Ants have evolved an acute sense of smell, which requires each sensory neuron to choose one scent receptor out of hundreds. In a new study published in Nature, researchers at New York University have discovered what ants use to solve this biological puzzle: a self-regulating system in which choosing one gene physically silences all its neighbors.
A high-stakes sense of smell
Ants communicate via pheromones to hunt, detect outsiders, and determine their role within a colony. Without precise control of olfactory receptors, ant society would unravel. When ants cannot smell, "they stop performing their duties, which leads to anarchy," explained Bogdan Sieriebriennikov, the first author of the study and a former postdoctoral researcher at NYU. "These ants get confused and attack each other. It starts with lack of communication and ends in catastrophe."
For this purpose, ants have evolved up to 500 olfactory receptor genes.
"Ants have a better sense of smell than us," noted Claude Desplan, a Silver Professor of Biology at NYU and the lead author of the study.
All animals, from insects to humans, need to ensure a single olfactory gene is active per neuron. In flies, the genome encodes the fate of each receptor neuron to express a unique receptor gene. Mice, who have more than 1,000 olfactory receptor genes, employ a complex system of random choice to specify a single active receptor in each neuron.
How do ants with several hundred genes switch on only the correct odor gene in the correct neuron? Finding an answer is challenging as ant olfactory genes are present in genomic clusters of up to 59 genes. The scientists began to uncover their solution by creating a map of gene activity for each neuron.
"Some cells expressed only the last gene of the cluster, others expressed the last two, others expressed the last three, and so on," described Sieriebriennikov. "It looked like a staircase and provided a clue to a new mechanism."
Evolution achieved this elegant result with "bulldozers"
Normally, transcription (where the DNA information is converted into messenger RNA to make proteins) stops at the end of each gene. Yet in genomic clusters of ant receptors, the machinery does not stop, continuing through all the downstream odor genes. Sieriebriennikov compared this to a "biological bulldozer" running relentlessly.
"Instead of stopping at the end of each gene, the transcriptional machinery keeps going. This runaway machinery drives through the fence and into all downstream genes, preventing the transcription machinery there from activating them," he said.
But what represses genes located upstream of the chosen receptor gene? The team discovered that the chosen gene also makes an RNA in the opposite direction (antisense RNA), with the bulldozer running the other way and preventing transcription of upstream genes. Therefore, once a gene is chosen by chance, it triggers a chain reaction turning off all its neighbors.
"The 'runaway bulldozer' is not an economical way of controlling genes," noted Sieriebriennikov. "But it happens a lot during evolution: When nature finds a solution that relies on chance but does its purpose, it stays."
"This beautiful yet unexpected mechanism tells you how nature can invent a new system to respect the 'one gene in each receptor neuron' rule," noted Desplan.
The 'chance but effective' solution may have parallels in humans. The wiring of our own brains depends on protocadherin genes which also exist in genomic clusters and follow a 'one gene per neuron' rule to ensure neurons connect correctly.
"Protocadherin genes also use antisense transcription to control how the chosen gene prevents expression of all others," explained Sieriebriennikov. "This is a striking case of convergent evolution. Ants and humans are very distant relatives, but when nature faces a similar problem, it may find a similar solution."
"This mechanism is an example of nature's efficiency, if not economy," said Olena Kolumba, a PhD student at NYU and the second author of the study. "What we call the 'bulldozer' is a clever, simple solution to the complex problem of choosing one gene. The fact that evolution landed on a similar logic for human protocadherins suggests it is a fundamental principle of gene regulation."
For Sieriebriennikov, the discovery shows the importance of embracing the unexpected.
"You might assume weird signals in the data are just noise," he said. "However, when we pay attention to the unusual, weirdness gets explained, leading to interesting discoveries."
Other study authors include Aurore de Beaurepaire, Jennifer Wu, Valentina Fambri, Eva Bardol, Yuwei Zhong, and Ildar Gainetdinov of NYU; Danny Reinberg of the University of Miami; and Hua Yan of the University of Florida. This research was supported by the National Institutes of Health (K99DC021991, R01AG058762, R01EY13010, R01DC020203), Tamkeen under the NYU Abu Dhabi Center for Genomics and Systems Biology (ADHPG-CGSB), and the Human Frontier Science Program (LT000010/2020-L).
