Journal of ISSN: 2581-7388 Biomedical Research and Reviews Volume 1: 2 J Biomed Res Rev 2018
A Genome Model to Explain Major Features of Neurodevelopmental Disorders
1 Bernard Friedenson* Department of Biochemistry and Molecular Genetics, University of Illinois Chicago, USA
Abstract Article Information
The purpose of this study was to understand the role of infection Article Type: Research in the origin of chromosomal anomalies linked to neurodevelopmental Article Number: JBRR115 disorders. In patients with neurodevelopmental disorders, DNA’s Received Date: 17 September, 2018 from viruses and bacteria including known teratogens were tested Accepted Date: 19 September, 2018 against chromosome anomalies known to cause the disorders. Results Published Date: 25 September, 2018 support a theory that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for *Corresponding author: Dr. Bernard Friedenson, De- neurons, lymphatic drainage, immunity, circulation, angiogenesis, partment of Biochemistry and Molecular Genetics, Col- barriers, structure, and chromatin activity were all found close together lege of Medicine, University of Illinois Chicago, 1853 West Polk Street, USA. Tel: +847-8271958, Email: in polyfunctional clusters that were deleted in neurodevelopmental molmeddoc(at)gmail.com disorders. These deletions account for immune, circulatory, and
Citation: Friedenson B (2018) A Genome Model to Explain rigorousstructural artifact deficits tests.that accompany In some patients, neurologic epigenetic deficits. In driver deleted mutations clusters, Major Features of Neurodevelopmental Disorders. J Biomed Res Rev Vol: 1, Issu: 2 (36-57). werespecific found and and repetitive may be functionally human DNA equivalent matched to infections deleting anda cluster passed or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences Copyright: © 2018 Friedenson B. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distri- database of genomic variants. These sequences were thousands of bp bution, and reproduction in any medium, provided the orig- andwere unequivocally associated with matched intellectual foreign deficits DNAs. and Analogous were not homologies included in were any inal author and source are credited. also found in chromosome anomalies of a recurrent neurodevelopmental human DNA segments are thus proposed to interfere with highly active breakdisorder. repair Viral during and bacterial meiosis, DNAsand sometimes that match delete repetitive polyfunctional or specific 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.
Keywords:Graphical representation Genome, Epigenetics,of the work isNeurodevelopmental shown in figure 1. disorders, Chromosome anomalies, Retrotransposon, Chromosome rearrangement, Neurologic disease, Birth defects, Development, Infection. Introduction An approach to preventing neurodevelopmental disorders is to gain better understanding of how neurodevelopment is coordinated and then to identify environmental and genomic factors that disrupt it. The development of the nervous system requires tight regulation and coordination of multiple functions essential to protect and nourish neurons. As the nervous system develops, the immune system, the circulatory system, cranial and skeletal systems must be synchronized and coordinated. Neurodevelopmental disorders follow the disruption of this coordination. www.innovationinfo.org
Figure 1: Graphical representation of the abstract.
causes chromosome anomalies. The generation of gametes resolution of balanced cytogenetic abnormalities greatly by meiosis is the most active period of recombination. Double improvesA significant the ability advance to document in genome changes sequence in regulation level strand breaks initiate meiotic recombination and hundreds and dosage for genes critical to the function of the neurologic system. Based on DNA sequence analyses, of recombination during meiosis differ markedly between malesof double and strand females. breaks Meiotic occur recombination [6]. The timing in and sperm duration cells as causing individual congenital disorders because they occurs continuously after puberty. Errors in spermatogenesis some chromosome rearrangements have been identified underlie a prevalent and recurrent gene rearrangement is poor understanding and no effective treatment for many that causes Emanuel syndrome. The phenotype of Emanuel ofdisrupt these genes overwhelming essential forabnormalities. normal development Signs and [1-3]. symptoms There syndrome includes intellectual disability, and dysmorphism include autism, microcephaly, macrocephaly, behavioral problems, intellectual disability, tantrums, seizures, respiratory problems, spasticity, heart problems, hearing [2]. In contrast, recombination in ova occurs in fetal life and thenThe meiosis exact is arrestedDNA sequences until puberty. of [7].known pathogenic rearrangements in unique, familial and recurrent congenital not correlate well with the outcome, genetic counseling is loss, and hallucinations [1]. Because the abnormalities do involving microbial DNA at homologous human sequences. disorders [1-3] makes it possible to test for a mechanism difficultSeveral and maternal uncertain factors [3]. are known to interfere with neurodevelopment including infection, and other lifestyle factors that subsequently alter the epigenome, but the chromatinFor retroviruses, interactions insertion that hotspots appear can to significantly be long range change in genetic events that lead to most neurodevelopmental the 3D structure of the genome and disrupt essential disorders can be screened for homology to infections in the disease, inheritance is usually autosomal dominant and contexttwo dimensions of altered [8]. chromatin Even rare structure and unique affecting developmental the immune thedisorders same arechromosomal not understood abnormalities [4]. In congenital occur in neurologicevery cell. system, the circulatory system, the formation of the brain- The present work explains how DNA from infections can circulation barriers and bone development. This screening cause chromosomal deletions, rearrangements, damaged may assist counseling, diagnosis, prevention, and early epigenetic controllers and abnormal chromatin topology. intervention. Some disorders may arise when infections replicate within The results showed that DNAs in some congenital neurodevelopmental disorders closely matches DNA in the CNS by taking advantage of immune deficiencies such multiple infections that extend over long linear stretches of human DNA and often involve repetitive human DNA activeas those DNA traced break backrepair toprocess deficient required microRNA during productionmeiosis, to sequences. Neurodevelopmental disorders are proposed to generate[5]. Disseminated gametes with infections mis-repaired may interfere DNA. In withthe zygote, the highly this
37 ISSN: 2581-7388 www.innovationinfo.org begin when parental infections cause insertions or interfere “Discontinuous Megablast” was used and the ten strongest with meiosis at both repetitive and unique human DNA homologies were measured in each run. Known teratogens sequences. The affected sequences are shown to exist as linear clusters of genes closely spaced in two dimensions. Interference from infection can delete or damage human occursincluded, when HIV-1, microbial N. and gonorrhoeae, human DNA and sequences N. meningitidis. have more gene clusters and epigenetic regulators that coordinate Significant homology (indicated by the homology score) neurodevelopment. This genomic interference accounts for minimize the chances for false positives, a cutoff for E values similarity than would be expected by chance (E values). To microorganisms was done by testing multiple variants of disordersimmune, circulatory, are thus viewedand structural as resulting deficits from that accompanyan assault complete
Figure 2: Close relationships between the nervous system and other essential functions developed during evolution. Genes for multiple interdependent systems appear in clusters on the same chromosomes. Nervous system genes are in close proximity to genes essential for the immune system, connections to lymphatic circulation, ability to form tight junctions, structural enclosures and chromatin control. Clusters of genes encoding these and other interdependent functions on chromosome segments are deleted in private neurodevelopmental disorders. These losses increase susceptibility to infections which are homologous to long stretches of human DNA. Genes are listed in the order they occur on the chromosome segment with the functions given to the right of the gene symbol. Blue genes are associated with the nervous system, pink with the immune system. Yellow genes have functions associated with angiogenesis, lymphangiogenesis, circulation or the development of barriers to the nervous system. Genes associated with the development of essential bone structure or connective tissues needed to protect and house the nervous system are light grey. Genes colored purple are associated with general functions required by all cells. The same gene may have several of these functions depending on its cellular location.
