🧬 Scientists Just Found a Hidden Layer of the Mammalian Genome

Our genes may be considerably more combinatorial than we realized.

Researchers have discovered that mammalian cells can take pieces of RNA copied from completely different genes — sometimes located on different chromosomes — and splice them together into a single messenger RNA. That hybrid RNA can then be used to manufacture a new protein containing parts encoded by both genes.

Using direct RNA sequencing, the team detected more than 30,000 candidate chimeric RNAs in mouse immune cells and more than 900 in human macrophages. Crucially, they then showed that at least one of these strange hybrids is not biological noise.

In mice, an inflammatory response causes two genes called Gsdmd and Tmem106a to combine into a chimeric RNA. Its resulting hybrid protein helps accelerate pyroptosis — the dramatic process in which infected immune cells rupture and release inflammatory signals. When researchers specifically blocked the hybrid protein, the mice became worse at controlling Salmonella infection. But they were also dramatically more resistant to lethal inflammation in a sepsis model.

Even stranger, inflammation appears to physically reorganize the genome: normally distant chromosome regions move closer together inside the nucleus, helping their RNA transcripts combine.

There is a major caveat. The detailed functional experiments were performed in mice. Similar chimeric RNAs exist in human immune cells, but scientists have not yet established what most of them do. The researchers themselves say it could take years to map their biological importance.

Still, if the phenomenon is widespread, our current catalogue of proteins may be missing an entire class of molecules hiding in combinations of genes we already thought we understood.

We finished sequencing the human genome more than two decades ago.

Apparently, reading the instruction manual was another problem entirely.

#Genetics #Biology #RNA #Genome #Immunology #Biotechnology #Science

https://www.nature.com/articles/s41586-026-10982-x

🧬 Life Uses 4 DNA Letters. Scientists Just Made 8 Work.

Every known organism on Earth writes its genetic instructions using the same four DNA letters: A, T, C and G.

Scientists have now shown that one of biology’s most fundamental molecular machines can read an alphabet containing eight.

Researchers tested E. coli RNA polymerase — the enzyme that reads DNA and turns its information into RNA — with synthetic DNA containing four additional chemical letters known as P, Z, B and S. Remarkably, the enzyme successfully recognized and transcribed the artificial base pairs using much of the same molecular machinery it employs for natural DNA.

Using cryo-electron microscopy at resolutions down to about 2.4 ångströms, the team could watch how the synthetic letters fit inside the polymerase. The artificial pairs adopted almost the same geometry as ordinary Watson–Crick DNA pairs, allowing the enzyme’s catalytic machinery to close around them and continue transcription. Researchers also engineered a modified version of one synthetic letter to reduce copying errors.

The implications are potentially enormous. A larger genetic alphabet could eventually produce RNA molecules with chemical capabilities unavailable to natural biology and might help scientists design new diagnostics, drugs and engineered biological systems. Expanded genetic alphabets have already been used experimentally to create molecules that recognize cancer cells.

But there is an important boundary: scientists have not created an eight-letter living organism here. The experiment demonstrates transcription by bacterial RNA polymerase; reliably replicating a full eight-letter genome and translating that expanded information into proteins inside living cells remain much harder problems.

For four billion years, life on Earth has been writing with four letters.

Apparently, biology’s machinery can read a bigger alphabet than evolution ever gave it.

#Genetics #DNA #SyntheticBiology #Biotechnology #RNA #Science

Primary paper — Nature Communications⁠