Recent origins and hidden diversity of cis-regulatory elements in mammals

Elaborating evolution pattern of cis-regulatory elements (CREs) situated within the broad non-coding regions are fundamental for understanding of genetic regulation across species. Here we surveyed active enhancers and promoters in brain, kidney and liver of 22 non-model mammalian species. Our analyses reveal that more than half of these regulatory elements exhibit pleiotropy both within and across tissues and species. Notably, species-specific enhancers and promoters predominantly originate from recently evolved DNA sequences, and increased gene regulatory complexity correlates positively with expression stability. Further exploring the common pattern of CREs reveals that both the diversity and abundance of these regulatory elements in mammalian genomes have been significantly underestimated. This study aligns CRE activity across diverse tissues and taxa, challenging the prevailing notion of overestimated tissue-specificity stemming from limited sampling.