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Gennadi V Glinsky - One of the best experts on this subject based on the ideXlab platform.
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Impacts of genomic networks governed by human-specific Regulatory Sequences and genetic loci harboring fixed human-specific neuro-Regulatory single nucleotide mutations on phenotypic traits of modern humans
Chromosome Research, 2020Co-Authors: Gennadi V GlinskyAbstract:Recent advances in identification and characterization of human-specific Regulatory DNA Sequences set the stage for the assessment of their global impact on physiology and pathology of modern humans. Gene set enrichment analyses (GSEA) of 8405 genes linked with 35,074 human-specific neuro-Regulatory single-nucleotide changes (hsSNCs) revealed numerous significant associations with morphological structures, physiological processes, and pathological conditions of modern humans. Significantly enriched traits include more than 1000 anatomically distinct regions of the adult human brain, many different types of cells and tissues, more than 200 common human disorders, and more than 1000 records of rare diseases. Thousands of genes connected with neuro-Regulatory hsSNCs have been identified, which represent essential genetic elements of the autosomal inheritance and offspring survival phenotypes. A total of 1494 hsSNC-linked genes are associated with either autosomal dominant or recessive inheritance, and 2273 hsSNC-linked genes have been associated with premature death, embryonic lethality, as well as pre-, peri-, neo-, and post-natal lethality phenotypes of both complete and incomplete penetrance. Differential GSEA implemented on hsSNC-linked loci and associated genes identify a set of 7990 hsSNC-target genes linked to evolutionary distinct classes of human-specific Regulatory Sequences (HSRS). Notably, the expression of a majority of these genes (5389 genes; 67%) is regulated by stem cell–associated retroviral Sequences (SCARS) and SCARS-regulated genes captured a dominant fraction (91%) of significant phenotypic associations linked with hsSNCs. Interrogations of the MGI database revealed readily available mouse models tailored for precise experimental definitions of functional effects of hsSNCs and SCARS on genes causally affecting thousands of mammalian phenotypes and implicated in hundreds of common and rare human disorders. These observations suggest that a preponderance of human-specific traits evolved under a combinatorial Regulatory control of distinct classes of HSRS and neuro-Regulatory loci harboring hsSNCs that are fixed in humans, distinct from other primates, and located in differentially accessible chromatin regions during brain development.
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impacts of genomic networks governed by human specific Regulatory Sequences and genetic loci harboring fixed human specific neuro Regulatory single nucleotide mutations on phenotypic traits of modern humans
bioRxiv, 2020Co-Authors: Gennadi V GlinskyAbstract:Abstract Recent advances in identification and characterization of human-specific Regulatory DNA Sequences set the stage for the assessment of their global impact on physiology and pathology of Modern Humans. Gene set enrichment analyses (GSEA) of 8,405 genes linked with 35,074 human-specific neuro-Regulatory single-nucleotide changes (hsSNCs) revealed a staggering breadth of significant associations with morphological structures, physiological processes, and pathological conditions of Modern Humans. Significantly enriched traits include more than 1,000 anatomically-distinct regions of the adult human brain, many different types of cells and tissues, more than 200 common human disorders and more than 1,000 records of rare diseases. Thousands of genes connected with neuro-Regulatory hsSNCs have been identified, which represent essential genetic elements of the autosomal inheritance and offspring survival phenotypes. A total of 1,494 hsSNC- linked genes are associated with either autosomal dominant or recessive inheritance and 2,273 hsSNC-linked genes have been associated with premature death, embryonic lethality, as well as pre-, peri-, neo-, and post-natal lethality phenotypes of both complete and incomplete penetrance. Differential GSEA implemented on hsSNC-linked loci and associated genes identify 7,990 genes linked to evolutionary distinct classes of human-specific Regulatory Sequences (HSRS), expression of a majority of which (5,389 genes; 67%) is regulated by stem cell-associated retroviral Sequences (SCARS). Interrogations of the MGI database revealed readily available mouse models tailored for precise experimental definitions of functional effects of hsSNCs and SCARS on genes causally affecting thousands of mammalian phenotypes and implicated in hundreds of common and rare human disorders. These observations suggest that a preponderance of human-specific traits evolved under a combinatorial Regulatory control of HSRS and neuro-Regulatory loci harboring hsSNCs that are fixed in humans, distinct from other primates, and located in differentially-accessible chromatin regions during brain development.
