Back 2.8 billion years ago, while Earth shifted its plates to make new continents and violent volcanoes produced new crust, life crafted a novel invention of its own.1,2 At first, the nucleus was perhaps nothing more than a membrane to wrap around DNA, but it later became central to manifold functions in eukaryotic cells, from storing and replicating genetic information to transcribing genes and manufacturing ribosomes. “The nucleus gives the very word ‘eukaryote’ meaning,” said Christopher Kay, an evolutionary biologist at the University of Bristol.
Though eukaryotic life would look very different without the nucleus, scientists remain uncertain over the evolutionary beginnings of this organelle. With no fossils from nearly three billion years ago, researchers turn to living species and their genomes to search for clues about ancestral nuclei.
Turning Cells Inside-Out or Outside-In
All eukaryotes—from single-celled amoebae and yeasts to multi-cellular fungi, plants, and animals—trace their history to a single prokaryotic ancestor. This was a species of archaea, the lesser-known prokaryotic domain that contains organisms that resemble bacteria in appearance but have a genetic kinship with eukaryotes.3 By sequencing the genomes of different archaea, scientists have zeroed in on the Asgard archaea, which are profuse with signature eukaryotic genes, making them the closest prokaryotic relatives to the archaeal ancestor of the eukaryotes.4
Scientists have pondered over multiple models for how this archaeal ancestor produced the nucleus, two of which are called the “inside-out” and “outside-in” models.5 These models attempt to explain how eukaryotic cells ended up with a nucleus attached to a braided network of tubules running through the cell called the endoplasmic reticulum (ER).
The inside-out version suggests the archaeon shapeshifted in an outward manner, forming cell membrane protrusions that fused at their tips to produce a new outer boundary, which became the new cell membrane. Internal fusions produced the ER, which was attached to the original cell membrane that became the nucleus. “At the end of the day, the nucleus is just a sub-compartment of the ER,” said Sven Gould, an evolutionary cell biologist at Heinrich Heine University Düsseldorf.
In a recent bioRxiv preprint that has yet to be peer reviewed, Fraser MacLeod, a microbiologist at the University of Cambridge, spotted protrusions in a sample of Asgard archaea, providing evidence that this protrusion-based model could be viable.6 Prokaryotes don’t typically form protrusions of their cell membrane because they are enclosed within a rigid cell wall, but the Asgard archaea are exceptional. “The Asgard archaea don’t seem to have a crystalline surface protein, but they do have a protein density on the surface. To me, it resembles Velcro,” MacLeod said. Possibly this material is flexible enough to allow protrusions to form, or perhaps it breaks down to avoid getting in the way. His team has yet to characterize the mechanism underlying this process, but they are working on it.
Ancestral cells could have formed the ER and nucleus using protrusions or invaginations of the cell membrane.
Erin Lemieux, Adapted from Kamal Nahas
The outside-in model, on the other hand, suggests that the ancestral archaeon started out with a smooth surface that invaginated in multiple places around the cell. These structures then fused at their internal tips to fully enclose the DNA. “You make them encompass the DNA a little bit more until you entirely englobe the nucleus,” Kay said. As with the inside-out model, the invaginations could have partially fused along their lengths to produce the ER.
In addition to spotting protrusions that support the inside-out model, MacLeod also found vesicles in the Asgard archaea—another feature normally absent from prokaryotes.6 Vesicles could only form if they broke off from invaginations of the cell membrane, so they provide evidence that the cell membrane can internalize in these archaea. Using low-resolution fluorescence microscopy, “we did notice that in those samples there were a few vesicles—not in most cells, but a few in some cells,” he said. This prompted him to take a closer look with high-resolution cryo-electron tomography. “That's when we saw huge numbers of vesicles, and vesicles within vesicles,” he explained.
Looking at Asgard archaea under the microscope revealed that these species are capable of both protrusions and invaginations, suggesting that either model could work. However, Gautam Dey, a cell biologist at the European Molecular Biology Laboratory, pointed to a problem with the inside-out model. It doesn’t explain how eukaryotes acquired another feature that defines them: mitochondria.
Scientists believe mitochondria appeared when the eukaryotic ancestor took up a bacterium that evolved into the energy-producing organelles.7 However, the protrusion-forming inside-out model struggles to explain this uptake, according to Dey, because the bacteria would end up trapped within the ER. “That would mean that these bacteria would need to find a way to enter the cytoplasm. And this, of course, hasn't really been explained,” Dey said. It adds an extra step to the model that makes it seem less likely according to Occam’s razor, the philosophical argument that the simplest explanation is probably the right one.8
The outside-in model, conversely, suggests that cells evolved the ability to internalize content from their exterior. Bacteria often enter cells today via phagocytosis and break free from the vesicle that encages them, providing a view for how mitochondria could have emerged within eukaryotic cells.9
Homing in on the Original Function of the Nucleus
Modern nuclei have myriad functions, not limited to sheltering DNA from viruses or providing a compartment for genes to switch on or off by wrapping around histone proteins.5 These and many other roles of the nucleus make it challenging for scientists to pinpoint why this organelle originally emerged.
