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Physics-tailored machine learning reveals unexpected physics in dusty plasmas
Dusty plasma is a mixture of ions, electrons, and macroscopic charged particles that is commonly found in space and planetary environments. The particles interact through Coulomb forces mediated by the surrounding plasma, and as a result, the effective forces between particles can be nonconservative and nonreciprocal. Machine learning (ML) models are a promising route to learn these complex forces, yet their structure should match the underlying physical constraints to provide useful insight. Here, we demonstrate and experimentally validate an ML approach that incorporates physical intuition to infer force laws in a laboratory dusty plasma. Trained on 3D particle trajectories, the model accounts for inherent symmetries, nonidentical particles, and learns the effective nonreciprocal forces between particles with exquisite accuracy ( R 2 > 0.99). We validate the model by inferring particle masses in two independent yet consistent ways. The model’s accuracy enables precise measurements of particle charge and screening length, identifying large deviations from common theoretical assumptions. Our ability to identify unknown physics from experimental data demonstrates how ML-powered approaches can guide new routes of scientific discovery in many-body systems. Furthermore, we anticipate our ML approach to be a starting point for inferring laws from dynamics in a wide range of many-body systems, from colloids to living organisms.
Data-driven equation discovery reveals nonlinear reinforcement learning in humans
Computational models of reinforcement learning (RL) have significantly contributed to our understanding of human behavior and decision-making. Traditional RL models, however, often adopt a linear approach to updating reward expectations, potentially oversimplifying the nuanced relationship between human behavior and rewards. To address these challenges and explore models of RL, we utilized a method of model discovery using equation discovery algorithms. This method, currently used mainly in physics and biology, attempts to capture data by proposing a differential equation from an array of suggested linear and nonlinear functions. Using this method, we were able to identify a model of RL which we termed the Quadratic Q-Weighted model. The model suggests that reward prediction errors obey nonlinear dynamics and exhibit negativity biases, resulting in an underweighting of reward when expectations are low, and an overweighting of the absence of reward when expectations are high. We tested the generalizability of our model by comparing it to classical models used in nine published studies. Our model surpassed traditional models in predictive accuracy across eight out of these nine published datasets, demonstrating not only its generalizability but also its potential to offer insights into the complexities of human learning. This work showcases the integration of a behavioral task with advanced computational methodologies as a potent strategy for uncovering the intricate patterns of human cognition, marking a significant step forward in the development of computational models that are both interpretable and broadly applicable.
Serum metabolic patterns reveal the diagnostic and prognostic role of alanine abnormality in ocular adnexal lymphoma
Ocular adnexal lymphoma (OAL) is the most common orbital malignancy in adults. Advanced tools for precise diagnosis and prognosis of OAL are in demand. Here, the nanoparticle-enhanced laser desorption/ionization mass spectrometry was applied for the construction of OAL-associated serum metabolic patterns (SMPs) from 239 participants (104 OAL and 135 non-OAL). Through machine learning, the diagnostic performance with an area-under-the-curve (AUC) of 0.901 was achieved for OAL based on SMPs. Furthermore, a diagnostic metabolic panel was constructed with an AUC of 0.875. Moreover, a prognosis scoring system was built and its desirable prediction efficacy for progression-free survival of OAL was confirmed ( P < 0.05). Specifically, the decreased serum alanine level was found to play both vital roles in the diagnosis and prognosis of OAL, and we demonstrated that uptake of alanine promotes glycolysis and cell growth in lymphoma cells. Our study highlights the value of the serum metabolite biomarkers in the clinical management of OAL.
