In Proterozoic oceans, unicellular ancestors of animals (holozoans) engaged in predator–prey interactions through phagocytosis—engulfing and digesting other eukaryotic cells. These encounters were not always lethal: prey sometimes escaped or damaged their predators, leaving behind cellular survivors bearing stress-induced genomic changes. We define “failed predation” as a predator–prey encounter in which engulfment occurs but digestion remains incomplete, allowing one or both participants to survive with varying degrees of cellular damage.

Unlike successful predation, which merely transfers energy, or failed capture, which leaves no lasting consequence, failed predation creates a unique selective scenario: survivors endure severe but non-lethal stress that may lead to heritable genomic alterations (Figure 1). This concept differs from the classical “frustrated phagocytosis,” a pathological process in modern immune systems where phagocytes encounter indigestible particles, leading to inflammation or cell death (Francis et al., 2022; Kzhyshkowska et al., 2015). In contrast, failed predation in our framework describes normal ecological interactions among unicellular eukaryotes, where incomplete digestion yields viable survivors carrying transmissible genomic changes rather than cellular dysfunction.

Such encounters likely produced an evolutionary feedback loop between phagocytosis and motility. Cells with higher motility could more effectively evade engulfment, while slower cells endured repeated predation stress, accumulating heritable genomic rearrangements that occasionally conferred new traits. Over evolutionary time, motility both shaped and was shaped by predation pressure—linking ecological behavior and genomic innovation within a single, self-reinforcing process. This framework extends traditional models of phagocytic interaction by embedding them within an ecological arms race, where motility emerged as the critical survival trait and a primary driver of evolutionary divergence.

Failed predation exposed both predator and prey to oxidative, enzymatic, and mechanical stress. Surviving cells activated repair pathways under extreme conditions—acidic pH, high reactive oxygen species, metal-catalyzed damage, and membrane rupture—that overwhelmed high-fidelity repair and triggered error-prone repair mechanisms such as non-homologous end joining (Anbar et al., 2007; Hanscom and McVey, 2020; Ratnaparkhe et al., 2018; Rodgers and McVey, 2016; Zhu et al., 2021). These stress-induced repairs produced bursts of chromosomal rearrangements, transposable element activation, and gene fusions—episodic genomic crises that accelerated variation generation. Unlike random mutation, these crises were ecologically triggered by failed predation, making variation frequency a function of encounter rate and motility.

The environmental backdrop likely intensified these effects. Mutation rates estimated from modern laboratory conditions (21% O₂, stable temperature) probably underestimate the potential for damage in ancient seas. Ediacaran–Cambrian oceans were relatively hypoxic (~2–10% PAL O₂), a condition that slows DNA-repair kinetics, while fluctuating temperatures and metal-rich waters promoted additional oxidative stress (Reinhard et al., 2016; Sperling et al., 2013). Under such conditions, the combined assault of acidification, oxidative radicals, and membrane rupture would have repeatedly overwhelmed high-fidelity repair, favoring rapid but inaccurate pathways that generated structural variants in bursts.

Importantly, even under normal circumstances, homologous recombination and replication stress can generate structural variation (Currall et al., 2013), but the cellular environment of failed predation created a far more extreme context. By concentrating multiple types of DNA damage within a narrow temporal window, it localized genomic instability without requiring globally deficient repair systems. In this way, failed predation acted as a naturally recurring, high-intensity generator of heritable genomic innovation—a cellular crucible where environmental stress, ecological interaction, and evolutionary potential converged.

