Biology subjects

Glinsky, G.

Publications and source records attributed to Glinsky, G..

5 recordsLinked to original sources

bioRxiv2023

Analysis of 8839 pan-primate retroviral LTR elements with regulatory functions during human embryogenesis reveals their global impacts on evolution of Modern Humans.

During millions years of primate evolution, two distinct families of pan-primate endogenous retroviruses, namely HERVL and HERVH, infected primates germline, colonized host genomes and evolved to contribute to creation of the global retroviral genomic regulatory dominion (GRD) operating during human embryogenesis. Retroviral GRD constitutes of 8839 highly conserved LTR elements linked to 5444 down-stream target genes forged by evolution into a functionally-consonant constellation of 26 genome-wide multimodular genomic regulatory networks (GRNs) each of which is defined by significant enrichment of numerous single gene ontology-specific traits. Locations of GRNs appear scattered across chromosomes to occupy from 5.5% to 15.09% of the human genome. Each GRN harbors from 529 to 1486 human embryo retroviral LTR elements derived from LTR7, MLT2A1, and MLT2A2 sequences that are quantitatively balanced according to their genome-wide abundance. GRNs integrate activities from 199 to 805 down-stream target genes, including transcription factors, chromatin-state remodelers, signal sensing and signal transduction mediators, enzymatic and receptor binding effectors, intracellular complexes and extracellular matrix elements, and cell-cell adhesion molecules. GRNs compositions consist of several hundred to thousands smaller gene ontology enrichment analysis-defined genomic regulatory modules (GRMs), each of which combines from a dozen to hundreds LTRs and down-stream target genes. Overall, this study identifies 69,573 statistically significant retroviral LTR-linked GRMs (Binominal FDR q-value < 0.001), including 27,601 GRMs validated by the single ontology-specific directed acyclic graph (DAG) analyses across 6 gene ontology annotations databases. These observations were corroborated and extended by execution of a comprehensive series of Gene Set Enrichment Analyses (GSEA) of retroviral LTRs down-stream target genes employing more than 70 genomics and proteomics databases, including a large panel of databases developed from single-cell resolution studies of healthy and diseased humans organs and tissues. Genes assigned to distinct GRNs and GRMs appear to operate on individuals life-span timescale along specific phenotypic avenues selected from a multitude of down-stream gene ontology-defined and signaling pathways-guided frameworks to exert profound effects on patterns of transcription, protein-protein interactions, developmental phenotypes, physiological traits, and pathological conditions of Modern Humans. GO analyses of Mouse phenotype databases and GSEA of the MGI Mammalian Phenotype Level 4 2021 database revealed that down-stream regulatory targets of human embryo retroviral LTRs are enriched for genes making essential contributions to development and functions of all major tissues, organs, and organ systems, that were documented by numerous developmental defects in a single gene KO models. Genes comprising candidate down-stream regulatory targets of human embryo retroviral LTRs are engaged in protein-protein interaction (PPI) networks that have been implicated in pathogenesis of human common and rare disorders (3298 and 2071 significantly enriched records, respectively), in part, by impacting PPIs that are significantly enriched in 1783 multiprotein complexes recorded in the NURSA Human Endogenous Complexome database and 6584 records of virus-host PPIs documented in Virus-Host PPI P-HIPSTer 2020 database. GSEA-guided analytical inference of the preferred cellular targets of human embryo retroviral LTR elements supported by analyses of genes with species-specific expression mapping bias in Human-Chimpanzee hybrids identified Neuronal epithelium, Radial Glia, and Dentate Granule Cells as cell-type-specific marks within a Holy Grail sequence of embryonic and adult neurogenesis. Observations reported in this contribution support the hypothesis that evolution of human embryo retroviral LTR elements created the global GRD consisting of 26 gene ontology enrichment-defined genome-wide GRNs. Decoded herein the hierarchical super-structure of retroviral LTR-associated GRD and GRNs represents an intrinsically integrated developmental compendium of thousands GRMs congregated on specific genotype-phenotypic trait associations. Many highlighted in this contribution GRMs may represent the evolutionary selection units driven by inherent genotype-phenotype associations affecting primate species fitness and survival by exerting control over mammalian offspring survival genes implicated in reduced fertility and infertility phenotypes. Mechanistically, programmed activation during embryogenesis and ontogenesis of genomic constituents of human embryo retroviral GRD coupled with targeted epigenetic silencing may guide genome-wide heterochromatin patterning within nanodomains and topologically-associated domains during differentiation, thus affecting 3D folding dynamics of linear chromatin fibers and active transcription compartmentalization within interphase chromatin of human cells.

genomics↗

bioRxiv2022

Molecular diversity and phenotypic pleiotropy of genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their impacts on pathophysiology of Modern Humans.