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a catalogue of 59 732 human specific Regulatory Sequences reveals unique to human Regulatory patterns associated with virus interacting proteins pluripotency and brain development
DNA and Cell Biology, 2020Co-Authors: Gennadi V GlinskyAbstract:Extensive searches for genomic regions harboring various types of candidate human-specific Regulatory Sequences (HSRS) identified thousands' HSRS using high-resolution next-generation sequencing technologies and methodologically diverse comparative analyses of human and nonhuman primates' (NHPs) reference genomes. In this study, a comprehensive catalogue of 59,732 genomic loci harboring candidate HSRS has been assembled to facilitate the systematic analyses of genomic Sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes. These analyses identified thousands of candidate HSRS and HSRS-harboring loci that appear inherited from ECAs, yet absent in genomes of our closest evolutionary relatives, chimpanzee and bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or Regulatory DNA. This pattern is particularly prominent for HSRS-harboring loci that have been putatively associated with human-specific gene expression changes in cerebral organoid models. A prominent majority of regions harboring human-specific mutations associated with human-specific expression changes during brain development is highly conserved in chimpanzee, bonobo, and gorilla genomes. Among NHPs, dominant fractions of HSRS-harboring loci associated with human-specific gene expression in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the gorilla genome. Analysis of 4433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of human-specific Regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult dorsolateral prefrontal cortex. These analyses demonstrate that modern humans captured unique genome-wide combinations of Regulatory Sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic Regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Genes encoding VIPs appear to represent a principal genomic target during evolution of human-specific Regulatory networks, which contribute to fitness of Homo sapiens and affect a functionally diverse spectrum of biological and cellular processes controlled by VIP-containing liquid-liquid phase-separated condensates.
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analysis of genomic loci harboring 59 732 human specific Regulatory Sequences reveals unique to human Regulatory patterns associated with brain development
bioRxiv, 2019Co-Authors: Gennadi V GlinskyAbstract:Abstract Extensive searches for genomic regions harboring various types of candidate human-specific Regulatory Sequences (HSRS) identified thousands’ HSRS using high-resolution next-generation sequencing technologies and methodologically diverse comparative analyses of human and non-human primates’ reference genomes. Here, a comprehensive catalogue of 59,732 genomic loci harboring candidate HSRS has been assembled to facilitate the systematic analyses of genomic Sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes. Present analyses identified thousands of HSRS that appear inherited from ECAs yet absent in genomes of our closest evolutionary relatives, Chimpanzee and Bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or Regulatory DNA. This pattern is particularly prominent for HSRS that have been putatively associated with human-specific (HS) gene expression changes in cerebral organoid models. Significant fractions of retrotransposon-derived loci transcriptionally-active in human dorsolateral prefrontal cortex (DLPFC) are highly conserved in genomes of Gorilla, Orangutan, Gibbon, and Rhesus (1,688; 1,371; 1,148; and 1,045 loci, respectively), yet they are absent in genomes of both Chimpanzee and Bonobo. A prominent majority of regions harboring HS mutations associated with HS expression changes during brain development is highly conserved in Chimpanzee, Bonobo, and Gorilla genomes. Among non-human primates (NHP), dominant fractions of HSRS associated with HS gene expression in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the Gorilla genome. Analysis of 4,433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of HS Regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult DLPFC. Present analyses demonstrate that Modern Humans captured unique combinations of Regulatory Sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic Regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Present analyses of HSRS support the model of complex continuous speciation process during evolution of the human lineage that is not likely to occur as an instantaneous event. Genes encoding VIPs may represent a principal genomic target of HS Regulatory networks, thus affecting a functionally diverse spectrum of biological processes controlled by VIP-containing liquid-liquid phase separated condensates.
Edward M. Rubin - One of the best experts on this subject based on the ideXlab platform.
