RetroSpect, a New Method of Measuring Gene Regulatory Evolution Rates Using Co-mapping of Genomic Functional Features with Transposable Elements

Abstract

Transposable elements (TEs) are selfish genetic sequences that proliferate in the host genomes by spreading their copies in new genomic locations. TEs reside in the genomes of all groups of living organisms. TE sequences may be recruited by the host cells to serve as regulatory sites for the neighboring genes. These regulatory sites can be transcription factor binding sites (TFBS), histone modification loci, DNase I hypersensitivity sites, etc. Insertion of a TE in a gene neighborhood changes an equilibrium of regulatory sequences controlling this gene functioning. The more regulatory sites can be identified within gene-proximate TEs, the faster should be the evolution of gene regulation. We proposed a method for measuring evolutionary rates of gene regulation based on relative quantitation of regulatory sites located within TEs next to gene transcriptional start sites. It allows interrogating regulatory evolution for organisms with TE-rich genomes. This method termed RetroSpect was applied first for studying human gene evolution using TFBS co-mapping with the human retroelements (REs). RE is a subgroup of TEs that was active in mammals before and after their radiation. We characterized human genes and molecular pathways either enriched or deficient in RE-linked TFBS regulation for 563 transcription factors in thirteen human cell lines. We found that major groups enriched by RE regulation deal with gene control by microRNAs, olfaction, color vision, fertilization, cellular immune response, amino acids and fatty acids metabolism and detoxication. The deficient groups were involved in protein translation, RNA transcription and processing, chromatin organization, and molecular signaling.