Many deleted gene clusters include long stretches and correlates with symptoms of the developmental disorder. of DNA strongly related to infections
To investigate the chromosomal segment deletions silencingFor example, provirus, deletion repressing of chromosome retrotransposons, 19q12-q13.11 responding occurs that cause neurodevelopmental disorders, homologies to toin patientviruses, DGAP125 specifying (Figure immune 2). The cell deletion lineages, causes and regulating deficits in deleted clusters. Strong homologies to infections were found interspersedinfection were throughout. tested in sequences To demonstrate within and theflanking extent these of apoptosis. The deleted 19q12-q13.11 band in DGAP125 had 76 matches to clostridium botulinum strain Mfbjuicb6. Many of these matches extended over 2800 bp at 72-73% these relationships, the deleted 4q34 chromosome segment homology with an E value of 0.0. The 5’ region included 43 of (Patient DGAP161 [1]) was tested for homology to the top ten stretches of homology to microorganisms are distributed matchesthe 76 matches to clostridium. to clostridium There coveringwere also about strong 2800 matches bp with to homologous microbes in 200 kb chunks. Figure 3 shows that Waddlia73% homology chondrophila (E=0.0). and The N.next gonorrhoeae. million bp had Other another shorter 33 tothroughout hundreds, giving chromosome a total of 4q34. many thousands Only 10 of homologous potentially microbes are shown for each 200 kb division, but there are up chromosomal anomalies are present in patient DGAP125. Stealth and HIV-1 teratogens and multiple other infections homologousA deeper analysismicroorganisms of the functions throughout of genes the 4q34within deletion. deleted chromosome segments predicts a predisposition to infection are homologous to these shorter anomalies (Figure 4). The large deletion in 19q12-q13.11 makes patient DGAP125 especially susceptible to infections and the results39 ISSN: 2581-7388 www.innovationinfo.org
Figure 3: Example of total homologies to microbial sequences dispersed throughout 4q34 deleted chromosome segment in patient DGAP161. The top 10 homologies were tested for each 200,000 bp segment, but there are many thousands more. These homologies are listed within each of these 57 segments in order of their maximum homology scores. The Y axis plots the total homology scores and the x axis lists the individual microorganism. The mean E value was 5.3e-90 (range 0.0 to 1e-87). F. tularensis had values of 33,368 and 79,059 which were truncated at 25000 to show more detail for the other microbial matches. are potentially devastating. The damage to defenses against EFTUD2 gene product associates with chromatin binding infection associates with coordinated genes for control of breathing, synapse organization and plasticity, neural crest formation, and transmission of nerve impulses. There are proteins as part of the spliceosome; SNRPN is required for epigenetic imprinting; TET1 is a methylation eraser. Short and production of connective tissue and bone. Other alsoDNA occurred sequences in (lessgenes than within 20,000 topology bp) deletedassociated from chromatin families simultaneous deficits in development of brain circulation [3] are also likely to damage epigenetic regulators. Mutations chromosome deletions with clustered genes have deficits in regionsFigure and 4 graphicallyin insulators relates (e.g. CTCF, DNA cohesinsequences complexes). in all viruses neuronalMicrobial accessory DNA functionshomologies like thosein areasin DGAP125. around a and bacteria in the NCBI database to DNA sequences around mutated epigenetic driver gene In most cases, there is robust evidence that the chromosomal In some patients with neurodevelopmental disorders, anomalybreakage atsites breakage based on sites the studycauses of the Redin neurodevelopmental and colleagues [1]. robust evidence exists that the disease is caused by a truncated disorder but there may also be cryptic rearrangements
total homology scores of microbes vs humans in individual weredriver tested gene [1].against The existinggene changes evidence identified of their as ability underlying to act elsewhere [2,3,12]. The figure shows wide differences in the asphenotypic epigenetic drivers regulators of congenitaland effectors neurologic of functions diseases like those [1] disorders. Patient DGAP154 has total homology scores of of the pathogenic driver genes are epigenetic regulators. For well over 50,000 while other patients (DGAP142, 172, and found in the chromosomal deletions. Table 1 shows that most 173)Within are well a few below hours 1000. of fertilization, global demethylation occurs and both maternal and paternal genomes reprogram example, gene products from FOXA1, PH21A, CHD7, and inactivatesTCF4 mediate a histone or regulate deacetylase, chromatin WAC remodeling; regulates ZBTB20histone and GATA3 help regulate chromatin architecture; CDKL5 expressionto highly open which chromatin induces [13]. an Removalinnate immuneof these epigeneticresponse. marks allows a sudden increase in L1 retrotransposon withubiquitination; histone hypermethylation SOX5 encodes a histone in schizophrenia; demethylase; KDM6AEHMT1 encodes a histone methyltransferase; MEF12C is associated controlledMany of the by chromosomeDNA methylation anomalies and studiedby piwi containinteracting L1- retrotransposon sequences. L1 transcriptional activity is encodes an epigenetic switch that specifies stem cell fate; 40 ISSN: 2581-7388 www.innovationinfo.org
Figure 4: Total scores for homologies among microorganisms and human chromosomal anomalies in 48 patients with neurodevelopmental disorders. The contributions from all homology scores for groupings or individual microorganisms that match the chromosomal anomaly in each patient are added together to form each bar in the graph. The microorganism homology scores are color-coded according to the type of individual microorganism. Of 1986 E values, the mean was 7.3e-13 [Range 8e-11 to 2E-168]. Some of the microorganisms found are not normally pathogenic but can become opportunistic pathogens if the immune system is impaired. Endogenous retroviral sequences may interfere with recombination or repair within a single cell. In a few cases homologies were so large that they would obscure all the other data so these were limited to a score of 12,000. This was done for DGAP154 (24,873 FOR HIV/HTLV) and is indicated on the graph.
RNA. Loss of epigenetic drivers can interfere with the In the 48 patients shown in Figure 4, multiple infections are candidates to cause the signs and symptoms in each Figure 5 summarizes this data and shows driver genes have epigeneticfunction of controlthese epigenetic functions control and most mechanisms of these (Tablefunctions 1). “short stature” which can be caused by exposure to many infectionsindividual in(Table the second 2). 8 orpatients third trimester. have growth The absence,retardation delay, or essential for neurodevelopment. impact chromatin 3D structure and multiple systems Multiple infections can cause these problems. For instance, Pathogenic driver gene mutations are roughly or impairment of speech were found in 20 of 48 patients [1]. equivalent to large chromosome deletions HIV-1 causes white matter lesions associated with language neurodevelopmental disorders are epigenetic regulators patients.impairments, and impaired fetal growth. There are nearly 50 Because most identified driver genes of matches to HIV-1 DNA in the chromosome anomalies of 35 or effectors, the functions they control were compared Stealth viruses are frequent matches to chromosome to those found in chromosomal deletions that cause neurodevelopmental disorders. Virtually all pathogenic viruses are mostly derivatives of herpes viruses such as driver genes or chromosomal deletions in congenital anomalies with about 35 matching sequences. Stealth neurologic disorders have strong relationships to effects patients or have other mechanisms to avoid recognition by on the immune system, angiogenesis, circulation and thecytomegalovirus immune response. (CMV) CMV that isemerge not a well-knownin immunosuppressed teratogen, craniofacial development. Deletions in affected members even though CMV is a major threat to infants. First trimester of families with neurodevelopmental disorders are also CMV infection can cause severe cerebral abnormalities
Multiple infections identified by homology match common cause of congenital deafness and can cause visual consistent with this conclusion (Table 1). followed by neurologic symptoms [14]. CMV is also a signs and symptoms of neurodevelopmental abnormalities. 27 of the 48 neurodevelopmental patients disorders had hearing loss or deafness. Stealth virus 1 refers to Simian cytomegalovirus (strain Colburn) African green monkey 41 ISSN: 2581-7388 www.innovationinfo.org
Figure 5: Driver genes truncated or deleted in congenital neurodevelopmental disorders are mainly epigenetic regulators or effectors. The pie chart shows the percentages of 46 driver genes that have the epigenetic functions indicated. Loss of these driver gene functions then impacts a group of functions that must be synchronized during the complex process of neurodevelopment. These are the same functions lost in deleted gene clusters.