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detection of weakly conserved ancestral mammalian Regulatory Sequences by primate comparisons
Genome Biology, 2007Co-Authors: Edward M. Rubin, Qianfei Wang, Shyam Prabhakar, Sumita Chanan, Jan Fang ChengAbstract:Background Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis-Regulatory elements based on constrained sequence evolution. However, these methods fail to detect functional elements that are too weakly conserved among mammals to distinguish them from non-functional DNA.
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detection of weakly conserved ancestral mammalian Regulatory Sequences by primate comparisons
Lawrence Berkeley National Laboratory, 2006Co-Authors: Edward M. Rubin, Qianfei Wang, Shyam Prabhakar, Sumita Chanan, Jan Fang ChengAbstract:Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis-Regulatory elements based on constrained sequence evolution. However, these methods fail to detect cryptic functional elements, which are too weakly conserved among mammals to distinguish from nonfunctional DNA. To address this problem, we explored the potential of deep intra-primate sequence comparisons. We sequenced the orthologs of 558 kb of human genomic sequence, covering multiple loci involved in cholesterol homeostasis, in 6 nonhuman primates. Our analysis identified 6 noncoding DNA elements displaying significant conservation among primates, but undetectable in more distant comparisons. In vitro and in vivo tests revealed that at least three of these 6 elements have Regulatory function. Notably, the mouse orthologs of these three functional human Sequences had Regulatory activity despite their lack of significant sequence conservation, indicating that they are cryptic ancestral cis-Regulatory elements. These Regulatory elements could still be detected in a smaller set of three primate species including human, rhesus and marmoset. Since the human and rhesus genome Sequences are already available, and the marmoset genome is actively being sequenced, the primate-specific conservation analysis described here can be applied in the near future on a whole-genome scale, to complement the annotation provided by more distant species comparisons.
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Genomic strategies to identify mammalian Regulatory Sequences
Nature Reviews Genetics, 2001Co-Authors: Len A. Pennacchio, Edward M. RubinAbstract:With the continuing accomplishments of the human genome project, high-throughput strategies to identify DNA Sequences that are important in mammalian gene regulation are becoming increasingly feasible. In contrast to the historic, labour-intensive, wet-laboratory methods for identifying Regulatory Sequences, many modern approaches are heavily focused on the computational analysis of large genomic data sets. Data from inter-species genomic sequence comparisons and genome-wide expression profiling, integrated with various computational tools, are poised to contribute to the decoding of genomic sequence and to the identification of those Sequences that orchestrate gene regulation. In this review, we highlight several genomic approaches that are being used to identify Regulatory Sequences in mammalian genomes.
Abraham Hochberg - One of the best experts on this subject based on the ideXlab platform.
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development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of h19 and igf2 p4 Regulatory Sequences
Journal of Translational Medicine, 2010Co-Authors: Doron Amit, Abraham HochbergAbstract:Background The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers (including bladder cancer), while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 Regulatory Sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder (treated with H19-DTA). However this targeted medicine approach could be limited, as not all cancer patients express high levels of H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different Regulatory Sequences, selected from the cancer-specific promoters H19 and IGF2-P4.
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development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of h19 and igf2 p4 Regulatory Sequences
Journal of Translational Medicine, 2010Co-Authors: Doron Amit, Abraham HochbergAbstract:The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers (including bladder cancer), while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 Regulatory Sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder (treated with H19-DTA). However this targeted medicine approach could be limited, as not all cancer patients express high levels of H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different Regulatory Sequences, selected from the cancer-specific promoters H19 and IGF2-P4. H19 and IGF2-P4 gene expression was tested in samples of Transitional Cell Carcinoma (TCC) of the bladder by in-situ hybridization (ISH) and by quantitative Real-Time PCR (qRT-PCR). The therapeutic potential of the double promoter toxin vector H19-DTA-IGF2-P4-DTA was tested in TCC cell lines and in heterotopic and orthotopic animal models of bladder cancer. Nearly 100% of TCC patients highly expressed IGF2-P4 and H19, as determined by ISH and by qRT-PCR. The double promoter vector exhibited superior tumor growth inhibition activity compared to the single promoter expression vectors, in cell lines and in heterotopic and orthotopic bladder tumors. Our findings show that bladder tumors may be successfully treated by intravesical instillation of the double promoter vector H19-DTA-P4-DTA. Overall, the double promoter vector exhibited enhanced anti-cancer activity relative to single promoter expression vectors carrying either gene alone.
