DSSS - Conservation of Gene Regulatory Domains with Highly Diverged Regulatory Elements Across Large Evolutionary Distances

Developmental gene expression is a remarkably conserved process and controlled by cis-regulatory elements (CREs) located within gene regulatory domains. These regulatory domains frequently overlap with conserved syntenic genomic regulatory blocks (GRBs) and Topologically Associating Domains (TADs). While CREs/enhancers can be conserved between distantly related species, the majority of enhancers lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that enhancers remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. I will present recent work in which we address this question by profiling the regulatory genome in the embryonic hearts of chicken and mouse at equivalent developmental stages. We developed a synteny-based algorithm, Interspecies Point Projection (IPP), which allows ortholog detection independent of sequence homology. Using IPP, we find up to 5-fold more orthologs than alignment-based approaches, suggesting widespread functional conservation of sequence-divergent CREs. Moreover, I will present our recent efforts in using methods from synthetic biology to replace entire regulatory domains from mouse with their chicken ortholog.