Evolutionary landscapes of zygotic genome activation across animals

Israel Campo-Bes, Federica Mantica, Jon Permanyer, Cristina Rodríguez-Marin, Kero Guynes, Tòt Senar-Serra, Gonzalo Quiroga-Artigas, Yan Liang, Allan M. Carrillo-Baltodano, Josefa Cruz, Rossella Annunziata, Sandra Chevalier, Marta Iglesias, Fumiaki Sugahara, Yi-Jyun Luo, Anna Schoenauer, Jorge Corbacho, Periklis Paganos, Filomena Caccavale, Rosa Maria Sepe, Luis P. Iñiguez, Mette Handberg-Thorsager, Christina Zakas, Ralf J. Sommer, Maria Ina Arnone, Alistair P. McGregor, Juan R. Martínez-Morales, Noriyuki Satoh, Hector Escriva, Stéphanie Bertrand, Arnau Sebé-Pedrós, Enrico D’Aniello, Juan Pascual-Anaya, Evelyn Houliston, Xavier Franch-Marro, David Martín, Ildiko M.L. Somorjai, Isabel Almudi, José M Martín-Durán, Yi-Hsien Su, Alejandro Burga, Salvatore D’Aniello, Manuel Irimia

Posted on: 26 May 2026

Preprint posted on 17 April 2026

61 species, 13 phyla, one simple geometric rule that appears to set when every embryo starts speaking through its own genome.

Selected by Panagiotis Giannios

Categories: developmental biology, evolutionary biology

Why I highlight this work

Zygotic genome activation (ZGA) is one of the earliest fate-defining events in animal development: the moment when an embryo stops running on maternal supplies and starts using its own genome. Once the embryonic genome is on, gastrulation, patterning and organogenesis can begin, making ZGA the upstream gate of the entire developmental program. However, most of what we know about it comes from a handful of model organisms, and the timing in those species differs so much (one cleavage in mouse, fourteen in Drosophila) that it has been hard to tell which features generalise.

What I liked about this preprint is that it reframes ZGA from a species-specific puzzle into a problem in evolutionary developmental logic. Instead of asking how ZGA works in species X, the authors ask what every animal embryo has to solve at the start of development, and whether there is a common rule underneath. Their answer is unusually clean.

Background

After fertilisation, embryos are governed by maternally deposited mRNAs and proteins. At some point, different in every species, the embryo takes over. Classical work on zebrafish, Xenopus and Drosophila proposed that this happens when the nuclear-to-cytoplasmic (N/C) ratio passes a threshold, titrating out a maternal repressor (reviewed in Kojima, Hoppe & Giraldez, Nat Rev Genet 2025). Whether this idea also holds for mammals, nematodes, cnidarians or ctenophores has remained an open question.

Key findings

The authors built a transcriptomic atlas of early embryogenesis across 61 species spanning 13 phyla, and inferred ZGA timing using three complementary signals: a transcriptome-wide PCA shift, the appearance of strongly upregulated genes, and an increase in intron/exon read ratios as a proxy for nascent transcription. ZGA timing varied from 1 to 14 cell cycles, with strong phylogenetic signal (Pagel’s λ = 0.99). The headline result is that a simple proxy for the egg N/C ratio: log10(genome size / egg volume), predicts the cell cycle of ZGA onset with adjusted R² = 0.75. The authors propose a predictive equation, and the relationship is robust to every dataset split tested. Even when Arabidopsis and maize are added, the same line still fits.

The other surprise is at the gene level. ZGA genes share consistent properties across animals. They are short, intron-poor, phylogenetically young, and enriched for chromatin and RNA-processing functions, still their identities are almost entirely lineage-specific. Of all the orthogroups examined, only one is consistently activated at ZGA across every animal group: the FET family (FUS, EWSR1, TAF15), RNA-binding proteins involved in co-transcriptional RNA processing. Taken together: a deeply conserved physical timer drives a strikingly flexible molecular program. The same problem is being solved over and over with a different gene toolset.

Geometry sets the schedule: a stoichiometric principle for ZGA timing – A conserved quantitative logic for the start of embryonic transcription: (Left) Across animal species, the timing of zygotic genome activation correlates strongly with an egg nuclear-to-cytoplasmic proxy, defined as genome size divided by egg volume. Species with relatively more nuclear material per unit cytoplasm activate their genome earlier, while species with lower initial values activate later. (Right) The schematic illustrates how successive cleavage cycles progressively increase nuclear DNA content relative to a fixed volume of cytoplasm until a physical threshold for large-scale zygotic transcription is reached. Together, these panels support the idea that embryos with vastly different developmental programmes may nevertheless use a shared stoichiometric principle to time the transition from maternal control to zygotic autonomy.

Figure credit: Adapted from Campo-Bes, Mantica et al. (2026), Evolutionary landscapes of zygotic genome activation across animals, bioRxiv, CC BY 4.0. Selected panels (g,j) from Figure 3 were cropped and combined for clarity.

What this could mean

For me, the most interesting implication is that ZGA looks less like a conserved gene program and more like a regulatory window opened on schedule by physical accounting; a window that newly evolved, lineage-specific genes can colonise. That helps explain something that has been puzzling for a long time: how can a process so universal involve genes that overlap so little between species? If the timing is set by geometry, the cast of characters is free to change.

