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With the advent of next-generation sequencing technologies, a considerable effort has been put into sequencing the epigenomes of different species. The efforts such as “Encode” and “Roadmap” epigenomics projects provide an opportunity to compare epigenomes across species (especially between human and mouse). This study is an effort to understand how different histone modifications vary/co-appear between orthologous regions of the two species. In this work, we have used various measures of orthologous similarity between each pair of orthologous genes and explore how histone modifications are conserved with respect to changes in these similarity measures. These measures of similarity include “codon usage frequency similarity” (CUFS), Ka/Ks ratio and gene expression similarity. Our simulation indicates that evolutionary selection pressure of an orthologous pair (Ka/Ks ratio) is more strongly correlated with its histone modification than any other similarity measure. We also found that genes with low Ka/Ks have more similar histone profiles across species than the ones with high Ka/Ks, suggesting more differential regulation for genes with higher selection pressure.