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Two distinct families of pan-primate endogenous retroviruses, namely HERVLand HERVH, infected primates germline, colonized host genomes, and evolved intothe global retroviral genomic regulatory dominion (GRD) operating during humanembryogenesis (HE). HE retroviral GRD constitutes 8839 highly conserved fixedLTR elements linked to 5444 down-stream target genes forged by evolution into afunctionally-consonant constellation of 26 genome-wide multimodular genomicregulatory networks (GRNs), each of which is defined by significant enrichmentof numerous single gene ontology (GO)-specific traits. Locations of GRNs appearscattered across chromosomes to occupy from 5.5%-15.09% of human genome. EachGRN harbors from 529-1486 retroviral LTRs derived from LTR7, MLT2A1, and MLT2A2sequences that are quantitatively balanced according to their genome-wideabundance. GRNs integrate activities from 199-805 down-stream target genes,including transcription factors, chromatin-state remodelers, signal-sensing andsignal-transduction mediators, enzymatic and receptor binding effectors,intracellular complexes and extracellular matrix elements, and cell-celladhesion molecules. GRNs compositions consist of several hundred to thousandssmaller GO enrichment-defined genomic regulatory modules (GRMs) combining froma dozen to hundreds LTRs and down-stream target genes, which appear to operateon individuals life-span timescale along specific phenotypic avenues to exertprofound effects on patterns of transcription, protein-protein interactions,developmental phenotypes, physiological traits, and pathological conditions ofModern Humans. Overall, this study identifies 69,573 statistically significantretroviral LTR-linked GRMs (Binominal FDR q-value threshold of 0.001),including 27,601 GRMs validated by the single GO-specific directed acyclicgraph (DAG) analyses across six GO annotations.

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