Targeted DNA sequences conservation analyses of 17 primate species demonstrated that human endogenous retroviruses (HERV) LTR7/HERVH and LTR5_Hs/HERVK appear to have distinct evolutionary histories charted by evidence of the earliest presence and expansion of highly-conserved (HC) LTR sequences. HC-LTR7 loci were mapped to genomes of Old World Monkeys (18% of all HC-LTR7 loci), suggesting that LTR7/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage. HC-LTR5_Hs loci have been identified in the Gibbons genome (24% of all HC-LTR5_Hs loci), suggesting that LTR5_Hs/HERVK successfully colonized primates germlines after the segregation of Gibbons species. Subsequently, both LTR7 and LTR5_Hs undergo a marked [~]4-5-fold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies. Consistent with previous reports, identified in this study 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of naive and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS regulatory LTRs appear linked with genes encoding markers of 12 distinct cells populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia. Granular investigations of genes linked with eleven LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout [~]30 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including 92 genes of Autosomal Dominant Inheritance and 93 genes of Autosomal Recessive Inheritance. One of the most informative categories of genes linked with LTR7 elements were genes implicated in functional and morphological features of central nervous system, including genes regulating synaptic transmission and protein-protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked regulatory targets identified significantly enriched sets of genes encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus amongst top significantly enriched records. These observations were validated and extended by identification and characterization of 1944 genes comprising high-fidelity down-steam regulatory targets of LTR7 and/or LTR5_Hs loci, which are markedly enriched for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimers, schizophrenia, and other brain disorders. Despite distinct evolutionary histories of retroviral LTRs, genes representing down-stream regulatory targets of LTR7 and LTR5_Hs elements exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. Observations reported in this contribution highlight the need to accelerate the in-depth experimental and translational explorations of these important genomic determinants of Modern Humans health and disease states.

genomics↗

bioRxiv2019

Human-specific regulatory features of brain development manifest staggering breadth of associations with physiological processes and pathological conditions of H. sapiens

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.

genomics↗

bioRxiv2018

Multi-species mosaicism of evolutionary origins of genomic loci harboring 59,732 human-specific regulatory sequences reflects a complex continuous speciation process of the human lineage

Nearly sixty thousand genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) have been identified using high-resolution sequencing technologies and methodologically diverse comparative analyses of human and non-human primates reference genomes. Here, the systematic analysis of evolutionary origins of 59,732 genomic loci harboring candidate HSRS has been performed to identify genomic sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes after the split of human and chimpanzee lineages. Present analyses revealed thousands of HSRS that appear inherited from ECAs yet bypassed genomes of our closest evolutionary relatives, Chimpanzee and Bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. The bypassing pattern is particularly prominent for HSRS putatively associated with development and functions of human brain. Significant fractions of retrotransposon-derived loci that are transcriptionally-active in human dorsolateral prefrontal cortex 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. These observations were independently corroborated by common evolutionary patterns of 248 insertions sites of African ape-specific retrovirus PtERV1 (45.9%; p = 1.03E-44) intersecting genomic regions harboring 442 HSRS, which are enriched for HSRS that have been associated with human-specific (HS) changes of gene expression in cerebral organoid models of brain development. A prominent majority of genomic regions harboring HS mutations associated with HS gene expression changes during brain development is highly conserved in Chimpanzee, Bonobo, and Gorilla genomes. Among nonhuman primates (NHP), most significant fractions of candidate HSRS associated with HS gene expression changes in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the Gorilla genome. Present analyses revealed 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. Evidence of multispecies evolutionary origins of HSRS support the model of complex continuous speciation process during evolution of Great Apes that is not likely to occur as an instantaneous event.

genomics↗

bioRxiv2016

Single cell analysis of lincRNA expression during human blastocyst differentiation identifies TERT (+) multi-lineage precursor cells

Chromosome instability and aneuploidies occur very frequently in human embryos, impairing proper embryogenesis and leading to cell cycle arrest, loss of cell viability, and developmental failures in 50-80% of cleavage-stage embryos. This high frequency of cellular extinction events represents a significant experimental obstacle challenging analyses of individual cells isolated from human preimplantation embryos. Here, we carried out single cell expression profiling analyses of 241 individual cells recovered from 32 human embryos during the early and late stages of viable human blastocyst differentiation. Classification of embryonic cells was performed solely based on expression patterns of human pluripotency-associated transcripts (HPAT), which represent a family of transposable element-derived lincRNAs highly expressed in human embryonic stem cells (hESCs) and regulating nuclear reprogramming and pluripotency induction. We then validated our findings by analyzing 1,708 individual embryonic cells recovered from more than 100 human embryos and 259 mouse embryonic cells at different stages of preimplantation embryogenesis. Our experiments demonstrate that segregation of human blastocyst cells into distinct sub-populations based on single-cell expression profiling of just three HPATs (HPAT-21; -2; and -15) appears to inform key molecular and cellular events of naive pluripotency induction and accurately captures a full spectrum of cellular diversity during human blastocyst differentiation. HPATs expression-guided spatiotemporal reconstruction of human embryonic development inferred from single-cell expression analysis of viable blastocyst differentiation enabled identification of TERT(+) sub-populations, which are significantly enriched for cells expressing key naive pluripotency regulatory genes and genetic markers of all three major lineages created during human blastocyst differentiation. Results of our analyses suggest that during early stages of preimplantation embryogenesis putative immortal multi-lineage precursor cells (iMPCs) are created, which then differentiate into trophectoderm, primitive endoderm and pluripotent epiblast lineages. We propose that cellular extinction events in cleavage-stage embryos are triggered by premature activation of HPAT lincRNAs reflecting failed iMPCs creation attempts.\n\nHighlightsO_LISingle cell analysis of 1,949 human & 259 mouse embryonic cells\nC_LIO_LIIdentification of 5 most abundant HPAT lincRNAs in viable human blastocysts\nC_LIO_LIExpression profiling of just 3 lincRNAs captures cellular diversity of human blastocysts\nC_LIO_LIIdentification & characterization of TERT(+) multi-lineage precursor cells\nC_LIO_LIMTTH/HPAT lincRNAs regulatory axis of naive pluripotency induction in vivo\nC_LI

genomics↗