Genomic regulatory architecture of human embryo retroviral LTR elements affecting evolution, development, and pathophysiology of Modern Humans

Two distinct families of pan-primate endogenous retroviruses, namely HERVL and HERVH, infected primates germline, colonized host genomes, and evolved into the global retroviral genomic regulatory dominion (GRD) operating during human embryogenesis (HE). HE 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 human genome. Each GRN harbors from 529-1486 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. GRNs compositions consist of several hundred to thousands smaller GO enrichment-defined genomic regulatory modules (GRMs) combining from a dozen to hundreds LTRs and down-stream target genes, which appear to operate on individuals life-span timescale along specific phenotypic avenues to exert profound effects on patterns of transcription, protein-protein interactions, developmental phenotypes, physiological traits, and pathological conditions of Modern Humans. Overall, this study identifies 69,573 statistically significant retroviral LTR-linked GRMs (Binominal FDR q-value threshold of 0.001), including 27,601 GRMs validated by the single GO-specific directed acyclic graph (DAG) analyses across six GO annotations.Comment: 66 pages, 16 figure