The biogenesis of multipass membrane proteins challenges the endoplasmic reticulum (ER) quality control, particularly when transmembrane segments contain polar or charged residues required for function. Fks1, the catalytic subunit of yeast β-(1,3)-glucan synthase, exemplifies this challenge because its large multipass transmembrane architecture must support glucan synthesis at the plasma membrane while also undergoing efficient biogenesis in the ER. Here, we investigate the cellular role of PBR1 (YNL181W), an essential gene whose role remains uncharacterized even though its predicted product has similarity to oxidoreductases. By integrating quantitative morphological profiling with global genetic interaction analysis, we found that PBR1 function converges on cell-wall biosynthesis and closely parallels that of FKS1. Partial loss of Pbr1 function caused temperature-sensitive growth defects but also impaired β-(1,3)-glucan synthesis, and weakened cell-wall integrity. Under these conditions, Fks1 failed to accumulate at the cell surface and, instead, accumulated in ER-associated compartments, where it exhibited reduced stability. Biochemical analyses revealed the accumulation of immature Fks1 species, including forms defective in glycosylation, consistent with compromised ER quality control. A spontaneous missense suppressor allele of FKS1 partially restored Fks1 stability and growth, supporting a functional relationship between the two proteins. Pbr1 is a cytosol-facing ER membrane protein that physically associates with Fks1, and structural modeling suggests that it adopts a Rossmann-like fold capable of binding pyridine nucleotides despite divergence from canonical catalytic motifs. Together, these findings identify Pbr1 as an ER-associated, chaperone-like factor required for the folding and maturation of Fks1.
Obesity-related type 2 diabetes (T2D) is currently defined by insulin resistance and impaired insulin secretion. Sulfonylureas, thiazolinediones, and insulin are effective at lowering glycemia yet have not consistently translated into improved long-term outcomes. In contrast, recent interventions often produce metabolic benefits that exceed expectations based on glucose lowering alone. These contrasting observations suggest that our understanding of T2D pathophysiology is incomplete. We propose that, in obesity-related prediabetes and early T2D, insulin resistance, attenuated glucose-stimulated insulin secretion, modest hyperglycemia, and glucosuria represent beneficial functional changes in response to nutrient excess. These allostatic adaptive responses limit glucose flux into metabolically vulnerable tissues and reduce nutrient stress (nutri-stress). From this perspective, T2D is not simply a failure of glucose regulation but a coordinated systemic allostatic response to chronic energy excess aimed at preserving metabolic homeostasis. Therapeutic success may depend not only on lowering glycemia but also on how interventions alter tissue-specific glucose handling and metabolic stress.
Most Mendelian diseases lack effective treatments, with current options often limited to symptomatic care rather than addressing the underlying genetic defect. In this opinion article, we argue that genetic suppressors, a specific class of modifier variants that can counteract the effects of disease-causing mutations, can identify promising new avenues for therapeutic intervention. We discuss the prevalence of potential suppressors across Mendelian diseases, describe approaches for their systematic identification, and consider their therapeutic relevance. As genome-wide screening technologies and machine learning methods continue to advance, we expect suppressor identification to accelerate in the near future. These suppressors present exciting opportunities for expanding our therapeutic arsenal and improving outcomes for individuals with inherited disorders.
Differences between partner gametes, which evolved repeatedly in eukaryotes, can contribute to the evolution of the sexes, sexual selection, and non-Mendelian inheritance. Yet, the empirical evidence for how functional asymmetries arise between initially equivalent gametes is limited. Here, we combine theoretical and experimental approaches in the fission yeast Schizosaccharomyces pombe to show how selective pressures acting concurrently on gametes and zygotes drive the evolution of gamete differences. We find that despite being morphologically identical, P- and M-type partner gametes invest asymmetrically in zygotic development by contributing different amounts of conserved meiotic cohesins. P-gametes preferentially produce the Rec8 cohesin that increases zygotic fitness but reduces gamete viability, revealing a trade-off between reproductive success and gamete survival. We demonstrate that this asymmetry is mediated by partner-specific communication and model its evolutionary dynamics using empirically determined parameters. Our results support classical theoretical predictions for the evolution of gamete differences and provide a mechanistic understanding of how molecular asymmetries between partners can originate from opposing selection pressures acting in species that lack morphologically distinct gametes.
A humble yeast cell is helping scientists answer a 50-year-old question: how did one partner evolve to invest more than the other?
Caption: The images show a pair of visually indistinguishable fission yeast gametes (left) that fuse to form a zygote (right). The schematic shows the evolutionary model used to explore how gamete asymmetries arise between initially equal partner cells. Credit:Vjestica lab, Center for Integrative Genomics, University of Lausanne, Switzerland Copyright: CC BY-NC
In a lab incubator in Lausanne, Switzerland, a single-celled yeast is doing something that looks, under a microscope, like an act of a caring parent.