How cancer arises: Genetics releases, plasticity creates, genetics stabilizes
Cancer is the origin of a novel tissue that attracts resources, spreads beyond boundaries, avoids normal controls, and escapes immunity. How does a novel tissue arise? The puzzle is that two seemingly different processes appear to be the primary driving force. On the one hand, overwhelming evidence links (epi)genetic driver mutations to the origin and progression of tumors. Common oncogenic mutations such as KRAS accelerate cell division, and common knockouts of tumor suppressors such as TP53 abrogate cell death or checks on cell division. On the other hand, cancerous tissues create complex traits that require intricate changes in cells and multiple interactions between different cell types. Such novelty often arises by hijacking the developmental plasticity that normally creates the diverse cells and tissues of our bodies from a single original zygotic cell. How can we reconcile the simple genetic changes in carcinogenesis with the complex developmental plasticity that creates novel tissues? This perspective advocates a new model. (Epi)genetic mutations release developmental plasticity. That developmental plasticity creates novel cellular interactions and complex tissues. Initially, novel traits created by developmental plasticity may not be stably heritable, thus subsequent (epi)genetic changes must stabilize the phenotypic novelty. Recent studies show how classic oncogenic and tumor suppressor driver mutations, such as KRAS and TP53 , may primarily act in early carcinogenesis as broad releasers of developmental plasticity rather than as stimulators of cell division or knockout of limitations on cellular clonal expansion. In the new model, genetics releases, plasticity creates, and genetics stabilizes.
Neuronal processes contain the essential components for the late steps of ribosome biogenesis
Neurons rely on spatial and temporal control of protein synthesis to respond rapidly and locally to external stimuli, a process facilitated by the dynamic localization and modification of ribosomes. While previous research has shown that neuronal activity can regulate ribosome localization and modify translation rates, little is known about ribosomal assembly within neuronal processes. Here, we investigated the potential for local ribosome maturation in rat neurons using proteomics, RNA sequencing, and imaging methods. We detected an abundance of ribosome biogenesis factors in distal neuronal compartments, particularly those associated with the late stages of ribosome assembly. Moreover, we detected cytosolic pre-ribosomal RNA species in dendrites, as well as the enzymes necessary for their processing, suggesting that local ribosome maturation can occur far from the nucleus. These findings challenge conventional models that confine ribosome biogenesis to nuclear and perinuclear regions and suggest that neurons may fine-tune local protein synthesis by regulating ribosome assembly near synaptic sites. This mechanism may enable rapid modulation of the translational capacity in response to physiological changes, regulating synaptic plasticity and local protein synthesis in neurons.
Six million years of vole dental evolution shaped by tooth development
Morphological change occurs over macroevolutionary timescales under the action of natural selection and genetic drift combined with developmental processes shaping organogenesis. Although determining their relative weight is made difficult by discrepancies between paleontological and neontological data, mammalian tooth morphology may bridge the gap between fossil record and laboratory observations. Fossils indicate that mammals have frequently diversified after evolving molars bearing more cusps, while developmental biology shows these emerge through the iterative signaling of enamel knots. However, this theoretical evo-devo model of mammalian tooth evolution has not been tested with empirical data from both fossils and laboratory experiments. In doing so, we identify a shared developmental basis for the convergent, ratcheted evolution of increasingly complex molars in arvicoline rodents (voles, lemmings, muskrats). Longer, narrower molars lead to more cusps throughout development and deep time, suggesting that tooth development directed morphological evolution. Both the arvicoline fossil record and vole tooth development show slower transitions toward the highest cusp counts. This pattern suggests that the developmental processes fueling the evolution of increasingly complex molars may also limit the potential for further complexity increases. Integrating paleontological and developmental data shows that long-term evolutionary trends can be accurately and mostly explained by the simple tinkering of developmental pathways.
SMARCA5 restricts chromatin accessibility to promote male meiosis and fertility in mammals
Establishment of correct chromatin configuration in male meiosis is essential for sperm formation and male fertility. However, how chromatin remodeling contributes to meiotic progression in male germ cells is not well understood. Here, we find that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis in mice. Male mice with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Conditional knockout of Smarca5 results in meiotic progression failure, with abnormal spermatocytes appearing at the pachytene stage of meiosis I and subsequent accumulation of defects in chromosome synapsis, DNA repair, and transposon control, along with elevated rates of apoptosis. SMARCA5 interacts with known cofactors BAZ1A/ACF and BAZ2A/TIP5, as well as numerous DNA repair and recombination factors, in the testis. Single cell RNA sequencing confirmed failure to achieve a normal transcriptional state in premeiotic spermatogonia and during meiotic prophase, with reduced levels of meiotic gene transcripts and increasingly aberrant transcriptional states at later stages of spermatogenic development. Transcriptional misregulation in meiotic prophase was preceded by a widespread increase in chromatin accessibility in spermatogonia at promoters and repeat elements. Our findings suggest that SMARCA5 restricts chromatin accessibility in male germ cells to guide appropriate chromatin remodeling during meiotic recombination, contrasting with its role promoting chromatin accessibility during female meiosis.