It is likely that most or all of these infections can interfere sequence identity have been isolated from human patients. Herpescytomegalovirus, simplex virus but closely is another related stealth viruses virus with that up directlyto 95% endogenous retroviral sequences. Most of these endogenous infects the central nervous system. Herpes simplex can sequenceswith neurodevelopment represent crippled (Tables infections 1-2). Figurethat cannot 4 includes travel between cells because they lack env genes needed to exit infected cells. However, HERV sequences are numerous and cause seizures (reported for 9 patients). retrotransposons can still interfere with recombination and disease of the nervous system affecting the spinal cord and DNA repair within their home cell. peripheralHTLV-1 nerves.is a retrovirus Neural fetalthat causescells are an more immune susceptible mediated to Deleted segments in familial chromosome anomalies point toward a general mechanism HTLV-1 infection than mature neurons. for infection as a cause of neurodevelopmental meningitisPatient and DGAP159 is a known has the cause strongest of neurodevelopmental homology to N. disorders meningitidis (Figure 2). N. meningitidis causes bacterial Effects of balanced translocations segregate only consistent with residual effects of bacterial meningitis such somewhat with the presence of neurodevelopmental defects. Signs and symptoms in patient DGAP159 are as hearing loss, developmental delay, speech failure and disorders. These discrepancies emphasize the need to visual problems. DNA from microbes not classified as teratogens can may also be other more cryptic chromosome abnormalities also affect fetal development andconsider that thewhole genome genome in 3sequencing dimensions of [8]. the Moreover, family may there be Not only known teratogens, but almost all microbial chromosomal translocations but do not have signs and DNA found in abnormal human chromosomes in congenital symptomsnecessary [3].of neurodevelopmental Members of some disease. families In carry three balanced of four neurologic disorders can have profound effects on a fetus or families with familial balanced chromosomal translocations, or microbial foreign DNA may contribute to developmental the results did not overlap any database of human reference errors.neonate Multiple (Table matches2). Figure may 4 implies represent that homologies any source to ofhuman viral genomes.patient specific Unbalanced unbalanced deletions deletions were were subjected also found to analysis [3] but DNA among stretches of viral and bacterial DNA. Homologies for infection homology but inversions, inverted duplications, found appear independent of whether microbes can insert insertions and additional balanced translocations were also present. Unbalanced deletions in the three families were ralstonia solanacearum, s. aureus, and stealth viruses are strongly homologous to infections or other foreign DNAs into human DNA. HIV, HPV16, HTLV-1, k. pneumoniae, include sequences that match one or more viruses, and 44 matchall found bacterial in at leastsequences. 10 patients. In most 38 chromosomal of 48 rearrangements anomalies, interrupted(Figure 6). Inby these agreement short cryptic with results rearrangements. in Table 1, critical multiple infections match a given anomalous DNA sequence. genes linked to epigenetic modifications were among those
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Table 1: Relationships of nervous system genes to epigenetic functions and to genes in the immune system, the circulatory system and structure in neurodevelopmental disorders.
Proposed primary phenotypic drivers of anomaly /Other likely contributors d=deletion, Association of pathogenic Relationship to T=truncation [1] or gene Relationship to immunity, Relationship to circulation Patient neurologic mutation [24] with bone, structural disrupted by structural infection and blood brain barrier nervous system function requirements variant [3] Bold entries are related to epigenetic regulation or chromatin modificatiom Fox G1 deletion in chromosome 14q12. Fox G1 regulates thymic epithelial cells [26], 14q12-q21.1 (d), NFKBIA NFKB1A regulates immune FoxA1 regulates (d), NKX2-1 (d) BAZ1A (d) NOVA1 regulates Dcc alternative and inflammatory responses. bone formation splicing during neuronal migration Deregulated in inflammatory FoxA1 can direct lineage through bone FOXA1 (d), many other and axon guidance in the spinal and infectious diseases. specific differentiation into DGAP002 morphogenetic genes deleted cord [25]. AKAP6 associated NKX2 is needed for spleen blood cells, neurons, or protein, required with cognition. FoxA1 dopamine development. BAZ1A: recovery myocytes. for intervertebral FoxA1 mediates chromatin synthesis from DNA damage. FoxA1 is disks remodeling characteristic of a population of regulatory T-cells. Downregulated in parasite infections. Required for proinflammatory Skeletal and FGFR1 (T), FGF Helps protect and maintain cytokine expression [28] craniofacial regulates chromatin the blood brain barrier [29] DGAP011 Axon guidance [27] FGFR1 may contribute to development, organization during Associated with vascular interaction between NK and chondrogenesis development remodeling. T-cells. and osteogenesis Encodes BHC80, a component Histone deacetylase interacts of a BRAF35 histone deacetylase Promotes angiogenesis, with repressor element 1 PHF21A (T), chromatin complex. Represses neuronal- endothelial cell survival. that controls the transition of DGAP012 regulator disrupted at specific genes, of fundamental Histone deacetylase Not found neuronal cells to glial cells breakpoint importance in the development of protects against ischemia through nitric oxide free both neuronal and nonneuronal and reperfusion injury. radicals [31]. tissues [30]. CDKL5 Rett syndrome, a post-natal neurologic disorder, CDKL5 (T) disrupted at PI3K-Akt pathway appearing after a period of near breakpoint, phosphorylates enriched (may be involved normal development. Mediates Deregulated inflammatory DGAP093 HDAC4 histone in tight junction opening) Not found MECP2 phosphorylation Induced response in microglia [33]. deacetylase causing Affects red blood cell by methylation inhibitors. Seizures cytoplasmic retention [32]. shape. may reflect CDKL5 role in dendritic arborization. WAC (T), at breakpoint, Required for autophagy and Required for cognition, prevention disrupted by translocation required for autophagosome Required for normal DGAP096 of intellectual disability, behavior Not found regulates histone formation [34]. DNA damage hematologic function. disorders. ubiquitination checkpoint activation. ZBTB20 (T), binds Promotes generation of Plasma cell differentiation, to genes that control Brain corpus callosum astrocytes involved in Regulates impaired innate immunity DGAP099 chromatin architecture development. Binds to genes blood-brain barrier [36]. chondrocyte dependent on TLR2 and TLR4 including MEF2c and controlling neuronal subtypes Controls expression of differentiation, [35]. SAT2b VEGFA in some settings. Promotes KDM6A (T). Histone Maturation of functional synapses Demethylase KDM6a osteogenic Demethylase and in cerebellar cortex, regulation epigenetically promotes IL-6 Stem cell migration of DGAP100 differentiation Epigenetic switch to by BDNF. Epigenetic switch to and IFN-β production in blood cell precursors [38] specify stem cell fate [37] regulate stem cell lineage fate macrophages
12p12.1-p11.22 (d), SOX5: Th17 cell SOX5 interacts with tight SOX5 (d), KRAS (d); differentiation; Linked to junction proteins such MED21(d) SOX5 is a cytoplasmic engulfment protein as ZO-5, occluding and histone demethylase at ELMO1 [40] LRMP, lymphoid claudin [42]. May control SOX5 Marker breakpoint disrupted by SOX5: Specifies cell fate of dorsal DGAP112 restricted membrane protein differentiation of neural gene for cartilage rearrangement. MED21 interneurons. High levels found in germinal stem cells into astrocytes. formation at breakpoint may be B-cells; KRAS involved in an KRAS may orchestrate required to displace innate immune pathway for circulation and blood histones to enable heat- recognizing DNA damage [41] vessel formation. shock response [39].
