The evolutionary dynamics of regulatory DNA in the mouse and human genomes. J. Vierstra1, E. Rynes1, R. Sandstrom1, R. E. Thurman1, J. A. Stamatoyannopoulos1,2 1) Genome Sciences, University of Washington, Seattle, WA, 98195; 2) Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, 98195.

   We used DNaseI hypersensitivity mapping to systematically delineate mouse regulatory DNA across 44 diverse cell types and primary tissues. In total we identified >1.3 million mouse DNaseI hypersensitive sites (DHSs), of which >450,000 are also detected in human tissues at orthologous sequence positions. Of these, ~50% show tissue-selective activity patterns similar to their human counterparts. We find that this small regulatory compartment is densely populated by virtually known classes of lineage-specifying transcriptional regulators. However, when compared with the mouse genome, the human genome has undergone extensive rewiring of its cis-regulatory architecture along several axes, including sequence remodeling of individual regulatory DNA regions and changes in their patterns of tissue selectivity. The transcription factor composition of individual regulatory DNA elements has undergone extensive turnover, with <15% of transcription factor recognition sequences positionally constrained, corresponding to ~30% of regulatory elements with functionally conserved chromatin accessibility. These changes coincide with pervasive repurposing (lineage switching) of regulatory DNA, due chiefly to evolutionary innovation of specific transcription factor recognition sequences that drive tissue specificity. Analysis of species-specific DHSs in both mouse and human exposes a potential critical role for repetitive DNA in evolution of regulatory DNA. We find that ~50% of species-specific regulatory DNA has arisen due to the massive expansion of repetitive elements that these expansions have occurred asymmetrically in mouse and human. Furthermore, these repeat expanded regulatory regions contain the recognition sequences for many transcriptional regulators that in many cases account for up to 20% of the total binding sites within the accessible genome. Taken together, our findings delineate a core mammalian regulon and provide extensive insights into the genesis, extinction, and evolutionary perpetuation of mammalian regulatory DNA.

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