Actions of the antiseizure drug carbamazepine in the thalamic reticular nucleus: Potential mechanism of aggravating absence seizures
Carbamazepine (CBZ) is a widely used antiepileptic drug effective in managing partial and generalized tonic-clonic seizures. Despite its established therapeutic efficacy, CBZ has been reported to worsen seizures in another form of epilepsy, generalized absence seizures, in both clinical and experimental settings. In this study, we focused on thalamic reticular (RT) neurons, which regulate thalamocortical network activity in absence seizures, to investigate whether CBZ alters their excitability, thereby contributing to the exacerbation of seizures. Using ex vivo whole-cell patch-clamp electrophysiology, we found that CBZ selectively inhibits the tonic firing of RT neurons in a dose-dependent manner without affecting burst firing. At the RT-thalamocortical synapse, CBZ significantly increases the failure rate of GABAergic synaptic transmission, with greater effects on somatostatin–than parvalbumin-expressing RT neurons. In vivo EEG recordings and open-field behavior in Scn8a med± mouse model confirmed that CBZ treatment exacerbates absence seizures, increasing both seizure frequency and duration while reducing locomotor activity. In addition, CBZ further amplifies the preexisting reduction in tonic firing of RT neurons in Scn8a med± mice. These findings uncover a mechanism by which CBZ exacerbates absence seizures through selective inhibition of RT neuron excitability and disruption of GABAergic synaptic transmission. This work provides mechanistic insights into the paradoxical effects of CBZ and suggests potential avenues for optimizing epilepsy treatment strategies.
Active bacterial baths in droplets
Suspensions of self-propelled objects represent a novel paradigm in colloidal science. In such “active baths,” traditional concepts such as Brownian motion, fluctuation–dissipation relations, and work extraction from heat reservoirs, must be extended beyond the conventional framework of thermal baths. Unlike thermal baths, which are characterized by a single parameter, the temperature, the fundamental descriptors of an active bath remain elusive. Particularly relevant are confined environments, which are common conditions for bacteria in Nature and in microbioreactor devices. In this study, buoyant passive tracers are employed as generalized probes to extract the properties of an active bath comprising motile bacteria confined within a droplet. By describing the bacterial suspension as a colored noise acting on the tracer, we extract the temporal memory τ b and characteristic intensity u b of such noise, finding that τ b varies little across the explored experimental conditions and u b is positively correlated with bacterial concentration. Notably, we put forward the generalizing concept of “bath diffusivity,” D b = u b 2 τ b , as a central predictor for the momentum transfer properties of this out-of-equilibrium situation. We show that D b scales linearly with bacterial concentration, modulated by a factor representing the role of confinement, expressed as the ratio of the confining radius to the probe radius. This finding, while still awaiting a complete theoretical explanation, offers insights into the transport or mixing properties of confined active baths and paves the way for a deeper understanding of active emulsions driven by confined active matter.
