In a study published in Nature Genetics, researchers have unveiled a method to identify conserved regulatory elements in the genomes of birds and mammals that control heart development, even when these elements no longer share detectable DNA sequence similarity.
The research addresses a long-standing paradox in evolutionary biology: although the hearts of vertebrates develop in strikingly similar ways, driven by the same core transcription factors (TFs) and signaling pathways, the underlying regulatory DNA sequences that control these processes often show little to no conservation at the sequence level across species.
“Embryonic development is driven by deeply conserved sets of transcription factors (TFs) and signaling molecules… For example, in the developing heart, patterning and morphological changes are conserved across vertebrates. The same key TFs in cardiac mesoderm are required in the two-chambered hearts of fish and the four-chambered hearts of birds and mammals, arguing for a common gene regulatory basis of embryonic development,” the article explains.
Traditionally, researchers have relied on DNA sequence alignments to trace these regulatory elements, known as cis-regulatory elements (CREs), across species. But as genomes evolve, these sequences often mutate too extensively for such comparisons to work. This has led scientists to speculate that many regulatory elements may remain functionally conserved despite lacking recognizable sequence similarity.
The study proposes a different approach. Instead of focusing solely on sequence similarity, the researchers combined chromatin accessibility data, an indicator of active regulatory DNA, with a computational technique that maps corresponding regions between species based on synteny, or the conserved order of genes on chromosomes.
By applying this method to developing mouse and chicken hearts, the team identified thousands of regulatory elements they describe as “indirectly conserved” (IC). These elements maintain their functional role and genomic context despite having diverged significantly in DNA sequence.
Functional tests in live embryos supported the findings: IC elements activated gene expression in a heart-specific manner, much like their sequence-conserved counterparts. Further analysis showed that IC elements shared similar chromatin marks and arrangements of transcription factor binding sites, though in more shuffled configurations, likely explaining why sequence-based methods have failed to detect them.
The discovery highlights how evolution preserves regulatory function even when DNA sequences drift apart, and it suggests that much more of the regulatory genome may be conserved across species than previously recognized. The study may also have broader implications for understanding how genomes encode developmental programs, particularly in the context of human disease and evolutionary biology.
By shifting focus from sequence to function and genomic context, this work opens new avenues for identifying hidden regulatory connections across the tree of life.