Failed predation generated genetic variation through three complementary routes (Figure 1):

(A) Prey escape with damage—prey partially digested or oxidatively stressed during attempted engulfment underwent error-prone repair, yielding rearranged genomes (Blackford and Jackson, 2017; Chang et al., 2017; Ciccia and Elledge, 2010; Hakem, 2008; Lieber, 2010); (B) Predator disruption—prey damaged predator membranes, leaking lysosomal contents that mutagenized the predator’s genome (Pauwels et al., 2017); and (C) Transient cellular mixing—partial membrane fusion created temporary chimeras permitting DNA exchange and transposable element activation (Galhardo et al., 2007; Lanciano and Mirouze, 2018; McClintock, 1984; Slotkin and Martienssen, 2007; Soucy et al., 2015). Each pathway amplified heritable genomic diversity under ecological selection. Critically, the likelihood of each event scaled inversely with motility: highly motile cells avoided encounters, while low-motility cells endured repeated genomic reshuffling. The recurrent nature of these interactions transformed phagocytosis from a feeding mode into a genomic innovation engine.

After each failed predation event, survivor cells faced multiple selective filters centered on metabolic autonomy and replicative competence. Only those retaining both capabilities—”complete survivors”—could recover and re-enter ecological cycles (Figure 1). These cells had to stabilize damaged genomes, restore energy balance, and maintain sufficient biosynthetic capacity to reproduce (Caetano-Anollés et al., 2009; Eigen, 1971; Fani, 2012; Szathmáry and Smith, 1995).

Motility added a third, decisive filter. Fast-moving cells could escape engulfment, while slower cells were repeatedly exposed to predation stress and accumulated heritable mutations. Under these conditions, variants that enhanced adhesion and cooperation gained a selective advantage, favoring survival through aggregation rather than individual escape. Facultative colonies in choanoflagellates such as Salpingoeca rosetta show that adhesion toolkits predate animals, but these colonies remain transient because individual cells retain motility (Dayel et al., 2011; Fairclough et al., 2010).

In contrast, animal multicellularity is obligate and differentiated, marked by stable adhesion, division of labor, and loss of independent motility in most somatic cells. We suggest that this transformation reflects distinct selective environments: retentively motile lineages experienced only intermittent pressure to aggregate (Track 2, Figure 2), whereas motility-lost lineages faced continuous predation without escape, selecting for irreversible adhesion and tissue-level organization (Track 1, Figure 2). Multicellularity has arisen many times across eukaryotes, but what distinguishes animals is the evolution of persistent, integrated multicellularity that became advantageous only when individual motility was no longer viable.

This selection regime—genomic stabilization through survival and functional adaptation through motility loss—might structure early holozoan evolution, driving a deep bifurcation between motile unicellular persistence and sessile multicellular innovation. The balance between these selective pressures prefigured the evolutionary divide separating modern choanoflagellates and metazoans (Figure 2).

An additional trajectory led to parasitism (Figure 1). Some survivors failed to maintain metabolic autonomy but retained replicative capacity, evolving toward parasitic lifestyles dependent on host cells for nutrients and protection. These metabolic-negative, replicative-positive lineages represent an alternative outcome of failed predation, demonstrating how the same cellular encounter could yield divergent evolutionary paths depending on which functions endured (Figure 1). In this broader framework, failed predation acted not as a singular event but as a recurrent selective crucible—sorting cells into distinct fates of autonomy, cooperation, or dependency, each shaping the early diversity of eukaryotic life.

Predation-induced genomic instability supplied abundant raw material for selection, but the rise of animal multicellularity required a distinctive evolutionary route. We propose that a single lineage—the Unicellular-grade Holozoan Precursor (UHP)—served as the key intermediary linking failed phagocytic predation to the emergence of complex metazoan-grade multicellularity.

Among the heterogeneous survivors of failed predation, the UHP combined three traits rarely united in other holozoans: metabolic autonomy, replicative robustness, and high cell-level motility. These properties allowed persistent exposure to predation pressures while maintaining ecological independence. Under such conditions, repeated episodes of predation-induced stress produced cumulative genomic innovation, particularly in adhesion, polarity, and stemness toolkits—gene families repeatedly implicated in early animal multicellularity.

