Retroelement-Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution.

Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS). RE-linked TFBS profile can serve as a marker of gene transcriptional regulation evolution. This approach allows for interrogating the regulatory evolution of organisms with RE-rich genomes. We aimed to characterize the evolution of transcriptional regulation for human genes and molecular pathways using RE-linked TFBS accumulation as a metric. We characterized human genes and molecular pathways either enriched or deficient in RE-linked TFBS regulation. We used ENCODE database with mapped TFBS for 563 transcription factors in 13 human cell lines. For 24,389 genes and 3124 molecular pathways, we calculated the score of RE-linked TFBS regulation reflecting the regulatory evolution rate at the level of individual genes and molecular pathways. The major groups enriched by RE regulation deal with gene regulation by microRNAs, olfaction, color vision, fertilization, cellular immune response, and amino acids and fatty acids metabolism and detoxication. The groups were involved in translation, RNA transcription and processing, chromatin organization, and molecular signaling. We identified genes and molecular processes that have characteristics of especially high or low evolutionary rates at the level of RE-linked TFBS regulation in human lineage.