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NRXN1 (T) Repressive Surface recognition molecule histone marker at C1qls belongs to the critical for organizing and forming breakpoint disrupted by inflammatory mediator TNF synapses; thousands of isoforms NRXN1 Regulates rearrangement, controls superfamily involved in innate DGAP124 due to alternative splicing. Some signaling for Not found choice of NRXN splicing immunity. Peptide derived from forms interact with C1qls in hematopoiesis [46]. isoform. Repressed by NRXN blocks formation of synaptic cleft suggesting relation histone methyl-transferase staphylococcal biofilms [45] to pruning connections [44]. [43] 19q12-q13.11 (d) DGAP125 See Fig 2 See Figure2 See Figure2 See Figure2 19:28,105,514-34,809,581 Markedly reduced PAK3 expression occurs in prion PAK3 (T), compensates diseases such as Creutzfeldt- Actin organization Dendritic cell growth. Synaptic DGAP127 for PAK1 which interacts Jacob disease in humans and and migration, spine Not found plasticity. with histone H3 scrapie in animals [47] MAPK morphogenesis signals, induced by activation of T-cells. P21 activated kinase. MYO6: endocytosis in Structural deficits in Col9A connective See Figure 2; SMAP1 defective macrophages. Inability to basement membrane as tissue, bone neurite outgrowth; FILIP1 DGAP133 6q13-q14.1 (d) process pathogens, defects part of blood-brain barrier, strength developmental signaling; LCA5 in autophagy; IRAK1BP1 deletion includes collagen blindness; SENP6 deregulated. Autophagy. genes 19A, 12A (Figure2) Contains genes essential for Intellectual disability associated LPAR6 cell-cell contact immunity: leukotriene receptor, with amyloid deposition due sites in endothelial TRIM13 deleted in lymphocytic to RB1, and ITM2B losses. cells. Proper vasculature DLeu2: Bone DGAP139 13q14.2 (d) See Figure 2. leukemia; RB1 potential PHF11 DNA double strand formation. DLEU2 control mineral density guardian of immune system; break resection, homologous of vascular endothelial NUDT15, removal of oxidative recombination [48]. cells. damage; Associated with Angelman syndrome and 2q21.3 MBD5 (T) Epigenetic microdeletion. Contributes to a regulator at breakpoint spectrum of neurodevelopmental Severe infections in the first Iron metabolism Control DGAP142 Histone acetylation Not found disorders, including autism and year of life [49]. of ferritin levels disrupted by schizophrenia, Insufficiency rearrangement. causes behavioral problems, cognition and motor delay. EFTUD2 (T)
[RNA splicing regulator In model system, mutation bone development, in spliceosome] at Pulmonary venous increases apoptosis and mitosis of mutation DGAP145 breakpoint disrupted by Innate immunity regulator drainage, normal heart neural progenitors [51] Essential associated with rearrangement Connects function for splicing, microcephaly methylated histone to regulated RNA splicing [50] Highly adaptable orphan pore ion channel required for NALCN (T) Disrupted at Leak conductance in neurons respiration, osmoregulation, DGAP147 Not found Not found breakpoint essential for function. scaffold for Src kinases. Src kinases are required to defend against infection XIAP: synaptic depression and XIAP: x-linked inhibitor of SMAD5: Gap junction and axon regeneration, long term apoptosis; Overexpression of tight junction formation; learning. THOC2 increases neurite SMAD5: Bone DGAP154 Xq25 (Duplication) XIAP suppresses apoptosis, vascular properties; extension. osteogenesis inhibits caspases and favors hematopoietic stem cell virus infection [52] development
EHMT1 Impairs expression of Establish expression potential protocadherins, regulators of for IFN genes. Required for EHMT1 (T)/GLP: neuronal diversity, growth and optimal cytokine response to Protects against cardiac Encodes a histone development [53]. Deficiency DGAP155 infection [55] Requirement hypertrophy [56], Osteogenesis methyltransferase, an causes increased hippocampal cell for memory formation and congenital heart disease epigenetic regulator. proliferation [54]. Required for dysregulated cytokine response memory, learning. and to repress predicts learning disability. non-neuronal genes in the brain FOXP1 (T)”PRMT5 recruitment to the FOXP1 T-cell regulation, cooperates promoter facilitates Controls gene expression required with NFKB for survival of Essential for H3R2me2s, SET1 Induces collagen synthesis DGAP157 for spatial learning and synaptic B-cells craniofacial recruitment, H3K4me3, [59] plasticity [58] development [60] and gene expression” [57] Disrupted by rearrangement. 44 ISSN: 2581-7388 www.innovationinfo.org
10p15.3-p14 (d) GATA3 (d) See Figure 2. GATA3 GATA3 is an immune Embryonic controls enhancer GATA3 development of neurons Cell adhesion and cell DGAP159 regulator. Loss increases, articular cartilage accessibility, recruits that contact cerebrospinal fluid junctions. Susceptibility to infection differentiation. chromatin remodeler to reprogram cells. HMGB2 encodes an RNA/ DNA sensor in innate immune response to nucleic acids Craniofacial AGA deletion causes lysosomal HPGD a proinflammatory Red blood cell skeleton, bone storage disease with brain gene; VEGFc lymphatic differentiation, circulation, structure, bone DGAP161 4q34 (d) (See Figure 2) damage. SPCS3 Pituitary hormone development and trafficking; cell adhesion, vascular differentiation, production. TENM nervous artery development and remodeling osteoblast system development vascular remodeling. ADAM29 differentiation cell adhesion and membrane structure. NODAL (T) targets kdm6b (an epigenetic regulator Nodal=”activin a” which of neuronal plasticity) NODAL Controls neuron survival encodes a mediator for NK osteoclast signaling in mouse by inducing neuroprotective Angiogenesis, red blood DGAP164 dendritic cell functions. Spleen, formation, brain. Rearrangement activity. Regulates early cell formation a part of the immune system, chondrogenesis also disrupts TET1 embryonic development. may not develop correctly, (a methylation eraser (demethylase) Brain morphology, memory Mutation may predispose to [61] Sodium ion permeability of DGAP166 SCN1A (T) viral infections that cause acute Not found Not found excitable membranes. Sensory encephalopathy. perception of pain. NR2F1 (T) Disrupted Controls identity of cortical by rearrangement, Angiogenesis, Patterning of the DGAP169 neuron progenitors. Induction of Not found Induces global chromatin lymphomagenesis [62] upper jaw [63] GABA positive neurons, repression ANO3: cervical dystonia; BBOX1 Mucin15, is essential for mucin DGAP173 11p14.2 (d) Not found Not found schizophrenia barriers to infection, NR5A1 (T) disrupted by Affects hypothalamus circuit. Sex Downregulated by influenza Regulator of angiogenesis DGAP186 rearrangement, participate development and formation of infection, activated by T-cell Not found [64] in resetting pluripotency steroidogenic tissues. stimulation Autoimmunity Sox5 interacts with tight junction proteins Marker gene for such as ZO-5, occluding SOX5 is a histone Specifies cell fate of dorsal cartilage formation, DGAP189 T-cell differentiation and claudin [42]. May demethylase interneurons. chondrocyte control neural stem differentiation cell differentiation into astrocytes. Spermine synthetase gene. Spermine synthesis impairs Polyamines such as spermine SMS (T) Drives biofilm formation by n. Regulates openings of Osteoblasto- are essential for growth and DGAP190 interactions among gonorrhoeae. Spermine may be lymph pores and regulates genesis, bone differentiation. Spermine controls nucleosomes. used as a nitric oxide releasing absorption [66] phenotype ion channel activity and has a role carrier in cognitive function [65]. Mutation causes hereditary spastic paraplegia. Critical for complex microtubule arrays in Regional blood flow to Oxidative stress associated Inhibits bone axons, spindles and cilia. Gene cerebrum DGAP193 SPAST (T) with inflammation [in prostate morphogenic controls endosome tubule fission, cancer] protein signaling mannose-phosphate endosome- Golgi trafficking and lysosome structure Intestinal immunity in dendritic NOTCH2 (T) disrupted Pathway is essential for Arterial differentiation and Osteoblast function cells, mucosal immunity, IFN DGAP199 at breakpoint by differentiation and survival of function, uterine blood to regulate bone secretion by T-cells, promotes rearrangement. neurons, axon development vessel remodeling formation T-cell cytotoxicity A component of the polycomb complex guides T-cell differentiation, maintains genes Associates with brain development AUTS2 (T) Disrupted targeted by EBV. Regulates [67], controls polycomb repressive at breakpoint by developmental gene MSX1 in DGAP201 complex1 Regulates actin Not found Not found rearrangement. Associated NK T-cells and in lymphoid cytoskeleton to control migration with chromatin structure progenitors [69]. Regulates and projections from neurons [68]. Rho GTPases [70], essential to protect from enteropathogenic bacteria [71]
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Promotes KDM6A (T) Histone Maturation of functional synapses KDM6a epigenetically osteogenic di/tri demethylase Stem cell migration of DGAP202 in cerebellar cortex, regulation by promotes IL-6 and IFN-β differentiation disrupted at breakpoint by blood cell precursors [38] BDNF production in macrophages rearrangement.