Importantly, this model distinguishes between the widespread, facultative multicellularity seen in extant choanoflagellates and the obligate, developmentally integrated multicellularity characteristic of animals. Like Salpingoeca rosetta, the UHP likely possessed a pre-existing ability to form temporary colonies; however, in lineages that became “unlucky” through loss of motility, escape from predators was no longer possible. In such sessile descendants, recurring failed predation acted as a potent molecular engine: stress-induced, error-prone repair promoted gene duplications, domain shuffling, and regulatory rewiring in adhesion modules. These changes favored stable, cohesive aggregates capable of damage repair, metabolic complementarity, and coordinated cell-cycle control—key transitions toward obligate multicellularity (Cohn, 2010; Hynes and Zhao, 2000; Nit et al., 2021; Zhang et al., 2021). Thus, animal multicellularity is hypothesized to arise not from de novo genetic invention but from reorganization and expansion of the UHP’s ancestral toolkit under persistent predation stress. The resulting mosaic genomic architecture may have predated the Cambrian and ultimately enabled the emergence of tissues, axes, and organ systems in crown-group animals (Figure 2).

We synthesize the preceding sections into the Predation–Motility Hypothesis, in which repeated cycles of failed predation generated bursts of genomic novelty, and motility determined which lineages experienced those events. The UHP represents the pivotal lineage in this feedback system. High-motility variants escaped frequent predation and remained largely unicellular, evolving into morphologically conserved choanoflagellate-like forms. Low-motility variants, by contrast, were repeatedly subjected to predation-induced stress, accumulating structural and regulatory innovations that enabled stable multicellular organization.

Comparative genomics supports this division: modern choanoflagellates exhibit high motility and conserved genomic architecture, whereas early metazoans show extensive chromosomal rearrangements, expanded adhesion and signaling gene families, and regulatory innovation. These differences trace back to contrasting evolutionary experiences within the same ancestral UHP framework. But sessile existence alone is not sufficient; it requires the genomic changes and ecological pressures proposed by the model. We emphasize that these predation–motility cycles achieved two things. First, they accumulated clustered structural variants near genes that later became essential for animal body-plan patterning. Second, they also generated latent developmental potential. This potential could subsequently be co-opted during the Ediacaran and rapidly elaborated during the Cambrian.

Mitochondrial endosymbiosis provides the most compelling empirical demonstration that phagocytosis can generate heritable, genome-wide innovation. Approximately 1.8–2.0 billion years ago, an α-proteobacterial ancestor was engulfed by a proto-eukaryotic host but escaped complete digestion, initiating extensive and heritable genomic restructuring within the host nucleus. More than 90% of the bacterial genome was transferred to the host nucleus through endosymbiotic gene transfer (EGT), while hundreds of bacterial-derived genes were integrated into novel eukaryotic biochemical and regulatory pathways (Gray, 2012; Martin et al., 2015; Timmis et al., 2004). Concurrently, mitochondrial DNA underwent rapid mutational change, deletion, and rearrangement, with ancestral gene orders still detectable in jakobids (Gray, 2012; Lang et al., 1997). This merger produced chimeric systems for transcription, splicing, and cell-cycle regulations that define modern eukaryotes (Koonin, 2015; Zaremba-Niedzwiedzka et al., 2017). These observations show that incomplete engulfment can trigger large-scale, heritable genomic transformation—the same class of cellular event proposed here for early holozoans during repeated failed predation.

Genomic analyses of early-branching animals—including sponges, ctenophores, and placozoans—reveal concentrated episodes of genomic reorganization marked by synteny breaks, chromosomal rearrangements, horizontal-gene-transfer candidates, and expansions of gene families for adhesion, signaling, and development. These patterns parallel expectations from the Predation–Motility Hypothesis: ancient holozoan cells engaged in phagocytic interactions that sometimes failed, exposing genomes to oxidative and enzymatic stress that promoted error-prone repair. These genomic changes are strategically concentrated within the developmental and stemness toolkit, featuring expansions of adhesion and signaling gene families that enabled new tissue organizations and body axes, coupled with regulatory rearrangements near key transcription factors that facilitated the evolution of novel gene regulatory networks for specialized cell types and structures (Sebé-Pedrós et al., 2017; Simakov et al., 2020). The resulting rearrangements might become heritable innovations, providing the raw material later amplified in the Cambrian. Collectively, these molecular signatures may represent “genomic fossils” of predation-driven stress and repair cycles—echoes of ancient ecological encounters that both relied on and re-shaped cellular communication networks (Erwin et al., 2011; Gladyshev et al., 2008; Simakov et al., 2013; Srivastava et al., 2010).

