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A Genome Model Linking Birth Defects to Infections

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A Genome Model Linking Birth Defects to Infections bioRxiv preprint doi: https://doi.org/10.1101/674093; this version posted June 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. A Genome Model Linking Birth Defects to Infections Bernard Friedenson Deparment of Biochemistry and Molecular Genetics College of Medicine University of Illinois Chicago Chicago, Illinois 60612 Abstract The purpose of this study was to test the hypothesis that infections are linked to chromosomal anomalies that cause neurodevelopmental disorders. In chil- dren 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 chro- matin 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 ac- company 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 inde- pendent studies of private, familial and recurrent chromosomal rearrangements, massive changes in homologous microbiomes were found and may drive rear- rangements 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 spe- cific 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. Keywords: 1; genome 2; epigenetics 3; neurodevelopmental disorders; 4; chromosome anoma- lies; 5; retrotransposon; 6; chromosome rearrangement; 7; neurologic disease; 8; birth defects; 9; development 10; infection bioRxiv preprint doi: https://doi.org/10.1101/674093; this version posted June 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Some infection DNA can integrate into human DNA (e.g. retroviruses) and many microbial DNAs can interfere with meiosis because of homologies to sections of human DNA (green stripes below). These events can drive deletion of gene clusters essential for coordinated neurodevelopment and can inactivate crucial epigenetic factors. Viral,Microbial bacterial homologies Nervous system Immunity homologies Red blood cells Structure Immunity Immunity Structure Nervous system Circulation Structure Immunity to human DNA Structure Nervous system Cell adhesion to human DNA Nervous system Nervous system Immunity Structure Angiogenesis Nervous system Nervous system Angiogenesis Nervous system (green stripes) Immunity Nervous system Immunity (green stripes) Gene cluster Nervous system Infections deleted in Missing meiosis Gene Cluster, Abnornal Microbiome,Epigenetics, MaternalEpigenetics factors Massive shiftschanges in homologous in homologous microbiome microbiome Truncated/deleted epigenetic driversdriver Intellectual disability Disrupted chromatin interactions Further infection Impaired circulation Craniofacial malformation Introduction tion of the neurologic system. Based on DNA se- An approach to preventing neurodevelopmen- quence analyses, some chromosome rearrangements tal disorders is to gain better understanding of have been identified as causing individual congenital how neurodevelopment is coordinated and then to disorders because they disrupt genes essential for identify interference from environmental, genom- normal development 1-3. There is poor understanding ic and epigenomic factors. The development of the and no effective treatment for many of these over- nervous system requires tight regulation and coordi- whelming abnormalities. Signs and symptoms include nation of multiple functions essential to protect and autism, microcephaly, macrocephaly, behavioral prob- nourish neurons. As the nervous system develops, lems, intellectual disability, tantrums, seizures, respi- the immune system, the circulatory system, cranial ratory problems, spasticity, heart problems, hearing and skeletal systems must all undergo synchronized loss, and hallucinations 1. Because the abnormalities and coordinated development. Neurodevelopmental do not correlate well with the outcome, genetic disorders follow the disruption of this coordination. counseling is difficult and uncertain 3. A significant advance in genome sequence level In congenital neurologic disease, inheritance is resolution of balanced cytogenetic abnormalities usually autosomal dominant and the same chromo- greatly improves the ability to document changes in somal abnormalities occur in every cell. The genetic regulation and dosage for genes critical to the func- events that lead to most neurodevelopmental dis- bioRxiv preprint doi: https://doi.org/10.1101/674093; this version posted June 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. page 3 4 orders are not understood but several maternal contrast to oocytes, meiotic recombination in sperm infections and other lifestyle factors are known to cells occurs continuously after puberty. interfere. The exact DNA sequences of known pathogenic DNA homology between microbes and hu- rearrangements in individual, familial and recurrent mans is a known fact and DNA swapping between congenital disorders 1-3 make it possible to test for vertebrates and invertebrates has been reported. association with foreign DNA. Even rare develop- An early draft of the human genome found human mental disorders can be screened for homology to genomes have undergone lateral gene transfer to infections within altered epigenomes and chromatin 5 incorporate microorganism genes . Lateral transfer structures. This screening may assist counseling, diag- from bacteria may have generated many candidate nosis, prevention, and early intervention. human genes 6. Genome-wide analyses in animals The results showed that DNA abnormalities in found up to hundreds of active genes generated by some neurodevelopmental disorders closely match horizontal gene transfer. Fruit flies and nematodes DNA in multiple infections that extend over long have continually acquired foreign genes as they linear stretches of human DNA and often resemble evolved. Although these transfers are thought to be repetitive human DNA sequences. Massive changes rarer in primates and humans, at least 33 previously in the identity and distribution of sets of homolo- unreported examples of horizontally acquired genes gous microorganisms that accompany chromosome were found 6. These findings argue that horizontal abnormalities may drive and stabilize them. Removing gene transfer continues to occur to a larger extent competition by changing the normal microbiome may than previously thought. Transferred genes that encourage pathogens. survive have been largely concerned with metabo- lism and make important contributions to increasing The affected sequences are shown to exist as biochemical diversity7. linear clusters of genes closely spaced in two dimen- sions. Interference from infection can also delete or The present work implicates foreign DNA damage human gene clusters and change epigenetic largely from infections as a cause of the chromo- functions that coordinate neurodevelopment. This some anomalies that cause birth defects. Infections microbial interference accounts for immune, circula- replicate within the human CNS by taking advantage tory, and structural deficits that accompany neuro- of immune deficiencies such as those traced back logic deficits. to deficient microRNA production8 or other gene losses. Disseminated infections can then interfere Congenital neurodevelopmental disorders are with the highly active DNA break repair process thus viewed as resulting from an assault on human required during meiosis. The generation of gametes DNA by foreign DNA and perhaps selection of by meiosis is the most active period of recombi- infecting microorganisms based on their similarity to nation which occurs at positions enriched in epi- host DNA. It is important to remember that effects genetic marks on chromatin. Hundreds of double in two dimensions can sometimes alter 3D topology strand breaks accompany meiotic recombination9. as well 10. Gametes
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