Transposable elements are the primary source of novelty in primate gene regulation

Abstract

Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNAseq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells

“…Likewise, we compared LTRs to either evolutionary conserved or human‐specific liver cis ‐regulatory elements (Appendix Fig S1B). In these tests, tissue‐specific and human‐specific elements reached the best similarity scores with LTRs, in agreement with earlier observations (Trizzino et al , , ).…”

“…We further tested whether the evolutionary age of the LTRs would affect their position relative to PEs (Appendix Fig S1G–I). Examinations of the profiles suggested that the ERV1 clade (approximately 170,000 copies) is better tolerated in the neighborhood of PEs than is the older ERVL clade (approximately 500,000 copies), in agreement with an earlier study showing that ERV1 is the most abundant LTR within cis ‐regulatory elements (Trizzino et al , ). The younger ERVKs were too few in number for the profiles to be meaningful (approximately 10,000 copies).…”

LINE- andAlu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV

“…More recently, Trizzino et al. () speculated that TEs, including L1s and Alu s, are the primary source of novelty in primate gene regulation. L1s and Alu s appeared at 16q24.1 location relatively recently during primate evolution, and substantial fraction of CNVs that they mediate are nonrecurrent.…”

Greater genetic and regulatory plasticity of retained duplicates in Epichloë endophytic fungi

“…Pairwise genetic distances of 1‐kb regions upstream of the coding sequence were calculated using mega‐cc 7 (Kumar, Stecher, Peterson, & Tamura, ) with the Kimura 2‐parameter model. Previous studies have indicated that transposons can insert in upstream regions (Butelli et al, ; Krishnan et al, ; Trizzino et al, ). To reduce the divergence bias caused by transposon insertions, we also calculated genetic distances after excluding 1‐kb regions that contain transposons.…”

“…Retained duplicate studies have indicated that transposons can insert in upstream regions (Butelli et al, 2012;Krishnan et al, 2018;Trizzino et al, 2017).…”