It is a single cell — no eyes, no brain, not even sexes in the way we usually think of. And yet, in the moments it courts a mate, it begins manufacturing a protein it may never get to use — a protein that will help its future offspring thrive, but that could kill it if the mating attempt fails.
This is Schizosaccharomyces pombe fission yeast, an organism that most of the time reproduces by simply dividing in two. But when it decides to find a partner and reproduce sexually, it reveals a clue to one of biology’s oldest question: how, across the kingdoms of eukaryotes, did sex repeatedly evolve unequal roles for the two partner cells — one investing enormously (think of a chicken’s egg, or fruits of a date palm) and the other investing comparatively little (a sperm cell, or a pollen grain)?
A new study, just published by researchers at the University of Lausanne and the Francis Crick Institute in London, gets us ever closer to an answer. And remarkably, it does so using this simple yeast that doesn’t even have sexes — just two mating types, humbly named “P” and “M”, that look completely identical to each other.
Evidence for a 50-Year-Old Idea
The textbook explanation for why egg and sperm cells evolved to be different traces back to 1972, to a theory proposed by biologists Geoff Parker, Robin Baker and Vic Smith. Their idea, elegant in its simplicity, goes like this: reproductive cells (gametes) face two competing interests when it comes to cell size: Make your gametes big and nutrient-rich, and you give your offspring the best possible start — but you can only afford to make a few of them. In contrast, make your gametes small and cheap, and you can make millions — but each one offers little to the offspring.
Over evolutionary time, the theory goes, the tension between the benefits and costs of cell size pushes partner gametes into two extremes: large, investment-heavy gametes (which we’ve come to call “egg cells”) and small, numerous, low-investment gametes (“sperm cells”). It’s a beautiful idea. The trouble is the proposed competing forces are difficult to observe and measure in a living organism — let alone catch them in the act of shaping gamete evolution.
That’s what makes the new study so exciting. The two teams of researchers didn’t just propose another model. They found a real, measurable trade-off, in a real organism, and then showed mathematically that it may, by itself, favour evolution of gametes where one partner invests more than the other.
Meet the Cohesin: Chromosome Organizer
To understand the discovery, you need to meet one VIP. The very important protein Rec8.
When any organism — yeast, fly, or human — reproduces sexually, it must undergo meiosis. During this process chromosomes have to be copied, paired up, and then carefully sorted so each offspring gets exactly the right amount of genetic material. A set of proteins responsible for guiding the chromosomes through this delicate process are called meiotic cohesins, and in many organisms, including fission yeast, one of them is named Rec8. Think of Rec8 as a molecular organizer, loaded onto chromosomes before they’re copied, keeping them in order and ensuring they are eventually neatly sorted. Too little Rec8, and chromosomes end up getting mixed up and incorrectly divided between the offspring — a problem that even in humans might may cause sterility.
The lead author of the study, Celso Martins, tells us with a grimace of surprise how he noticed something strange while watching fission yeast mate with a 100-fold magnification: “You see, the P- and M-cells are indistinguishable when you visualize them in plain light. But when using a method to look how they are making Rec8, I was stunned that the P-type cells reliably started making Rec8 first, much more and before their M-type partner” . This wasn’t a fluke of one experiment; it held up across hundreds of mating pairs, and across several related genes involved in the same chromosome-sorting machinery.
But how would two seemingly “identical” cell types manage to behave differently?
A Head Start for the Offspring
The researchers traced the asymmetry to the way partner cells communicate to each other. As gametes search for a mate, they release and detect pheromones — a kind of scent-based conversation. The team found that P-cells are more strongly activated by their M-partner’s pheromone, which switches on a cascade of genes, Rec8 among them, earlier and more forcefully in the P-cell. When the researchers deleted the relevant pheromone genes, the entire pattern flipped: M-cells became the early, high-volume Rec8 producers instead of P-cells. This suggested that it doesn’t matter which parent is producing Rec8, and raised the question does the early start in Rec8 production matter at all?
The answer is yes, and Aleksandar Vještica who supervised the Lausanne team explains why: “When sex culminates in fusion between the two yeast partners, the newly formed cell — now called a zygote — rushes into the delicate meiotic process of copying and sorting its chromosomes for the next generation. This is done so quickly that there’s barely any time to manufacture the Rec8 cohesin “organizer” once fusion happens and most of it has to already be on hand”. Consistent with that idea, when they prevented Rec8 production in the P-cell, the chromosome sorting in zygotes became faulty and the resulting offspring was dramatically less likely to survive. This contrasts the experiments where preventing M-cells from making Rec8 did not cause any defects. Thus, it turns out that that the early-arriving P-cell supply of Rec8 isn’t a curiosity. It’s doing the heavy lifting that makes successful reproduction possible.
