Analysis of 8839 pan-primate retroviral LTR elements with regulatory functions during human embryogenesis reveals their global impacts on evolution of Modern Humans
Authors: Glinsky Gennadi V. 
Published: August 2023

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. GRN’s 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 human’s 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.