A comparative encyclopedia of DNA elements in the mouse genome has been developed by the Mouse ENCODE Consortium, mapping transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains across diverse mouse cell and tissue types. By comparing these data with the human genome, the study confirms substantial conservation in newly annotated functional sequences but also reveals significant divergence in transcriptional regulation, chromatin state, and higher-order chromatin organization. These findings highlight the wide range of evolutionary forces acting on genes and their regulatory regions, providing a resource for mammalian biology and human disease research. The study shows that while the mouse and human genomes share many protein-coding genes, there are substantial differences in their regulatory sequences. The mouse genome is pervasively transcribed, with 46% of its exonic nucleotides transcribed, compared to 39% in the human genome. The study identified 1.5 million DNase I hypersensitive sites (DHSs) and 2.1 million ChIP-seq peaks, revealing widespread transcriptional activities, dynamic gene expression, and chromatin modification patterns. These data also show that a large portion of the cis-regulatory landscape has diverged between mouse and human, although the magnitude of divergence varies across different classes of elements. The study also found that mouse and human transcription factor networks are more conserved than cis-regulatory DNA, and that species-specific regulatory sequences are enriched for particular classes of repetitive DNA elements. Chromatin state landscapes in both species are relatively stable, with developmentally stable and evolutionarily conserved chromatin domains. The study also identified that replication timing boundaries are conserved between mouse and human, with the highest conservation observed in boundaries preserved in multiple cell types. The study further shows that chromatin state maps can be used to identify potential sites for functional characterization in mouse for human GWAS hits. The results suggest that chromatin state maps can be used to identify potential sites for functional characterization in mouse for human GWAS hits. The study also found that large-scale chromatin domains are developmentally stable and evolutionarily conserved, with replication timing boundaries showing significant conservation between mouse and human. Overall, the study provides a comprehensive catalog of potential functional elements in the mouse genome, highlighting the differences and similarities between mouse and human genomes, and offering a valuable resource for mammalian biology and human disease research.A comparative encyclopedia of DNA elements in the mouse genome has been developed by the Mouse ENCODE Consortium, mapping transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains across diverse mouse cell and tissue types. By comparing these data with the human genome, the study confirms substantial conservation in newly annotated functional sequences but also reveals significant divergence in transcriptional regulation, chromatin state, and higher-order chromatin organization. These findings highlight the wide range of evolutionary forces acting on genes and their regulatory regions, providing a resource for mammalian biology and human disease research. The study shows that while the mouse and human genomes share many protein-coding genes, there are substantial differences in their regulatory sequences. The mouse genome is pervasively transcribed, with 46% of its exonic nucleotides transcribed, compared to 39% in the human genome. The study identified 1.5 million DNase I hypersensitive sites (DHSs) and 2.1 million ChIP-seq peaks, revealing widespread transcriptional activities, dynamic gene expression, and chromatin modification patterns. These data also show that a large portion of the cis-regulatory landscape has diverged between mouse and human, although the magnitude of divergence varies across different classes of elements. The study also found that mouse and human transcription factor networks are more conserved than cis-regulatory DNA, and that species-specific regulatory sequences are enriched for particular classes of repetitive DNA elements. Chromatin state landscapes in both species are relatively stable, with developmentally stable and evolutionarily conserved chromatin domains. The study also identified that replication timing boundaries are conserved between mouse and human, with the highest conservation observed in boundaries preserved in multiple cell types. The study further shows that chromatin state maps can be used to identify potential sites for functional characterization in mouse for human GWAS hits. The results suggest that chromatin state maps can be used to identify potential sites for functional characterization in mouse for human GWAS hits. The study also found that large-scale chromatin domains are developmentally stable and evolutionarily conserved, with replication timing boundaries showing significant conservation between mouse and human. Overall, the study provides a comprehensive catalog of potential functional elements in the mouse genome, highlighting the differences and similarities between mouse and human genomes, and offering a valuable resource for mammalian biology and human disease research.