Human embryo retroviral LTR elements: a pan-primate epigenetic architect contributing to evolution, development, physiological traits, and pathological phenotypes of Modern Humans.

Abstract

Abstract Evolution created two distinct families of pan-primate endogenous retroviruses, namely HERVL and HERVH, which infected primates’ germline, colonized host genomes, and evolved into the global retroviral genomic regulatory dominion (GRD) operating during human embryogenesis. Retroviral GRD constitutes 8839 highly conserved fixed 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 (GO)-specific traits. Locations of GRNs appear scattered across chromosomes to occupy from 5.5%-15.09% of the human genome. Each GRN harbors from 529–1486 human embryo retroviral LTRs derived from LTR7, MLT2A1, and MLT2A2 sequences that are quantitatively balanced according to their genome-wide abundance. GRNs integrate activities from 199–805 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 GO enrichment-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 GO-specific directed acyclic graph (DAG) analyses across 6 GO annotations. Gene Set Enrichment Analyses (GSEA) of retroviral LTRs down-stream targets employing > 70 genomics and proteomics databases (DB), including a large panel of DB developed from single-cell resolution studies of healthy and diseased human’s organs and tissues, demonstrate that genes assigned to distinct GRNs and GRMs appear to operate on individuals’ life-span timescale along specific phenotypic avenues selected from a multitude of GO-defined and signaling pathways-guided frameworks to exert profound effects on patterns of transcription, protein-protein interactions (PPI), developmental phenotypes, physiological traits, and pathological conditions of Modern Humans. GO analyses of Mouse phenotype DB and GSEA of the MGI Mammalian Phenotype Level 4 2021 DB 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 corroborated by documented numerous developmental defects in a single gene KO models. Genes comprising candidate down-stream regulatory targets of human embryo retroviral LTRs are engaged in 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 DB and 6584 records of virus-host PPIs documented in Virus-Host PPI P-HIPSTer 2020 DB. 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. 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-phenotype associations. Highlighted specific GRMs may represent the evolutionary selection units which are 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.