The cellular mechanisms central to our model—phagocytosis, DNA-damage repair, and membrane dynamics—are ancient eukaryotic features that long predate animal origins (Mills, 2020; Prorok et al., 2021; Zachar and Boza, 2020). Phylogenetic analyses indicate that phagocytosis arose or expanded multiple times during the Neoproterozoic, coinciding with holozoan diversification (Mills, 2020). When eukaryote-eukaryote engulfment failed, both predator and prey experienced acute oxidative and enzymatic stress, activating repair pathways—homologous recombination and non-homologous end joining—that could generate large-scale rearrangements (Chang et al., 2017; Dupré-Crochet et al., 2013; Hakem, 2008; Lieber, 2010; Yang et al., 2018). The outcome—clustered structural variants and novel gene fusions—is precisely what the hypothesis predicts. Thus, the molecular toolkit required for phagocytosis-induced genome remodeling was already present in the UHP lineage, awaiting ecological activation through recurrent failed predation.

Transposable elements (TEs) provide an additional, independently supported route by which stress during failed predation could produce heritable genomic change. TEs are ancient, widespread, and stress-responsive across eukaryotes (Gladyshev et al., 2008; Lanciano and Mirouze, 2018; Slotkin and Martienssen, 2007). Laboratory studies show that oxidative and DNA-damage stress can derepress TE silencing, generating transcriptional bursts and new insertions that restructure nearby chromosomal regions (Galhardo et al., 2007; McClintock, 1984). Because the enzymatic machinery for TE mobilization—reverse transcriptases, integrases, and small-RNA suppression pathways—was already present in the UHP’s ancestral genome, predation-induced crises could readily activate these elements. Each failed-predation event thus coupled physical DNA exchange with TE-driven insertional bursts, producing the clustered rearrangements observed in early metazoan genomes (Kapitonov and Jurka, 2008; Pritham, 2009; Rebollo et al., 2012; Slotkin and Martienssen, 2007).

Modern ecosystems provide mechanistic analogs for how predation drives accelerated evolution. Although direct evidence of heritable genomic change from failed eukaryote–eukaryote phagocytosis is lacking, analogous processes occur in microbial predators. The bacterium Bdellovibrio bacteriovorus and predatory myxobacteria exhibit extensive horizontal gene transfer and accessory-genome expansion linked to predatory lifestyles (Hobley et al., 2012; Phillips et al., 2022). Eukaryotic phagocytes also display oxidative DNA damage during feeding, while some prey—such as fungi—can survive engulfment via non-lytic exocytosis, occasionally exporting intact genetic material (García-Rodas et al., 2011; Kalafati et al., 2022; May et al., 2016; Zauberman et al., 2008). Predator–prey co-culture experiments further show rapid phenotypic and genomic shifts under predation stress (Matz and Kjelleberg, 2005). These examples confirm that predator–prey interactions can act as evolutionary accelerators, creating heritable variation above background mutation rates and illustrating the ecological plausibility of predation-induced genomic instability.