Qianfei Wang - One of the best experts on this subject based on the ideXlab platform.
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detection of weakly conserved ancestral mammalian Regulatory Sequences by primate comparisons
Genome Biology, 2007Co-Authors: Edward M. Rubin, Qianfei Wang, Shyam Prabhakar, Sumita Chanan, Jan Fang ChengAbstract:Background Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis-Regulatory elements based on constrained sequence evolution. However, these methods fail to detect functional elements that are too weakly conserved among mammals to distinguish them from non-functional DNA.
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detection of weakly conserved ancestral mammalian Regulatory Sequences by primate comparisons
Lawrence Berkeley National Laboratory, 2006Co-Authors: Edward M. Rubin, Qianfei Wang, Shyam Prabhakar, Sumita Chanan, Jan Fang ChengAbstract:Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis-Regulatory elements based on constrained sequence evolution. However, these methods fail to detect cryptic functional elements, which are too weakly conserved among mammals to distinguish from nonfunctional DNA. To address this problem, we explored the potential of deep intra-primate sequence comparisons. We sequenced the orthologs of 558 kb of human genomic sequence, covering multiple loci involved in cholesterol homeostasis, in 6 nonhuman primates. Our analysis identified 6 noncoding DNA elements displaying significant conservation among primates, but undetectable in more distant comparisons. In vitro and in vivo tests revealed that at least three of these 6 elements have Regulatory function. Notably, the mouse orthologs of these three functional human Sequences had Regulatory activity despite their lack of significant sequence conservation, indicating that they are cryptic ancestral cis-Regulatory elements. These Regulatory elements could still be detected in a smaller set of three primate species including human, rhesus and marmoset. Since the human and rhesus genome Sequences are already available, and the marmoset genome is actively being sequenced, the primate-specific conservation analysis described here can be applied in the near future on a whole-genome scale, to complement the annotation provided by more distant species comparisons.
Doron Amit - One of the best experts on this subject based on the ideXlab platform.
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development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of h19 and igf2 p4 Regulatory Sequences
Journal of Translational Medicine, 2010Co-Authors: Doron Amit, Abraham HochbergAbstract:Background The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers (including bladder cancer), while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 Regulatory Sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder (treated with H19-DTA). However this targeted medicine approach could be limited, as not all cancer patients express high levels of H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different Regulatory Sequences, selected from the cancer-specific promoters H19 and IGF2-P4.
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development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of h19 and igf2 p4 Regulatory Sequences
Journal of Translational Medicine, 2010Co-Authors: Doron Amit, Abraham HochbergAbstract:The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers (including bladder cancer), while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 Regulatory Sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder (treated with H19-DTA). However this targeted medicine approach could be limited, as not all cancer patients express high levels of H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different Regulatory Sequences, selected from the cancer-specific promoters H19 and IGF2-P4. H19 and IGF2-P4 gene expression was tested in samples of Transitional Cell Carcinoma (TCC) of the bladder by in-situ hybridization (ISH) and by quantitative Real-Time PCR (qRT-PCR). The therapeutic potential of the double promoter toxin vector H19-DTA-IGF2-P4-DTA was tested in TCC cell lines and in heterotopic and orthotopic animal models of bladder cancer. Nearly 100% of TCC patients highly expressed IGF2-P4 and H19, as determined by ISH and by qRT-PCR. The double promoter vector exhibited superior tumor growth inhibition activity compared to the single promoter expression vectors, in cell lines and in heterotopic and orthotopic bladder tumors. Our findings show that bladder tumors may be successfully treated by intravesical instillation of the double promoter vector H19-DTA-P4-DTA. Overall, the double promoter vector exhibited enhanced anti-cancer activity relative to single promoter expression vectors carrying either gene alone.
