrD/AcrF multidrug resistance protein, an EzrA septation ring formation regulator, and a spore protease. We also identified a CRISPR locus and acas3gene. We screened 2,584C. difficilegenomes available and detected 149 prophages sharing ≥80% nucleotide identity with phiCD211 (5% prevalence). Overall, phiCD211-like phages were detected inC. difficilestrains corresponding to 21 different multilocus sequence type groups, showing their high prevalence. Comparative genomic analyses revealed the existence of several clusters of highly similar phiCD211-like phages. Of note, large chromosome inversions were observed in some members, as well as multiple gene insertions and module exchanges. This highlights the great plasticity and gene coding potential of the phiCD211/phiCDIF1296T genome. Our analyses also suggest active evolution involving recombination with other mobile genetic elements.IMPORTANCEClostridioides difficileis a clinically important pathogen representing a serious threat to human health. Our hypothesis is that genetic differences between strains caused by the presence of integrated prophages could explain the apparent differences observed in the virulence of differentC. difficilestrains. In this study, we provide a full characterization of phiCD211, also known as phiCDIF1296T, the largest phage known to infectC. difficileso far. Screening 2,584C. difficilegenomes revealed the presence of highly similar phiCD211-like phages in 5% of the strains analyzed, showing their high prevalence. Multiple-genome comparisons suggest that evolution of the phiCD211-like phage community is dynamic, and some members have acquired genes that could influence bacterial biology and fitness. Our study further supports the relevance of studying phages inC. difficileto better understand the epidemiology of this clinically important human pathogen.

scholarly journals Integrated computational and experimental identification of p53, KRAS and VHL mutant selection associated with CRISPR-Cas9 editing

2018 ◽  
Author(s):  
Sanju Sinha ◽  
Karina Barbosa Guerra ◽  
Kuoyuan Cheng ◽  
Mark DM Leiserson ◽  
David M Wilson ◽  
...  
Keyword(s):  
Gene Editing ◽  
Mutant Cell ◽  
Cell Types ◽  
Driver Mutations ◽  
Mutant Selection ◽  
Cancer Driver ◽  
Genome Wide ◽  
A Genome ◽  
Induced Changes ◽  
Different Cell Types

AbstractRecent studies have reported that CRISPR-Cas9 gene editing induces a p53-dependent DNA damage response in primary cells, which may select for cells with oncogenic p53 mutations11,12. It is unclear whether these CRISPR-induced changes are applicable to different cell types, and whether CRISPR gene editing may select for other oncogenic mutations. Addressing these questions, we analyzed genome-wide CRISPR and RNAi screens to systematically chart the mutation selection potential of CRISPR knockouts across the whole exome. Our analysis suggests that CRISPR gene editing can select for mutants of KRAS and VHL, at a level comparable to that reported for p53. These predictions were further validated in a genome-wide manner by analyzing independent CRISPR screens and patients’ tumor data. Finally, we performed a new set of pooled and arrayed CRISPR screens to evaluate the competition between CRISPR-edited isogenic p53 WT and mutant cell lines, which further validated our predictions. In summary, our study systematically charts and points to the potential selection of specific cancer driver mutations during CRISPR-Cas9 gene editing.

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