Two modern biological processes illuminate how cellular stress can generate heritable variation:

(1) Chromosomal instability in cancer shows that overwhelmed repair systems can produce catastrophic rearrangements and rapid adaptive diversification (Cesare and Reddel, 2010; Hanahan and Weinberg, 2011; Maciejowski and de Lange, 2017; Pickett and Reddel, 2015). Similarly, failed predation imposes concentrated oxidative and mechanical stress that biases repair toward error-prone pathways, creating clustered variants—a somatic-level analog of our mechanism. (2) Intracellular parasitism exemplifies alternative evolutionary outcomes of failed cellular engulfment. Many modern parasites persist within host digestive compartments, having evolved mechanisms to tolerate or evade phagolysosomal stress. These lineages typically lose metabolic autonomy while retaining replicative capacity—corresponding to the “metabolic–negative, replicative–positive” trajectory predicted by our model (Figure 1). Examples include Leishmania within macrophages (Carneiro and Peters, 2021; Hsiao et al., 2011; Huynh et al., 2006); phagocytosis-adapted biotrophs such as Phytomyxea and giant viruses that exploit host phagocytic machinery for entry and gene exchange (Aquino et al., 2024; Garvetto et al., 2023).

Collectively, these analogs reveal a continuum of outcomes arising from cellular crises: from cooperative multicellularity to parasitism. Though occurring in modern contexts, they affirm the plausibility that ancient phagocytic encounters could have produced viable, genetically divergent lineages—survivors that mobilized DNA, adapted to stress, and explored new evolutionary spaces much like those that eventually gave rise to animals.

Algae offer an instructive comparison. Although they occupied the same Neoproterozoic oceans as holozoans, most algal lineages were photosynthetic with rigid cell walls that prevented phagotrophic among themselves (Domozych et al., 2012; Leliaert et al., 2012). Lacking predator–prey interactions, they experienced lower oxidative stress and thus evolved primarily through gene and whole-genome duplications rather than recurrent chromosomal rearrangements (Qiao et al., 2019). This ecological contrast underscores a key prediction of the Predation–Motility Hypothesis: lineages shielded from phagocytic stress followed slower routes to complexity, while phagotrophic holozoans—subject to failed predation—underwent accelerated genomic innovation. Some mixotrophic algae, capable of both photosynthesis and phagotrophy, represent intermediate cases (Flynn et al., 2013).

The Cambrian radiation represents a polythetic evolutionary transition—one requiring multiple necessary but individually insufficient conditions to converge simultaneously. It reflects not only the sudden origin of novelty but also an ecological window that favored the retention and elaboration of variants accumulated during earlier cryptic evolution. It was a “Goldilocks” (enabling–amplifying) context created by a unique convergence of permissive conditions that boosted diversification within animal precursors rather than a single external trigger. This window amplified the effects of the repeated predation–selection cycles that had been operating throughout the Ediacaran. Critically, the Cambrian radiation occurred well above the phylogenetic node of multicellularity—which had been achieved hundreds of millions of years earlier in the Ediacaran (~900–635 Ma). The diversification is not about organisms becoming multicellular, but about multicellular lineages rapidly elaborating distinct architectural solutions: segmented versus non-segmented body plans, bilateral versus radial symmetry, jointed appendages versus parapodia, exoskeletons versus endoskeletons. These phylum-defining architectural features represent the outcome of Hox cluster rearrangements (referring to the Homeobox genes that control the body axis and segment identity in animals), regulatory network rewiring, and gene family expansion specific genomic changes with direct developmental consequences. The cellular predation-motility hypothesis addresses how cellular-level genomic stress generated these architectural variants throughout the Ediacaran, and why the Cambrian provided uniquely favorable conditions for their ecological elaboration and stabilization.

Three factors converged: First, preexisting genetic variation from Ediacaran cryptic evolution. Molecular clocks indicate that many animal lineages diverged in the Ediacaran yet remained ecologically cryptic and morphologically simple. Genomically altered UHP variants provided the biological substrate for later elaboration (Cunningham et al., 2017; dos Reis et al., 2015). These lineages already carried adhesion and stemness toolkits generated by predation-induced genomic reshuffling, ready to be redeployed once ecological opportunity arose.