Modulates neuron excitability. SATB2(T) Disrupted Helps specify neuron subtype. Autophagy, senescence, Up regulated at breakpoint by Characteristic of migrating glia- Cytoskeletal organization. during guided bone DGAP211 rearrangement. Epigenetic Not found like cells that differentiate into Enhances gene expression in regeneration of the functions, interacts with integrated neurons in neonatal pre-B cells craniofacial region. chromatin remodelers. cortex [72] CUL3 (T) Ubiquitin Component in Ubiquitin ligase Determine surface level ligase recruited to complex collaborates with other of integrins in endothelial Integrates collage regulate chromatin complexes. Regulation of this Regulates levels of reactive cells, angiogenesis. secretion into DGAP219 pattern of lymphoid pathway controls brain size and oxygen species, ion handling Mediates VEGFR craniofacial bone effector programs. connectivity. Pathway affected in brain signaling. Epigenetic formation [73] Disrupted at breakpoint of may be involved in autism and regulator rearrangement. schizophrenia. EBV/HHV-4 infection has Promotes potential to induce anti-Sm SNRPN-SNURF (T)/ osteogenic antibodies [75]. HIV-1 Tat SMN; PWCR; SM-D; differentiation Ability of neurons to regenerate associates with snRNP [76]. DGAP232 sm-N; RT-LI; HCERN3; Not found of bone marrow axons [74] CMV may have a role in SNRNP-N; Required for embryonic regulation of autoantibodies epigenetic imprinting. connective tissue to snRNPs SNRPN imprinting stem cells. center Associated with Angelman syndrome and 2q21.3 MBD5 (T) Epigenetic microdeletion. Contributes to a regulator histone spectrum of neurodevelopmental Severe infections in the first Iron metabolism Control DGAP235 acetylation disrupted Not found disorders, including autism and year of life [49]. of ferritin levels at breakpoint of schizophrenia, Insufficiency rearrangement. causes behavioral problems, cognition and motor delay. Regulates adult neurogenesis Needed for CHD7 (T) Chromatin Mutation associated with severe DGAP239 [77], promotes neural stem cell Not found craniofacial remodeler. combined immunodeficiency proliferation development Significantly enriched in brain Promotes neuronal differentiation inflammation in malaria. [78] Cerebellar development, DGAP244 CTNND2 (T) Induces NFKB inflammatory Not found Spine architecture myoclonic tremor and epilepsy, response related to infection. anxiety, cognition. [79] EBV/HHV-4 infection has Promotes potential to induce anti-Sm SNRPN-SNURF (T)/ osteogenic antibodies [75]. HIV-1 Tat SMN; PWCR; SM-D; differentiation Ability of neurons to regenerate associates with snRNP [76]. DGAP278 sm-N; RT-LI; HCERN3; Not found of bone marrow axons [74] CMV may have a role in SNRNP-N; Required for embryonic regulation of autoantibodies epigenetic imprinting connective tissue to snRNPs SNRPN imprinting stem cells. center T. spiralis infection; skeletal Controls proliferation pain in acute infectious Required to initiate and migration of mononucleosis [82]; chondrocyte MEF2C (T), Associated vascular smooth increased expression of hypertrophy. with disease histone muscle cells. Targets Regulates cortical synapses and inflammatory cytokine IL-33 Antisense DGAP301 hypermethylation aquaporin channels to behaviors [81] in HIV infection. Activated transcript [80].. Disrupted by regulate angiogenesis by inflammation. Inhibits associated with rearrangement and vasculogenesis of granulocytes in favor of bone mineral endothelial cells [84]. monocytes, T-cell receptor density Responds to VEGFA. apoptosis [83] 18p11.32-p11.22 deletion: This histone deacetylase interacts PHF21A (T) PHF21A TGIF1 immune homeostasis, Not found for with repressor element 1 that Encodes BHC80, a regulation of CD4+ T-cells; Not found for PHF21a, but PHF21a but DGAP316 controls the transition of neuronal component of a BRAF35 NDUF2: control of stress contained in deletion contained in cells to glial cells through nitric histone deacetylase responses deletion oxide free radicals; complex.
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IRAK1BP1 encodes an interleukin 1 receptor associated kinase 1 binding protein IL-1 receptor associated kinases See Figure2 contains LCA5, are critical regulators of 6q14.1 (d) TBX18 (d): ELOV4 genes for vision, HTR1B innate immunity. TBX18 is DGAP317 Heart muscle function Not found IRAK1BP1; IBTK gene for neurotransmission. overexpressed in areas of DOPEY nerve myelin formation inflammation and interstitial fibrosis; IBTK Regulates inflammation induced by NFKB pathway in macrophages and neutrophils See Figure 2. Neuronal migration and axon Associated with maternal GRIN2B (T) Reflects projections in developing herpes simplex virus 2 MGH7 changes in methylation brain. Long term depression of infection. In some rat strains Not found Not found levels in epilepsy [85] hippocampus membrane currents, may respond to prenatal stress synaptic plasticity [86] CHD8 (T) As a chromatin insulator it blocks effects of nearby enhancers. Strongly upregulated by CHD8 interacts with the Enhanced expression in inhibitory maternal immune activation MGH8 insulator binding protein neurons causes excess of excitable in response to infection during Not found Not found CTCF. CTCF-CHD8 neurons [87]. Brain development pregnancy. ATP dependent complex insulates and chromatin remodeler [88]. epigenetic regulates at active insulator sites. TCF4 (T)Regulated by Regulates susceptibility to HIV- Regulates synaptic plasticity and histone deacetylases. 1 in macrophages and resistance Osteogenesis, memory. Recruits histone acetyl MGH9 Binding sites overlap of monocytes; down regulated Angiogenesis Chondrogenic transferases to affect chromatin histone acetylation of by viral infection; represses differentiation remodeling [90] enhancers [89] inflammation PHIP (pleckstrin homology PHIP (T), linked to domain interacting protein): PHIP [Pleckstrin homology histone methylation [91] Pleckstrin homology domains domain only] NMDA receptor Disrupted at breakpoint by regulate macrophage migration Potential role in NIJ2 trafficking and synaptic plasticity. Bone metabolism rearrangement. into inflammatory sites and angiogenesis [92] MYO6 neurotransmission, differentiation; MYO6: receptor endocytosis MYO6 (T) endocytosis in macrophages. autophagy. Upregulation increases innate NIJ5 IL1RAPL1 (T) Synapse formation, cognition and adaptive immune responses. Not found Skeletal growth Apoptosis Controls lineage differentiation KAT6B (T)/ MORF/ in development of immune Skeletal formation, NIJ6 MYST4 Lysine acetyl Corpus callosum formation, system. Involved in Hematopoiesis premature skull transferase. pathogenesis of hematologic suture fusion malignancies [93] In pathway that regulates Brain formation, corpus callosum Balance between Embryonic NFIA (T) regulated by inflammation, controls myeloid NIJ14 development, spinal cord and oligodendrocytes and articular cartilage chromatin structure [94] cell differentiation and neocortical development astrocytes. differentiation maturation in septic mice. One of the transcription factors On infection induced acute drop NIJ15, NIJ6 MYT1L (T) Not found Not found needed to convert cells to neurons in oxygen tension [95] Controls NFAT signaling. Controls calcium signals Long term memory formation, Integrates stress responses Bone ROC4 CAMTA1 (T) that activate a cardiac gene ALS survival, behavior, ataxia Associated with shifts in differentiation program microbiome [96] A component of the polycomb complex, guides T-cell differentiation, maintains genes Regulates actin cytoskeleton to targeted by EBV. Regulates AUTS2 (T Associated with control migration and projections developmental gene MSX1 in ROC17 H3K4me3 and epigenetic from neurons [68]. Replication Not found Not found NK T-cells and in lymphoid control hotspot where copy number progenitors [69]. Regulates Rho variation occurs. GTPases [70] which protect from entero-pathogenic bacteria [71] Required for T-cell Osteogenic cell Learning and memory, early development in combination Controls cadherin at cell- differentiation, ROC23 TCF12 (T) neuron proliferation during brain with E2A [98] Critical regulator cell junctions fusion of fibrous development [97] of mesoderm and hematopoietic skull sutures specification [99]