Lysosomal glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway contributing to Parkinson’s disease
Parkinson’s disease is characterized by loss of dopamine neurons that project to the dorsal striatum, and mutations in LRRK2 and GBA1 are the most common genetic causes of familial Parkinson’s disease. Previously, we showed that pathogenic LRRK2 mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which normally support dopamine neurons vulnerable in PD. Here, we show that GBA1 mutations also impair Hedgehog signaling and Hedgehog-dependent neuroprotective factor production by a distinct mechanism. Loss of GBA1 activity increases lysosomal accessible cholesterol and thus decreases accessible cholesterol in primary cilia of cultured cells; this change in lipid composition blocks ciliary Hedgehog signaling that depends on accessible cholesterol. Consistent with defects in Hedgehog signaling in the mouse dorsal striatum, GBA1 mutant mice show reduced Hedgehog-induced Gdnf RNA expression in striatal cholinergic interneurons, with no detectable impact on cilia formation. Also, both LRRK2 and GBA1 mutations suppress Hedgehog-induced Bdnf expression in striatal astrocytes. These findings underscore the role of Hedgehog signaling in the nigrostriatal circuit and reveal a convergent mechanism by which distinct LRRK2 and GBA1 mutations may contribute to PD pathogenesis.
Trauma-predictive brain network connectivity adaptively responds to mild acute stress
Past traumatic experiences shape neural responses to future stress, but the mechanisms underlying this dynamic interaction remain unclear. Here, we assessed how trauma-related brain networks respond to current acute stress in real time. Using a machine learning approach, we trained and tested brain functional connectivity networks to predict past trauma exposure in a community sample of adults ( N = 170). We then evaluated the response of these trauma-predictive brain networks to an acute emotional and physiological stressor in a subsample of participants ( N = 92) and to a pharmacological manipulation (hydrocortisone) in an independent crossover study ( N = 27). We found that connectome-based predictive modeling successfully predicted past trauma exposure. The network associated with greater trauma exposure showed high involvement of salience network connections, with model prediction driven by connectivity in the medial frontal cortex, salience network, motor regions, default mode network, and cerebellum. Notably, connectivity in this trauma-predictive network was significantly attenuated following an acute stressor relative to control. A similar pattern was observed in the pharmacology sample, with decreased connectivity under hydrocortisone compared to placebo within this trauma-predictive network. Finally, attenuated trauma-predictive network connectivity after acute stress was associated with lower depressive symptoms in the stress-exposed group, but not control group. These findings suggest that stress may induce blunted connectivity of brain networks related to past traumatic experiences and that the reduced engagement of these trauma-predictive brain networks may facilitate adaptive regulatory response to later stress.
Identification of an on-pathway intermediate illuminates the kinetic competition between protein folding and misfolding
Our current understanding of protein folding is based predominantly on studies of small (<150 aa) proteins that refold reversibly from a chemically denatured state. However, as protein length increases so does the competition between off-pathway misfolding and on-pathway folding, creating a more complex energy landscape ("folding funnel"). Little is known about how intermediates populated during the folding of larger proteins affect navigation of this more complex landscape. Previously, we reported extremely slow folding rates for the 539 aa β-helical passenger domain of pertactin (P.69T), including conditions that favor the formation of a kinetically trapped, off-pathway partially folded state (PFS). Existence of an on-pathway intermediate for P.69T folding was speculated but its characterization remained elusive. In this work, we exploited the extremely slow kinetics of PFS unfolding to develop a double-jump “denaturant challenge” assay. With this assay, we identified a transient unfolding intermediate, PFS*, that adopts a similar structure to PFS, including C-terminal folded structure and a disordered N terminus, yet unfolds much more quickly than PFS. Additional experiments revealed that PFS* also functions as an on-pathway intermediate for P.69T folding. Collectively, these results support a C-to-N-terminal model for P.69T folding, with folding initiated in the C-terminus with the rate-limiting formation of the transient on-pathway PFS* intermediate, which sits at the junction of the kinetic competition between folding and misfolding. Notably, processive folding from C-to-N terminus also occurs during C-to-N-terminal translocation of P.69T across the bacterial outer membrane. These results illuminate the crucial role of kinetics when navigating a complex energy landscape for protein folding.
Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib
Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific antigens that are endogenously produced. HapImmune™ technology utilizes covalent inhibitors directed to an intracellular cancer driver to create cancer-specific neoantigens in the form of drug–peptide conjugates presented by class I MHC molecules. Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug–peptide/MHC complex. Thus, this technology can unite targeted and immune therapies. In the present study, we examined whether this approach could generalize to another FDA-approved KRAS(G12C) inhibitor, adagrasib, whose chemical structure and cysteine reactivity differ substantially from sotorasib. We developed antibodies selective to adagrasib-KRAS(G12C) peptides presented by HLA-A*03 and A*11 that also show cross-reactivity to other KRAS(G12C) inhibitors presented in the same manner. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition distinctly different from that of sotorasib-directed HapImmune antibodies. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development.
C11orf54 catalyzes L-xylulose formation in human metabolism
Excretion of L-xylulose is the hallmark of pentosuria, the fourth of Garrod’s inborn errors of metabolism, yet the molecular basis for L-xylulose formation remains unknown. Here, by projecting coevolutionary data for 511,114 orthogroups across 1,929 eukaryotic genomes onto metabolic maps, we screen for unmapped genes in human metabolism. Among these, we show that the DUF1907 domain of C11orf54 catalyzes formation of L-xylulose by establishing a zinc-coordinated Michaelis complex with β-keto-L-gulonate (BKG). The identification of BKG decarboxylase completes the pentose pathway, in which pentose sugars are produced by decarboxylation of nonphosphorylated hexose precursors. The pathway was present in the unicellular ancestor of animals and is conserved in all deuterostomes, in contrast to the alternative L-ascorbate (vitamin C) biosynthesis pathway. An increased flux toward pentoses may have represented an evolutionary tradeoff, favoring energy metabolism and redox cofactor balance at the expense of ascorbate biosynthesis in organisms, such as humans and other Haplorhini primates, where dietary vitamin C intake prevents scurvy.
<i>DICER-LIKE 5</i> loss causes thermosensitive male sterility in durum wheat and reveals an AU-rich motif guiding 24-nt phasiRNA biogenesis
Reproductive, male-enriched small RNAs are present in flowering plants and animals, yet their role in plants remains underexplored. We generated dicer-like 5 ( dcl5 ) mutants in durum wheat ( Triticum turgidum ssp. durum 2n = 4× = 28; AABB), revealing temperature-sensitive genic male sterility. Loss of DCL5 depleted premeiotic and meiotic 24-nt phasiRNA production, correlating with sterility under standard growth conditions and partial fertility recovery at higher temperatures. A single functional DCL5 allele restored complete fertility, presenting a promising alternative to current methods for hybrid production. We demonstrate that premeiotic 24-nt phasiRNA biogenesis is independent of miRNA-mediated cleavage and driven by a conserved motif initiating DCL5 activity. In the dcl5 mutant developing under sterility-inducing conditions, developmental defects are observed during pollen maturation, rather than at peak 24-nt phasiRNA accumulation in premeiotic and meiotic anthers. Although no visible morphological abnormalities were apparent during early development, single-cell RNA sequencing revealed that dcl5 mutant cells exhibit transcriptional profiles distinct from those of wild-type cells, when premeiotic 24-nt phasiRNAs are accumulating at the early developmental stage. Finally, the coexpression of Argonaute ( AGO1b , AGO4a, and AGO6 ) homeologs in 24-nt phasiRNA-producing cells identifies candidate effectors and suggests a role for 24-nt phasiRNAs in transcriptional gene silencing.
Evolution and evolvability of rifampicin resistance across the bacterial tree of life
Predicting the ability of bacteria to develop antibiotic resistance is challenging, especially for the vast majority of species for which no experimental data are available. Here, we investigated the evolvability and intrinsic presence of rifampicin resistance across the bacterial tree of life. We compiled a comprehensive panel of known rifampicin resistance mutations, comprising 57 amino acid substitutions within the gene rpoB . We then screened more than 18,000 genomes from all major bacterial groups for the presence of those mutations and determined which mutations can evolve through point mutations. Our results demonstrate that although the evolvability of individual mutations varies considerably across species, overall predicted evolvability is high and relatively homogeneous across bacterial taxa. Rifampicin resistance mutations are present intrinsically in 8% of species that tend to be phylogenetically clustered. Our analysis provides a global picture of the mutational landscape of rifampicin resistance, affording insight into existing observations and informing future discoveries such as the identification of probiotics.