Second, Resource Abundance and Physiological Capacity (The Intensity Amplifier): This factor represents the traditional view that rising oxygen levels, warm shallow seas, and phytoplankton expansion provided the physiological headroom for larger bodies and active metabolisms (Butterfield, 2007; Stockey et al., 2024; Zhang et al., 2014, 2025). However, in the context of our model, these conditions primarily acted as an intensity amplifier: (A) higher encounter rates accelerated the iteration rate of predation-induced genomic-stress cycles; and (B) greater physiological headroom supported the energetic cost of testing new, complex morphologies. The Cambrian was not merely a time of “more mutations” but specifically a time of more architecturally consequential genomic changes, generated at higher frequency through intensified predation stress and filtered through ecological selection for morphological disparity.

Third, Low Ecological Incumbency and Competitive Release (The Persistence Window): This factor also reflects the established understanding that simple Early Cambrian food webs offered low competitive exclusion (Budd, 2008; Butterfield, 2007; Stockey et al., 2024; Zhang et al., 2014). In our framework, this provided the essential persistence window for architectural variants (continuously generated through predation-induced genomic stress since the Ediacaran) to refine and stabilize. (A) Open niche space and (B) reduced predation pressure allowed incipient body plans the time to refine developmental programs before facing competition from more efficient forms.

The Cambrian’s low incumbency thus created an extended developmental “sandbox” where architectural variants—continuously generated through predation-induced genomic stress since the Ediacaran—could finally elaborate beyond simple prototypes into the phylum-level diversity observed in the fossil record. Additionally, the Cambrian arms race between predators and prey is selected specifically for morphological divergence rather than convergence. Rising predation pressure favored defensive innovations (exoskeletons, protective spines, burrowing), evasive strategies (directed swimming, rapid escape responses), and resource partitioning (different feeding modes accessed through different body architectures). This ecological context—where novelty itself conferred survival advantage—meant that different Hox cluster arrangements, symmetric patterns, and appendage architectures were all potentially viable solutions to the same ecological challenges. The result was divergent morphological evolution producing phylum-level disparity, rather than convergent evolution producing optimal solutions. This explains why the Cambrian generated multiple distinct architectural solutions (arthropod segmentation, molluscan modularity, chordate axial patterning) to the challenges of multicellular life, rather than a single optimal design.

Unlike modern oceans—characterized by high incumbency and complex predator–prey networks that block fundamentally novel entrants—the Cambrian offered ecological space for major innovations. Together, these conditions created a “Goldilocks” moment that enabled and amplified genomic innovation, yielding the observed diversification of animal body plans (Figure 2).

Two comparisons show why animal-like radiations are rare. First, Paleoproterozoic “non-radiation.” Despite the Great Oxidation Event (~2.4 Ga) supplying oxygen and productivity, no animal-like radiation occurred because the first eukaryotes (LECA)—and certainly UHP—had likely not yet evolved. This comparison confirms that geochemical change alone is insufficient to trigger a body-plan radiation (Betts et al., 2018; Brocks and Summons, 2003; Holland, 2006; Li et al., 2025; Zhang et al., 2014). Second, post-Cambrian ecosystems. Although the underlying molecular mechanisms (e.g., phagotrophy, DNA repair) persist and conditions still support large, active organisms, high ecological incumbency and complex food webs now raise an impassable barrier to founding new phyla. The capacity for macroevolutionary novelty—the formation of new phyla (disparity)—was uniquely available during the Cambrian’s low-incumbency window. In contrast, later diversification events, such as post-extinction radiations, generated massive increases in species diversity but generally occurred within the established architectural constraints of the phyla that originated in the Cambrian.

This asymmetry explains why only one major animal-like diversification occurred. By the late Ediacaran, UHP variants and possibly other mechanisms generated precursor cells had already passed the key genetic and cellular filters; Cambrian ecosystems then amplified their retention and elaboration. When the Cambrian “Goldilocks” emerged, it both (1) increased predator–prey encounter frequencies, raising the iteration rate of predation-induced genomic innovation, and (2) provided the ecological room for novel variants to persist long enough to elaborate into stable multicellular architectures (Figure 2).