References

Kojima ML, Hoppe C, Giraldez AJ. The maternal-to-zygotic transition: reprogramming of the cytoplasm and nucleus. Nat Rev Genet. 2025 Apr;26(4):245-267. doi: 10.1038/s41576-024-00792-0. Epub 2024 Nov 25. PMID: 39587307; PMCID: PMC11928286.

bioRxiv 2026.04.16.718233; doi: https://doi.org/10.64898/2026.04.16.718233

Questions for the authors:

The N/C-ratio proxy beautifully explains ZGA timing across animals, but the molecular mechanism reading this physical timer remains an open question. Given your findings, do you suspect a conserved class of factors (such as histones) is being titrated across all species, or is it more likely that convergent evolution has led different lineages to use entirely different molecular effectors to read the same physical principle?
The FET family being the orthogroup consistently activated at ZGA across all examined clades is a striking result. Do you view these RNA-binding proteins as a minimal, ancestral “ZGA toolkit“? Furthermore, what specific mechanistic role do you hypothesize they play during this massive transcriptional awakening?
Your proxy metric relies on total egg volume, which in yolk-rich embryos is likely to overestimate the actual transcriptionally active cytoplasm. Do you have a sense of how much of the residual variance in your model (the remaining 25%) might be absorbed if we could accurately measure and substitute an “active cytoplasm” estimate for those specific clades?

Tags: animal evolution, arabidopsis, blastula, cnidarian, comparative transcriptomics, ctenophore, developmental timing, drosophila, early embryogenesis, egg volume, evo-devo, evolutionary developmental biology, fet family, fish, fly, frog, gastrulation, gene age, intron-exon ratio, maize, maternal-to-zygotic transition, metazoa, mouse, mzt, n/c ratio, nematode, nuclear-to-cytoplasmic ratio, oocyte, plants, rna binding proteins, sea urchin, transcriptomic atlas, worm, xenopus, zebrafish, zga, zygotic genome activation

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Author's response

Israel Campo-Bes, Federica Mantica and Manuel Irimia shared

1. The N/C-ratio proxy beautifully explains ZGA timing across animals, but the molecular mechanism reading this physical timer remains an open question. Given your findings, do you suspect a conserved class of factors (such as histones) is being titrated across all species, or is it more likely that convergent evolution has led different lineages to use entirely different molecular effectors to read the same physical principle?

It remains unclear at this point if a universal molecular mechanism, and if so which one, is responsible for detecting the DNA-to-cytoplasm ratio critical for ZGA. Various experiments suggest that histones per se do not determine ZGA onset in some lineages, such as mammals. However, we think it is likely that histones ancestrally played a role in the “universal” N/C timing mechanism. The titration model would indeed molecularly align with the N/C ratio model if the total pool of maternal histones deposited in the egg correlated with egg volume, but this is something that should be tested across species. These “reading” molecular mechanisms can nevertheless diverge and drift in different lineages, as long as adequate ZGA timing is maintained. Moreover, we do not claim that every species will necessarily follow this DNA-to-cytoplasm ratio logic, as some may have conceivably evolved strategies to evade it. As a rule of thumb, we would argue that the egg DNA-to-cytoplasm ratio provides the time window for ZGA and, once this is established, multiple molecular mechanisms and gene regulatory networks can evolve on top of it to solidify and fine-tune this timing. It is therefore not unexpected that, in some lineages, some of these mechanisms, such as activation by specific transcription factors, may become fully dominant.

2. The FET family being the orthogroup consistently activated at ZGA across all examined clades is a striking result. Do you view these RNA-binding proteins as a minimal, ancestral “ZGA toolkit”? Furthermore, what specific mechanistic role do you hypothesize they play during this massive transcriptional awakening?

This was indeed a surprising result. We would be cautious about arguing that FET proteins necessarily play the same role across all lineages, but given that they are highly conserved, multifunctional RNA-binding proteins, it is conceivable that they represent a fundamental component of the ZGA toolkit across animals. One possible role is that they regulate maternal RNA dynamics, including RNA stability, localization, and translation, which are essential for accurate ZGA onset and progression. Also, many maternally deposited or newly expressed chromatin remodelers, which could act as direct activators of genome awakening, may be evolving so rapidly that current orthogroup inference tools are unable to reliably identify their homologs across distant species. In our analysis, we focus on genes that are upregulated across animals, and these genes may not necessarily correspond to the very first activators of ZGA. Instead, they may be required to ensure that development proceeds correctly and to extend or stabilize genome activation during subsequent cell cycles. Therefore, while FET proteins may form part of a conserved ZGA-associated program, the initial trigger of genome awakening (the first “domino pieces” to fall) may still be maternally deposited. In this scenario, FET proteins could contribute to the broader regulation and maintenance of the ZGA transition.

3. Your proxy metric relies on total egg volume, which in yolk-rich embryos is likely to overestimate the actual transcriptionally active cytoplasm. Do you have a sense of how much of the residual variance in your model (the remaining 25%) might be absorbed if we could accurately measure and substitute an “active cytoplasm” estimate for those specific clades?

This is a very good point, and we mention it as a potential caveat of our study. We do think that a more accurate estimation of the transcriptionally “active” cytoplasm could explain an even higher proportion of variance in our model. If the yolk-containing portion of the cytoplasm does not contribute to the pool of ZGA activators or repressors, then it should ideally be excluded or corrected for in the model. This should be assessed systematically across species, although the magnitude of the improvement would likely vary across clades depending on egg architecture and yolk organization. For species with telolecithal eggs, such as fish and chickens, we could already exclude the yolk from our volume calculations because it is clearly segregated from the functional cytoplasm (i.e., concentrated at one pole). However, we have not yet corrected for the more homogeneous or non-localized yolk distribution found in species such as frogs, insects, and some other invertebrates, where distinguishing active cytoplasm from yolk-rich cytoplasm is much more challenging. Thus, refining estimates of active cytoplasmic volume across clades is likely to further improve the explanatory power of our model.

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