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

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

A Genome Model to Explain Major Features of Neurodevelopmental Disorders

10.20944/preprints201809.0272.v1 ◽

2018 ◽

Author(s):

Bernard Friedenson

Keyword(s):

Dna Sequences ◽

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.

A Genome Model Linking Birth Defects to Infections

10.1101/674093 ◽

2019 ◽

Author(s):

Bernard Friedenson

Keyword(s):

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

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

Biomedical Informatics Insights ◽

10.1177/1178222619863369 ◽

2019 ◽

Vol 11 ◽

pp. 117822261986336 ◽

Cited By ~ 1

Author(s):

Bernard Friedenson

Keyword(s):

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.

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Scientific Reports ◽

10.1038/s41598-021-86041-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joseph J. Rossi ◽

Jill A. Rosenfeld ◽

Katie M. Chan ◽

Haley Streff ◽

Victoria Nankivell ◽

...

Keyword(s):

Protein Function ◽

Transcriptional Activity ◽

Complete Loss ◽

Loss Of Function ◽

Targeted Disruption ◽

Clinical Exome Sequencing ◽

Partner Protein ◽

The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

Human DNA sequences homologous to a protein coding region conserved between homeotic genes of Drosophila

Cell ◽

10.1016/0092-8674(84)90261-7 ◽

1984 ◽

Vol 38 (3) ◽

pp. 667-673 ◽

Cited By ~ 121

Author(s):

Michael Levine ◽

Gerald M. Rubin ◽

Robert Tjian

Keyword(s):

Dna Sequences ◽

Homeotic Genes ◽

Coding Region ◽

Protein Coding ◽

Human Dna

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

Genetics Research ◽

10.1017/s0016672300026409 ◽

1984 ◽

Vol 44 (2) ◽

pp. 219-224 ◽

Cited By ~ 10

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.

Molecular cloning and chromosomal localization of DNA sequences associated with a human DNA repair gene.

Molecular and Cellular Biology ◽

10.1128/mcb.5.2.398 ◽

1985 ◽

Vol 5 (2) ◽

pp. 398-405 ◽

Cited By ~ 28

Author(s):

J S Rubin ◽

V R Prideaux ◽

H F Willard ◽

A M Dulhanty ◽

G F Whitmore ◽

...

Keyword(s):

Dna Repair ◽

Dna Sequences ◽

Chromosomal Localization ◽

Excision Repair ◽

Repair Process ◽

Human Cells ◽

Gene Products ◽

Repair Gene ◽

Human Dna ◽

Dna Repair Gene

The genes and gene products involved in the mammalian DNA repair processes have yet to be identified. Toward this end we made use of a number of DNA repair-proficient transformants that were generated after transfection of DNA from repair-proficient human cells into a mutant hamster line that is defective in the initial incision step of the excision repair process. In this report, biochemical evidence is presented that demonstrates that these transformants are repair proficient. In addition, we describe the molecular identification and cloning of unique DNA sequences closely associated with the transfected human DNA repair gene and demonstrate the presence of homologous DNA sequences in human cells and in the repair-proficient DNA transformants. The chromosomal location of these sequences was determined by using a panel of rodent-human somatic cell hybrids. Both unique DNA sequences were found to be on human chromosome 19.

Molecular cloning and characterization of an activated human c-raf-1 gene

Molecular and Cellular Biology ◽

10.1128/mcb.7.5.1776-1781.1987 ◽

1987 ◽

Vol 7 (5) ◽

pp. 1776-1781

Author(s):

M Fukui ◽

T Yamamoto ◽

S Kawai ◽

F Mitsunobu ◽

K Toyoshima

Keyword(s):

Dna Sequences ◽

Promoter Sequence ◽

Small Population ◽

Dna Transfection ◽

Amino Terminal ◽

Human Dna ◽

Nih 3T3 ◽

Amino Terminal Sequence ◽

Tumor Dna

Results of previous studies have shown that a raf-related transforming DNA sequence is present in NIH 3T3 transformants that are derived from GL-5-JCK human glioblastoma DNA transfection. The transforming DNA was molecularly cloned by using cosmid vector pJB8 to determine its structure and origin. Analyses of selected clones revealed that the transforming DNA consisted of three portions of human DNA sequences, with the 3' half of the c-raf-1 gene as its middle portion. This raf region was about 20 kilobases long and contained exons 8 to 17 and the poly(A) addition site. RNA blot analysis showed that the raf-related transforming DNA was transcribed into 5.3-, 4.8-, and 2.5-kilobase mRNAs; the 2.5-kilobase transcript was thought to be the major transcript. Immunoprecipitation analyses revealed that a 44-kilodalton raf-related protein was specifically expressed in the NIH 3T3 transformants. The raf-related transforming DNA was considered to be activated when its amino-terminal sequence was truncated and the DNA was coupled with a foreign promoter sequence. On hybridization analysis of the original GL-5-JCK glioblastoma DNA, no rearrangement of c-raf-1 was detectable in the tumor DNA. The rearrangement of c-raf-1 may have occurred during transfection or may have been present in a small population of the original tumor cells as a result of tumor progression.

Karyotype Characterization of Nine Periwinkle Species (Gastropoda, Littorinidae)

Genes ◽

10.3390/genes9110517 ◽

2018 ◽

Vol 9 (11) ◽

pp. 517 ◽

Cited By ~ 3

Author(s):

Daniel García-Souto ◽

Sandra Alonso-Rubido ◽

Diana Costa ◽

José Eirín-López ◽

Emilio Rolán-Álvarez ◽

...

Keyword(s):

Dna Sequences ◽

Chromosome Numbers ◽

Gene Clusters ◽

Chromosomal Mapping ◽

Closely Related Species ◽

Submetacentric Chromosome ◽

The Family ◽

Littorina Arcana

Periwinkles of the family Littorinidae (Children, 1834) are common members of seashore littoral communities worldwide. Although the family is composed of more than 200 species belonging to 18 genera, chromosome numbers have been described in only eleven of them. A molecular cytogenetic analysis of nine periwinkle species, the rough periwinkles Littorina arcana, L. saxatilis, and L. compressa, the flat periwinkles L. obtusata and L. fabalis, the common periwinkle L. littorea, the mangrove periwinkle Littoraria angulifera, the beaded periwinkle Cenchritis muricatus, and the small periwinkle Melarhaphe neritoides was performed. All species showed diploid chromosome numbers of 2n = 34, and karyotypes were mostly composed of metacentric and submetacentric chromosome pairs. None of the periwinkle species showed chromosomal differences between male and female specimens. The chromosomal mapping of major and minor rDNA and H3 histone gene clusters by fluorescent in situ hybridization demonstrated that the patterns of distribution of these DNA sequences were conserved among closely related species and differed among less related ones. All signals occupied separated loci on different chromosome pairs without any evidence of co-localization in any of the species.