Studies in Asgard archaea suggest the nucleus may have evolved to uncouple transcription from translation.6 In nucleus-free prokaryotes, a ribosome will begin synthesizing protein from an mRNA transcript before it has been fully transcribed from a gene, coupling the two processes. In eukaryotes, however, the mRNA must finish forming in the nucleus before it can travel to the cytoplasm to meet ribosomes. This buffer period likely allowed for the evolution of the eukaryotic feature alternative splicing, whereby segments of mRNA are cropped out while still in the nucleus so that a single gene can code for multiple proteins.10 This expands the variety of gene products eukaryotes can make.
Asgard archaea also appear to decouple transcription from translation for unknown reasons, MacLeod said. “When they have protrusions, they often have their DNA localized to their cell body and then their ribosomes located in their protrusions,” he added. If the common ancestor of Asgard archaea and eukaryotes experienced a selection pressure to decouple transcription and translation, this may have driven the evolution of the nucleus.
Timing Mitochondria and the Nucleus with Molecular Clocks
Some scientists think the nucleus may have evolved in response to selection pressures imposed by mitochondria. “I was one of those people,” Kay said. One idea is that the nucleus shelters and protects DNA from reactive oxygen species produced by the energy powerhouses.11 Another theory is that the mitochondria provided a surge in the cell's energy supply that fueled the evolution of the nucleus. “If it was me as an engineer, I would get the mitochondria in first, and then the energy it generates permits the evolution of these more complex systems,” such as the nucleus and other eukaryotic organelles, Kay said.
To determine whether mitochondria played a role in the origin of the nucleus, Kay and his colleagues turned to molecular clock analysis. Each time the cell makes a compartment, like the nucleus or mitochondria, it needs to duplicate some genes to contribute to that compartment, so the goal was to pinpoint the timing of those duplication events and determine the order of appearance of organelles, Kay said. The duplications that led to the nucleus date back to 2.8 billion years ago, whereas those for the mitochondria trace back to only 2.4 billion years, meaning the two organelles debuted approximately 400 million years apart.1
“We have evidence for the formation of the nuclear compartment a good deal before the mitochondria—good enough that they probably don't overlap,” Kay concluded, ruling out the possibility that the nucleus evolved in response to the energy surplus provided by mitochondria. In fact, Kay thinks the energy budgets of prokaryotes and eukaryotes may not differ as much as previously thought. Though prokaryotes lack energy-demanding organelles, they use more energy to divide faster than eukaryotes.
Since the inside-out model implies that the nucleus evolved simultaneously with mitochondria as the cell protrusions wrapped around and enclosed bacterial endosymbionts, Kay is in favor of the outside-in model instead. “None of that requires the existence of a mitochondria. That's what makes our hypothesis a little new,” he noted.
Not everyone agrees that mitochondria’s involvement should be ruled out just yet. Since the molecular clock data has large error bars, Gould takes it with a pinch of salt. He argued that if the nucleus were present 400 million years before mitochondria, descendants of mitochondria-lacking eukaryotes should still exist today, but none have been discovered. “Why is it all gone, and the only ones that survived and have maintained their complexity are the ones that had mitochondria?” Gould asked. It seems unlikely to him that none of the nucleus-bearing, mitochondria-lacking eukaryotes would have stuck around.
In due course, MacLeod will explore other features hiding in Asgard microbes. “One thing that we're interested in is trying to cultivate different Asgard archaea with different degrees of evolutionary relationship to eukaryotes, so that we can really do comparative biology to try to understand what an ancestral population might have looked like.” As coverage breadthens and molecular clocks improve, scientists may get closer to deducing how the nucleus came to be all those millennia ago.
- Kay CJ, et al. Dated gene duplications elucidate the evolutionary assembly of eukaryotes. Nature. 2026;650(8100):129-140.
- Lubnina NV, Slabunov AI. Reconstruction of the Kenorland supercontinent in the Neoarchean based on paleomagnetic and geological data. Moscow Univ Geol Bull. 2011;66(4):242-249.
- Brown JR, Doolittle WF. Archaea and the prokaryote-to-eukaryote transition. Microbiol Mol Biol Rev. 1997;61(4):456-502.
- Zaremba-Niedzwiedzka K, et al. Asgard archaea illuminate the origin of eukaryotic cellular complexity. Nature. 2017;541(7637):353-358.
- Baum B, Spang A. On the origin of the nucleus: A hypothesis. Microbiol Mol Biol Rev. 2023;87(4):e00186-21.
- MacLeod FI, et al. An Asgard archaeon with internal membrane compartments. Biorxiv. 2025.11.06.686947.
- Fan L, et al. Phylogenetic analyses with systematic taxon sampling show that mitochondria branch within Alphaproteobacteria. Nat Ecol Evol. 2020;4(9):1213-1219.
- Coelho MTP, et al. A parsimonious view of the parsimony principle in ecology and evolution. Ecography. 2019;42(5):968-976.
- Moldovan A, Fraunholz MJ. In or out: Phagosomal escape of Staphylococcus aureus. Cell Microbiol. 2019;21(3):e12997.
- Weixlbaumer A, et al. Coupling of transcription and translation in Archaea: Cues from the bacterial world. Front Microbiol. 2021;12:661827
- Schavemaker PE, Muñoz-Gómez SA. The role of mitochondrial energetics in the origin and diversification of eukaryotes. Nat Ecol Evol. 2022;6(9):1307-1317.