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Sox5 interacts with tight junction proteins such SOX5 is a histone Specifies cell fate of dorsal as ZO-5, occluding and Marker gene for ROC43 T-cell differentiation demethylase interneurons. claudin [42]. May control cartilage formation differentiation of neural stem cells into astrocytes. EBV/HHV-4 infection has Promotes potential to induce anti-Sm osteogenic antibodies [75]. HIV-1 Tat SNRPN-SNURF (T) differentiation Ability of neurons to regenerate associates with snRNP [76]. ROC62 Required for epigenetic Not found of bone marrow axons [74] CMV may have a role in imprinting embryonic regulation of autoantibodies connective tissue to snRNPs SNRPN imprinting stem cells. center Critical control of early NFIX (T) controlled by Differentiation of stem cells in Survival of immature Bone development, UTR7 B-cell lymphopoiesis and methylation hippocampus hematopoietic cells density myelopoiesis. Bone homeostasis, DYRK1A Regulates T DYRK1A (T), histone Dopaminergic cell survival, brain Angiogenesis in chondrocyte UTR12 cells [100], controls bone phosphorylation growth endothelium development, homeostasis skeletal formation Associated with Angelman syndrome and 2q21.3 MBD5 (T) Epigenetic microdeletion. Contributes to a Severe infections in the first regulator disrupted in spectrum of neurodevelopmental Iron metabolism Control UTR13 year of life [49]. Epigenetic Not found topology associated disorders, including autism and of ferritin levels regulator. domain schizophrenia, Insufficiency causes behavioral problems, cognition and motor delay. ZBTB20 (T), binds Lymphoid development and Terminal to genes that control function, Development and Astrocyte response to differentiation UTR17 chromatin architecture Regulation of neurogenesis function of B-cells, Plasma cell injury, gliogenesis of hypertrophic including MEF2c and differentiation, [35] chondrocytes SAT2b) Levels altered in response to maternal infection with Coordinates bone Increases neuronal differentiation, Influenza virus in mice. Robust Controls cadherin formation and regulates development of neural UTR20 FOXP2 (T) evidence links maternal expression in development progenitors in mammalian cortex infections to schizophrenia neuroepithelium [103] [101] [102]. Regulatory T-cell function. Cerebellar hypoplasia. NSD1 (T) lysine Cytoskeletal regulation in neurons, Caspase activation in UTR21 Lymph circulation. Bone development methylation directional cortical neuron macrophages. migration Several sodium channel genes required to control neuronal NOSTRIN controls nitric oxide FIGN affects astrocyte TTC21B UTR22 2q24.3 (d) SCN9A (d) excitability deleted. TTC21B gene production, CERS6 related to migration, XIRP2, CERS6 craniofacial for organizing brain development; T-cell activity and apoptosis. cardiac health development STK39 regulates brain volume. NCALD1 exists as myristoylated and non Affected myristoylated forms. member of Calcium sensor in neurons Endocytosis Calcium signaling Histone deacetylase 11 family 1 is a myristoyl hydrolase [104]. NPL - N-acetylneuraminate lyases regulate cellular May lead to altered sialic acid Enzyme with markedly Affected concentrations of sialic metabolism required for brain increased expression in Strongrelationships Enzyme activity member of acid by mediating the development; e.g neuronal cell neutrophils and monocytes between sialic acid demonstrated in blood family 1 reversible conversion adhesion and myelin associated during inflammatory response and bone formation of sialic acid into glycoproteins [105] after stroke [106]. N-acetylmannosamine and pyruvate BCAR3. A candidate epigenetic mediator for Affected Endothelin-1 signaling. Arrests cell cycle increased adult body member of Edothelin 1 is a potent in response to mass index in socially family 1 vasoconstrictor tensile stress [108] disadvantaged females [107]
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ZNF423 - zinc finger protein 423 epigenetic Osteoblast Affected modifications associated Cell division and repair of Development of B-lymphoid vis adipocyte member of with obesity [109], Purkinje neuron progenitors cell lineage lineage [110], family 2 methylation marker for osteoarthritis age prediction. RAP1GDS1 - RAP1 Affected GTP-GDP dissociation Orients migration of multipolar T-cell homeostasis, limits TLR Vascular endothelial member of stimulator 1[111]. neurons during development Bone growth inflammatory response junction stability family 3 Antagonizes some [112], histones.
Table 2: Recurrent infections found to have homology to chromosomal abnormalities in neurologic birth defects can cause developmental defects.
Numbers of Patients with chromosomal Recurrent Infections matching DNA CNS, physiologic and or teratogenic effects if known. abnormalities with significant homologies to rearrangements in congenital neurologic this infection disorders
Impaired fetal growth, premature delivery, chorioamnionitis, deciduitis, immunodeficiency. HIV-1 causes white matter lesions HIV-1, HIV-2 600 matches in 36 patients associated with language impairments. HIV-1 infects CNS by targeting microglial cells.
Part of a group of infections that coexist with other viral HPV16 infections, bacterial infections, and chemicals in autism syndrome 35 patients disorders [113].
Staphylococcal infection, (s. aureus, s. May infect brain and interfere with normal nerve transmission. 206 matches in 40 patients capitis, s. epidermidis) Causes meningitis, Brain abscess. Major hospital pathogens
Stealth viruses are mainly herpes viruses such as CMV that can Stealth viruses, CMV, HHV-4/EBV, herpes avoid recognition by the human immune response. Associated 425 matches in 39 patients simplex, SV40 with neurologic impairments, hearing loss, ophthalmic problems.
Opportunistic bacterial pathogen, associated with pneumonia and neonatal sepsis, especially in patients with compromised Ralstonia solanacearum immunity on ventilator. Has some resemblance to other human 158 matches in 44 patients pathogens including Borrelia, Bordetella, Burkholderia, and a “blood disease pathogen.”
Associated with neuropathy. Immune mediated disease of the HTLV-1 nervous system affects spinal cord and peripheral nerves. Fetal 24 patients neural cells are highly susceptible to infection
BeAn 58058 is almost identical (97%) to cotia virus which BeAn 58058 virus, Bandra megavirus can infect human cells [114]. Represents a distinct branch of 50 matches in 36 patients poxviruses [115]
Klebsiella pneumoniae, e coli Neonatal pneumonia and sepsis. 35 patients
7 patients: DGAP099, DGAP127, DGAP137, Human respiratory syncytial virus Kilifi Neonatal pneumonia, trouble breathing DGHAP159, DGAP167, DGAP172, DGAP225
Recently discovered. Causes preterm birth, miscarriage, Waddlia Chondrophila spontaneous abortion. Chlamydia like micro-organism. Survives 26 different patients in macrophages, multiplies in endometrial cells
Bacteria that can cause damage to human DNA. Premature birth, Patient DGAP159 shows 25 different homologies miscarriage, severe eye infection in infant. Antibodies to N. Neisseria meningitidis, N. gonorrhoeae to N. meningitidis. DGAP017 and in DGAP101 gonorrhoeae impair out-growth of neurites, and cross react with have homology to N. gonorrhoeae. specific brain proteins.
13 patients: DGAP012, DGAP93, DGAP100, Gram-negative bacterium found in cases of acute bacterial DGAP125, DGAP133, DGAP134, DGAP154, Pseudomonas putida meningitis [116]. Reported in contaminated water and DGAP159, DGAP167, DGAP169, DGAP170, heparinized flush solutions [117] DGAP220, ROC17
High catalase activity may disable immune defenses depending on Exiguobacterium oxidotolerans DGAP127, DGAP225 peroxide.
