Research Indicates Long-range Gene Regulation Evolved Over 650 Million Years Ago

Distal regulation—the capacity to control genes across vast distances, spanning tens of thousands of DNA letters—emerged during the early stages of animal evolution, approximately 650-700 million years ago (the Kleigenian era).

Distal adjustment relies on the physical folding of DNA and proteins, along with intricate loops.

This mechanism enables regions distant from a gene’s starting point to activate their functions.

This additional regulatory layer may have assisted the first multicellular organisms in developing specialized cell types and tissues without necessarily inventing new genes.

Key innovations likely originated from marine creatures or common ancestors shared by all existing animals.

Ancient organisms developed the ability to fold DNA in a controlled manner, forming 3D loops that facilitated direct contact between different segments of DNA.

“These organisms can utilize their genetic toolkit in various ways, akin to a Swiss Army knife, which allows them to fine-tune and explore innovative survival strategies,” explains Dr. Nacional Accidental Accidental Genmica, a postdoctoral researcher at the Center for Genome Regulation.

“I was surprised to find that this level of complexity dates back so far.”

Dr. Kim and his team discovered these insights by examining some of the oldest branches of the animal family tree, including species such as walnut-shaped comb jellies (Mnemiopsis leidyi), placozoans, cnidarians, and sponges.

They also investigated single-celled relatives that share a common ancestor with animals more recently.

“Studying unique sea creatures enables us to uncover much new biology,” states Professor Arnau Sebe-Pedrós, a researcher at the Center for Genome Regulation.

“Previously, we focused on comparing genomic sequences, but thanks to new techniques, we can now analyze the gene regulatory mechanisms that influence genomic function across species.”

A large individual of Mnemiopsis leidyi with two aboral ends and two apical organs. Image credit: Jokura et al., doi: 10.1016/j.cub.2024.07.084.

Researchers applied a method known as Micro-C to map the physical folding patterns in each of the 11 types of DNA analyzed. To provide context, each human cell nucleus contains approximately 2 meters of DNA.

Scientists sifted through 10 billion sequencing data points to create detailed various 3D genome maps.

Although no evidence of distal regulation was found in single-celled relatives of animals, early branches such as comb jellies, placozoans, and cnidarians exhibited numerous loops.

Over 4,000 loops were identified across the genome, particularly in the sea walnut.

This discovery is remarkable considering its genome consists of roughly 20 million DNA characters.

In contrast, the human genome contains 3.1 billion characters, with our cells housing tens of thousands of loops.

Previously, distal regulation was believed to have first emerged in the last bilateral ancestors, which appeared on Earth around 500 million years ago.

However, the comb jelly’s lineage branched off early from other animal lineages roughly 650-700 million years ago.

“The debate over whether the comb jelly predates the sponge in the tree of life has persisted in evolutionary biology, but this study suggests that distal regulation occurred at least 150 million years earlier than previously thought,” the authors concluded.

A paper detailing these findings was published today in the journal Nature.

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IV Kim et al. Chromatin loops are characteristic of the ancestors of animal regulatory genomes. Nature Published online on May 7, 2025. doi:10.1038/s41586-025-08960-W