The Cost of Being Prepared
If making Rec8 is good for the offspring of sexual reproduction, then why don’t both P- and M-cells make it? Here is where the story takes its sharpest turn — and where the deeper evolutionary question finally gets an answer.
Making Rec8 before mating is a gamble. It pays off handsomely if a partner is found. But fission yeast mating, like dating in any species, doesn’t always go smoothly. Some cells engage in courtship, start producing Rec8 in anticipation of fusing with a partner — and then are abandoned, or out-competed by a rival for the same partner.
When the researchers tracked what happens to these “jilted” cells, the results were striking. Gametes that had switched on Rec8 but failed to fuse were roughly ten times more likely to stop growing or die altogether. Rec8, the molecular organizer that guides chromosomes through sexual reproduction, turns out to be dangerous when deployed outside sex — it scrambles the chromosomes when a cell tries to reproduce by dividing. And because P-cells are the ones predisposed to switch Rec8 on early, they bear the brunt of this cost. The team confirmed this with a clever long-term experiment: when they let populations of P- and M-cells repeatedly mate, the proportion of P-cells in the population steadily decreased — unless the Rec8 gene was deleted entirely, in which case neither mating type had any advantage.
In other words, P-cells pay a real, measurable price for their investment toward the next generation in the form of Rec8.
Real Numbers Bridge the Trade-Off and the Theory
Discovering a cost and a benefit is one thing. Showing that this single trade-off is consequential for the evolution of asymmetry between two mating types is another challenge entirely — and it’s where the Crick Institute’s theoretical biologist Zena Hadjivasiliou came in: “I have been interested since my doctoral studies in how asymmetries in sexual reproduction evolve. Thus, I was very excited when the Lausanne team contacted us and shared their findings. They caught an organism in the very earliest stages of gamete asymmetries, which allowed them to experimentally manipulate and even measure the costs and benefits of the asymmetric factor. We immediately started to build a mathematical framework that captures the lifecycle of the fission yeast, and identified what are the important behaviours that we would need to quantify together and provide new, molecular evidence for this powerful, 50 years-old idea on how sexes evolve”.
The Crick team built a mathematical model of the yeast life cycle and let virtual populations evolve over thousands of generations. The model asked a simple question: starting from two mating types that invest identically, will natural selection favour one type investing more than the other?
The answer was yes — but only under specific, identifiable conditions as explained by Harry Booth who carried out the mathematical analyses: “When sex is reasonably likely but not certain to succeed and the total benefit of Rec8 to a zygote is large enough, the model showed that symmetric investment becomes an unstable strategy. This is because it exposes both partners to a high risk of dying if the mating fails. Instead, populations evolve toward one partner investing heavily and the other holding back to reduces the overall risk of death”. The teams then experimentally measured costs and benefits of Rec8 as real input obtained from living fission yeast cells. They introduced these findings into their model to see that the real-world numbers landed squarely inside the zone where the asymmetry evolves.
Why a Humble Yeast Matters
Every plant and animal with separate sexes — including humans — descended from ancestors that, at some point in deep evolutionary history, had gametes much like the yeast: identical in size and shape and with no obvious reason to specialize. Something pushed those ancestor gametes toward divergence, toward the enormous asymmetries we see today between egg and sperm cells. That differentiation between gametes shaped much of subsequent evolution of the sexes and how parents influence their offspring. For example, in humans, whether a gene is switched on or silenced can depend on which parent it came from — a phenomenon called parental imprinting. Some genes only function when inherited from the mother, others only from the father and that parent-of-origin logic begins, at its root, with the asymmetry between gametes.
While the seminal work of Parker, Baker and Smith provided a powerful idea, this study offers the direct, mechanistic evidence for how asymmetries between partner gametes can begin to mount — not through some dramatic mutation that makes one gamete suddenly larger, but through a subtle molecular trade-off: a single gene that helps the next generation but endangers the parent who supplied it. A quantum of parental care.
The study, “Meiotic cohesin Rec8 imposes fitness costs on fission yeast gametes favoring the evolution of parental bias in gene expression (link)” was conducted by researchers at the Center for Integrative Genomics, University of Lausanne, and the Mathematical and Physical Biology Laboratory at the Francis Crick Institute, London, in collaboration with University College London. It is now available in the journal Proceedings of the National Academy of Sciences (PNAS). The authors thank the funders at the Swiss National Science Foundation (Eccellenza grant PCEFP3_187004/1), the European Research Council (grant 949914, ZygoticFate), the University of Lausanne, the European Molecular Biology Organisation (ALTF 89-2022), and the Francis Crick Institute, whose core funding comes from Cancer Research UK, the UK Medical Research Council, and Wellcome.