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Table 3. Independent evidence that microbial genomes have regions of homology to human DNA as predicted by results. Length of homology Microbe Human chromosome homologies %homology, E value (bp) N. gonorrhoeae strain 1090 NotI sites 233-345 100%, 5e-89 N. gonorrhoeae WHO-L genome (GenBank: 700 bp on Chr 3, 15, X and 3 700 99-100% LT591901.1) N. gonorrhoeae strain 1090 Clone image 519 79% S aureus Cu transport ATPase 1198 98%, E=0.0 NC_007795.1 Staphylococcus aureus subsp. P143 mRNA 642 70%, E=9e-58 aureus S capitis ABC8 218 71%, 5e-15 MRSA Succinate CoA ligase, Chr13 769 67% s-adenosyl-homocysteine hydrolase >NM_001242673.1 Homo sapiens adenosylhomocysteinase like 1 (AHCYL1), Ralstonia solanacearum transcript variant 2, mRNA (Transcript variant 2 easily 791 69%. 2e-73 produced >100 significant matches to other microbial sequences) Pseudomonas putida strain IEC33019 chromosome, complete genome Many hundreds of homologies e.g. homo sapiens sequence 674 bp 92%, E=0.0 NCBI Reference Sequence: NZ_ around Not1 site clone HSJ-DM24RS CP016634.1 vs strain T1E (CP003734.1) C botulinum HSP70 member 9 1066 65% E=5e-54 C botulinum BrDura Human cDNA 692 83%, E=0.0 Phosphoglycerate dehydrogenase, 734 66% E=9e-71 fumarate hydratase 1034 67% E=3e-63 Waddlia chondrophila (CP001928.1) whole elongation factor alpha 992 71%E=1e-112 genome 2.1 million bp hsp70 family member 9 1548 65% E=1e-68 aldehyde dehydrogenase 1168 64% E=1e-30 67% BeAn 58058 virus NM_001165931.1 9 Closely cotia virus and other pox viruses) Ribonucleotide regulatory subunit (Homo sapiens ribonucleotide reductase > 100 significant ribonucleotide reductase regulatory subunit M2 (RRM2), 870 68%, 8e-69 matches to cotia virus (90% homology), transcript variant 1, mRNA) Volepox, monkeypox, cowpox, and vaccinia virus e.g. 675/939 bp(72%) E=4e-136 Cowpox, KY369926.1 Description Cowpox virus strain Kostroma_2015, At least 100 homologies. Homologies to ribonucleotide 2279 bp at 69% homology complete genome reductase, z-protein mRNA, transmembrane BAX inhibitor 68-78% homology (E=0.0) Molecule type motif, EF hand domain containing EFHC2 nucleic acid Query Length 223595 Up to 98% identity for all 28 HIV-1 28 different isolates Alu homology bp7300 to 8000 sequences HTLV1 J02029 vs HTLV1/HAM Long Homologous to hydroxysteroid dehydrogenase like 1 2162 bp at 97% homology 97% homology terminal repeat variant, mRNA for hGLI2 (E=0.0)
Microbial homologies in a recurrent translocation of a chromosome segment with homologies to infection have been deleted in affected family members. detected during spermatogenesis and not during other A model for infection interference in processes.De novo These translocations translocations t(11;22) have have been so farattributed only been to neurodevelopment
To determine whether these structure might arise because Infection DNA occurs in neurodevelopmental disorders microbialpalindromic infection structures interferes that induce with genomic normal instability chromatin [2]. that undergo autosomal dominant inheritance so microbial structures, homology testing of sequences in the recurrent DNA must be present in gametes from one parent. The mechanism proposed in Figure 8 is based on data showing 7 shows strong homology to bacterial and viral sequences inbreakpoint the breakpoint t(8;22)(q24.13;q11.21) region. Sequences [2] was from conducted. an unaffected Figure human chromosomes. Large amounts of foreign, infection DNAsignificant present homologies during human with microbial meiosis withinfections its many on multiple double with homologies to more diverse microbes than are present strand breaks and the most active period of recombination mother carry a balanced translocation rearrangement [2] produce defective gametes. in affected cases (Figure 7). This supports the idea that parts 50 ISSN: 2581-7388 www.innovationinfo.org
The resemblance of foreign microbial DNA to the host idea that homologies among repetitive human sequences background DNA may be a major factor in selection of infection and in human ability to clear the infection. Only one rare defective gamete is shown in Figure 8 but the male and microbes are real. In contrast, LINE-1 elements generates four gametes during meiosis beginning at puberty. (NM_001330612, NM_001353293.1, NM_001353279.1) had Only one gamete survives in the female because three no significant homology to bacteria and viruses. breakpoints involved in neurodevelopmental disorders were polar bodies are generated. Both balanced and unbalanced The 1986 microbial homologues to human DNA near translocations can give rise to chromosome anomalies such as deletions and insertions because infection DNA can composed of 126 different viral or bacterial sequences. 24 different strains of Neisseria meningitidis in patient DGAP159 interfere with break repairs during meiosis. The presence had 100% identity to human genomic rearrangements with ofinsert a preexisting itself (e.g. exogenous balanced orchromosomal endogenous translocationretroviruses) orin matchestotal scores included of 385 several to 637 5’UTR and like expected sequences, values elongation of 8e-13. the family disrupts normal chromatin structure, producing factorThe 25th alpha, N. meningitidis isopentenyl strain pyrophosphate was 98% identical. transferase-like Human translocation increases the chances of generating a defective gameteboth affected during meiosis. and unaffected members [3]. The familial mitochondrialprotein, NADH G dehydrogenases.elongation factor, Clostridiumand heat shock specifically protein Tests for artifacts in matches to human-microbial matched sections of human ATPases, and ATP synthases, DNA hsp70 (mRNA). A 1004 bp fragment of waddlia chondrophila occurred 32 times near neurodevelopmental breakpoints strongand had matches full-length to human 89% homologycaspase recruitment to human calcyclindomain Genome rearrangements for patient data in Figure 4 [1] binding protein (E=0.0). Waddlia chondrophila also had produced 1986 matches with E AluJ, AluS and AluY sequences were tested for homology to homologousenvironment to or microbes maternal factorsand present [16]. Bothnear non-Alubreakpoints and DNA sequences by human Alu elements [15], about 450 involvedAlu regions in humanaccount neurodevelopmental for 90% (113 of 126) disorders. of the sequences viruses and bacteria. About 190 Alu sequences resembled a microbial sequence with an E value <1e-10, supporting the Figure 6: Unbalanced deletions present in an affected family are homologous to microorganisms. Family members affected by intellectual disability in families with apparently balanced translocations have other chromosome abnormalities including unbalanced deletions, insertions, etc [3]. Deletions are shown as homologous to bacterial and viral DNA, but insertions were also found to have similar homologies. Total homology scores for bacterial and viral homologies in each of the three affected patients are plotted. 51 ISSN: 2581-7388 www.innovationinfo.org 1800 4000 1600 3500 1400 3000 1200 2500 1000 2000 800 1500 Total Homology Score Total 600 1000 500 400 0 200 Cotesia congregata Cotesia Orpheovirus IHUMI-LCC2 Orpheovirus Orpheovirus IHUMI-LCC2 Orpheovirus Candidatus Sulcia muelleri Candidatus Candidatus Suclia muelleri Candidatus Sulcia muelleri Candidatus Buchnera aphidicola str. 5A str. aphidicola Buchnera Candidatus Sulcia muelleri Candidatus Buchnera aphidicola str. JF98 str. aphidicola Buchnera Buchnera aphidicola str. LL01 str. aphidicola Buchnera Serratia symbiotica Strain STs Strain symbiotica Serratia Serratia symbiotica str. ‘Cinara cedri’ ‘Cinara str. symbiotica Serratia cedri’ ‘Cinara str. symbiotica Serratia cedri’ ‘Cinara str. symbiotica Serratia Corynebacterium phage P1201 phage Corynebacterium Endosymbiont of Sipallinus gigas Endosymbiont Orpheovirus IHUMI-LCC2 genome assy genome IHUMI-LCC2 Orpheovirus Serratia symbiotica str, ‘Cinara cedri’ ‘Cinara str, symbiotica Serratia Candidatus Sulcia muelleri strain BGSS Sulcia muelleri strain Candidatus Candidatus Sulcia muelleri isolate SMTERVAC isolate Sulcia muelleri Candidatus SMTERVAC isolate Sulcia muelleri Candidatus Candidatus Sulcia muelleri isolate SMTERVAC isolate Sulcia muelleri Candidatus Candidatus Suclia muelleri isolate SMAURBIH isolate Suclia muelleri Candidatus Candidatus Gracilibacteria bacterium HOT-871 bacterium Gracilibacteria Candidatus Candidatus Sulcia muelleri isolate SMAURJAP Sulcia muelleri isolate Candidatus Candidatus Sulcia muelleri isolate SMAURBIH Sulcia muelleri isolate Candidatus Candidatus Gracilibacteria bacterium HOT-871 bacterium Gracilibacteria Candidatus Buchnera aphlidicola (Schlechtendalia chinensis) (Schlechtendalia aphlidicola Buchnera Buchnera aphidicola str. JF99 (Acyrthosiphon pisum) str. aphidicola Buchnera Buchnera aphidicola (Schlechtendalia chinensis) strain SC chinensis) strain (Schlechtendalia aphidicola Buchnera Buchnera aphidicola str. Tuc& ( Acyrthosiphon pisum) Tuc& str. aphidicola Buchnera Figure 7: Microbial homologies in cases from a maternal recurrent translocation. Parental translocation t (8;22) in Family FHU13-027 from Mishra and colleagues [2] is homologous to microorganisms as shown for der (8) and for der (22) separated by space in the figure. The sequence is from a normal healthy mother who inherited from a female proband the balanced translocation t (8;22). More limited sets of micro-organisms are present in affected case 12 and case 13 (green bars) implying that DNA homologous to the other microorganisms has been lost. Tests for DNA sequence artifacts To further test the possibility that some versions of over about 2853 bp E=0.0. Similarly, the full genome of these microbial sequences were sequencing artifacts or waddlia chondrophila (2.1 million bp) was homologous to were contaminated by human genomes, microbial genomes multiple human genes (Table 3). represented in the Figures and other arbitrarily selected to insert their sequences in human DNA or have other microbial genomes were tested for homology to human methodsRetroviral of infection infections and transmission, identified in such Fig as 1 by are inhibiting known genomes. Results of these reversed-analyses make it unlikely that the human-microbial matches are errors or artifacts. Substantial similarities between partial and complete key protective mechanisms. For example, HIV-1 destroys microbial DNAs and human DNAs were universal and helped helper T-cells after uptake by a specific receptor. Like other develop the model