Conservation and divergence in higher order chromatin structure
Chambers, Emily Victoria
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Aspects of higher order chromatin structure such as replication timing, lamina association and Hi-C inter-locus interactions have been recently studied in several human and mouse cell types and it has been suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and little is known about the characteristics of any divergent loci defined. Here we generate an orthologous dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between different mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the majority of the orthologous genome. This broad similarity is observed in spite of the substantial time since the species diverged, differences in experimental procedures among the datasets examined, and the presence of cell type specific structures at many loci. However, we also identify hundreds of regions showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. Divergent regions are enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in mammalian evolution. They are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions may underlie divergent regulation. Divergent regions show unusual shifts in compositional bias, sequence divergence and are unevenly distributed across both genomes. We investigate the mechanisms of divergence in higher order structure by examining the influence of sequence divergence and also many features of primary level chromatin, such as histone modification and DNA methylation patterns. Using multiple regression, we identify the dominant factors that appear to have shaped the physical structure of the mammalian genome. These data suggest that, though relatively rare, divergence in higher order chromatin structure has played important roles during evolution.