in Figure 7. inretroviruses, the congenital HIV-1 abnormalities DNA becomes in incorporated neurodevelopmental into host cells. HIV-1 and other retroviral insertions were found Homologies between multiple strains of the same microbe and all human sequences were tested. Homologies disorders. HIV-1 isolate SC007 from India, partial genome to human sequences were found across multiple strains of stretch(GenBank: of human KY713228.1) DNA surrounding had 85% identity a rare NotI over restriction 686 bases site.to an HIVIgG2 homologies lambda antibody were andvery 82% commonly homology found to a 412among bp to some human gene product was found but there was not the same microorganism (Table 3). In other cases, homology human sequences of neurodevelopmental disorders. To test for human sequence contaminants in these matching HIV same microorganism. In these cases, the human gene was testedsufficient against data allavailable bacteria, to and compare viruses. multiple There wereversions hundreds of the sequencesequences, compendium an Alu homologous were compared. region of All the 28 HIV-1HIV sequences genome (bp 7300 to 9000) in 28 different HIV-1 isolates in an HIV of significant matches. The complete clostridium botulinum had matches to the same region of human DNA, with up to genome had significant homology to human enzyme CDKL2 (86%) on chromosome 4. The region on chromosome 4: 98% identity to the human sequences. The best match was 579,587-75,632,298 spanned 52712 bp and was filled with only one sequence of zika virus matched humans in a short AluY, and AluJ. Clostridium itself however did not have to a LINCRNA on chr11:74,929,289-74,929,412. In contrast, over 50 Alu repeats, including multiple versions of AluS, homology with long stretches on other chromosomes segment of human-like DNA on the 3’ end. This homology homology to Alu repeats. Clostridium also had significant virus was not considered further. was not found in 20 additional zika virus sequences so zika including chromosomes 2, 3, 10, 15, 1, 5 with 74% homology 52 ISSN: 2581-7388 www.innovationinfo.org It is almost impossible to completely exclude the of autophagy may lead to abnormal pruning of neural possibility of sequencing artifacts or contamination of connections during postnatal development. microbial sequences with human sequences. However Aggregated gene damage accounts for immune, human DNA contamination in many laboratories over many rather than reflecting widespread, wholesale error due to years, the vast majority of microbial homologies more likely circulatory, and structural deficits that accompany suggest that infection sequences have been selected because neurologic deficits. Other gene losses listed in Table 1 and they are homologous to regions of human DNA. This may be perception,in deleted chromosomeskull size, muscle segments tone (Figureand many 1) accountother non- for a driving force behind the much slower evolution of Alu DNA. neurologicdeficits in signs cardiac of neurodevelopmental function, hearing, bone disorders. structure, pain Discussion The arrangement of genes in clusters converging on Long stretches of DNA in many infections match repetitive the same biological process may simplify the regulation human DNA sequences which occur hundreds of thousands and coordination between neurons and other genes during of times. Individual microorganisms also match non- neurodevelopment and neuroplasticity. Genes that are repetitive sequences. Human infections may be selected for required for related functions, requiring coordinated and initially tolerated because of these matches. Infections regulation have been shown to be organized into individual can cause mutations by interfering with the most active period of recombination which occurs during the generation intimately connected to chromatin architecture and of gametes, an ongoing process in males. Infections such as topologically associated domains [20]. Neurons are exogenous or endogenous retroviruses are known to insert clustered arrangement of co-regulated accessory genes is thatthe epigenetichomology to landscape microbial [21].infections A disadvantage or other causes of the of match infection DNA generate chromosomal anomalies chromosome anomalies anywhere in the cluster can then becauseinto DNA hotspotssimilarities [8]. Humanbetween DNA microbial sequences and that humanclosely ruin complex critical neurological processes. Epigenetic regulators that affect multiple functions required by the genetic background of an individual may be a key factor in same process make their mutation especially critical. DNA cause interference with meiosis (Fig. 7). Thus, the determining the susceptibility to infection and to the effects Longer range developmental interactions in chromosome of infection. At the genetic level, this suggests selective regions exacerbate the effects of infection. Mutations or pressures for infections to develop and use genes that are similar to human genes and to silence or mutate microbial occur in neurodevelopmental disorders. Functions that genes that are immunogenic. Infection genomes evolve mustdeletions be (Figuresynchronized 1 and Tableduring 1) showneurodevelopment that this effect canare grouped together on the same chromosome region and can genes in infections that have long stretches of identity with be lost together. This is consistent with the idea that the rapidly on transfer to a new host [17]. The presence of organization of crossover chiasmata during meiosis allows as non-self. For example, there is no state of immunity to the coordinated evolution and control of gene sets required N.human gonorrhoeae. genes makes One the reason infection for thismore is difficult that there to recognize are long by the same essential process. stretches of N. gonorrhoeae DNA that are almost identical to human DNA. Alu sequences and other repetitive elements Microbial DNA sequences are unlikely to be contaminants are thought to underlie some diseases by interfering with or sequencing artifacts. They are all found connected to correct homologous recombination as in hereditary colon human DNA in disease chromosomes; multiple sequences from different laboratories are all homologous to the same occur is not well understood. The presence of infection DNA Alu sequence. Alu element-containing RNA polymerase II thatcancer is homologous [18] or abnormal to multiple, splicing. long Why stretches this does of human not always DNA may mask proper recombination sites and encourage this rRNA synthesis and may regulate nucleolar assembly as abnormal behavior. thetranscripts cell cycle (AluRNAs) progresses determine and as the nucleolar cell adapts structure to external and Neurons and cells in the immune system are interacting systems, sensing and adapting to their common environment. near or within Alu repeats, regardless of whether they occur These interactions prevent multiple pathological changes signals [22]. HIV-1 integration occurs with some preference in introns or exons [23]. with different chromosome anomalies. This variability and betweenin many disordersthe immune [19]. system Many and genes the nervousthat are system.implicated It was in The patients indicated in Fig. 3 have different disorders neurodevelopmental diseases, reflect the strong relationship to study by conventional approaches. The techniques used herethe rarity might of eventually the anomalies help predict makes thethese lifelong disorders susceptibility difficult always possible to find functions within the immune system to a given infection of an individual. However, the methods tofor more genes global involved developmental in neurodevelopmental neurologic defectsdisorders including (Figs 1 used suffer from the inability to absolutely identify one intellectualand 4). Damage disability. to genes These essential microbial to prevent homologies infection include leads infection and to distinguish infection by one microorganism known teratogens. Analysis of mutations within clusters of from multiple infections. genes deleted in neurodevelopmental disorders predict loss of brain-circulatory barriers, facilitating infections. Damage Conclusion to cellular genes essential for the immune related function • DNAs in some congenital neurodevelopmental disorders 53 ISSN: 2581-7388 www.innovationinfo.org Figure 8: Model for interference with meiosis by DNA from infections leading to neurodevelopmental disorders. After duplication of parental chromosomes prior to generation of gametes, DNA from infections associates with strands of DNA in the many places including repetitive sequences of human DNA closely matching infection DNA. In addition, retroviruses and retrotransposons may integrate their DNA. These events interfere with reductive cell division, topological relationships among chromosomes, epigenetic regulation and high-fidelity break repair. Interference from microorganisms may favor the illegitimate combinations due to palindromes reported by Mishra and co-workers. Hundreds of DNA breaks occur during meiosis and incorrect repair of these breaks is known to occur [1], causing chromosome anomalies such as deletions (shown). Clustered genes responsible for linked functions and epigenetic regulation in neurodevelopment are lost or displaced. Other chromosome segments with microbial homology do not contain identified genes but may be essential control regions or they may be involved in chromatin structures. There are about one million Alu repeats alone in the human genome and many match sets of infections in individual neurodevelopment disorders. More private matches also occur. When combined with effects from other microorganisms this can cause severe disruption of base pairing in gamete generation. closely matches DNA in multiple infections that extend Biochemistry and Molecular Genetics and the College of over long linear stretches of human DNA and often Medicine at UIC. involve repetitive human DNA sequences. The affected sequences are shown to exist as linear clusters of genes Conflicts of Interest closely spaced in two dimensions. • Interference from infection can delete or damage human ReferencesThe author declares no conflict of interest. gene clusters and epigenetic regulators that coordinate The neurodevelopment. This genomic interference accounts genomic landscape of balanced cytogenetic abnormalities associated 1. Redin C, Brand H, Collins RL, Kammin T, Mitchell E, et. al. (2017) 2. with human congenital anomalies. 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