Evolutionary features in a minimal physical system: Diversity, selection, growth, inheritance, and adaptation
We present a simple physical model that recapitulates several features of biological evolution, while being based only on thermally driven attachment and detachment of elementary building blocks. Through its dynamics, this model samples a large and diverse array of nonequilibrium steady states, both within and between independent trajectories. These dynamics exhibit directionality with a quantity that increases in time, selection, and preferential spatial expansion of particular states, as well as inheritance in the form of correlated compositions between successive states, and environment-dependent adaptation. The model challenges common conceptions regarding the requirements for life-like properties: It does not involve separate mechanisms for metabolism, replication, and compartmentalization; stores and transmits digital information without template replication or assembly of large molecules; exhibits selection both without and with reproduction; and undergoes growth without autocatalysis. As the model is based on generic physical principles, it is amenable to various experimental implementations.
ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis
The acrosome is a crucial organelle essential for sperm function and male fertility. During acrosome biogenesis, numerous proacrosomal vesicles (PAVs) are transported to the concave region of the nuclear membrane and fuse to form the acrosome. However, the mechanisms governing the fusion of PAVs to form the acrosome remain poorly understood. Here, we identify endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1), a conserved protein, as a key factor in PAVs fusion during acrosome biogenesis. Male mice lacking Elapor1 ( Elapor1 −/− ) are infertile, exhibiting defective acrosome biogenesis and a globozoospermia-like phenotype. Using cryo-electron microscopy revealed that ELAPOR1 forms a square planar homodimer in cis, which assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation. Notably, ELAPOR1 exhibits dual membrane orientation, with a predicted N in − C out topology and a noncanonical N out − C in topology in vesicles. The noncanonical N out − C in topology enables ELAPOR1 to function as a tethering factor bridging vesicles through head-to-head homophilic interactions. A mutant ELAPOR1 (ELAPOR1 4HA ) incapable of copper chelation forms cis homodimers but fails to mediate homophilic interactions in vitro, leading to defective PAVs fusion in mice, phenocopying the Elapor1 -deficient mice. Additionally, ELAPOR1 was shown to interact with soluble N-ethylmaleimide sensitive factor attachment protein receptors protein STX12. Conditional knockout of Stx12 in germ cells resulted in similar defects in acrosome biogenesis. Collectively, our findings suggest that ELAPOR1 functions as a tethering factor that regulates PAV fusion through a copper-dependent mechanism.
Tat-dependent bundling pilus of a halophilic archaeon assembles by a strand donation mechanism and facilitates biofilm formation
Diverse extracellular filaments present on the surface of archaea mediate multiple key processes, such as motility, adhesion, and biofilm formation. Although several archaeal filament types have been characterized in considerable detail, many remain understudied, particularly those utilizing noncanonical secretion systems. Here, we describe the Tafi bundling pilus that facilitates biofilm formation in the haloarchaeon Natrinema sp. J7-2. Unlike previously characterized archaeal pili, Tafi is secreted via the twin-arginine translocation (Tat) pathway, which transports fully folded proteins across the cytoplasmic membrane. Structural analysis reveals that although Tafi pili assemble via a canonical strand-donation mechanism, the pilin subunit (TafE) adopts a distinct structural topology that sets it apart from the previously characterized Sec-dependent pilins that form bundling pili in archaea. Sequence analyses show that TafE homologs are also present in thermophilic archaea from different phyla, but Tat-signal sequences are exclusive to pilins of halophilic archaea. Nevertheless, we find that Tat signal peptides in haloarchaeal TafE-like pili were exchanged back to the Sec signal peptides on multiple independent occasions. These findings expand our understanding of the diversity and evolution of archaeal extracellular filaments and highlight the Tat pathway as a route for pilus assembly in halophilic archaea.
Whole-genome duplication increases genetic diversity and load in outcrossing <i>Arabidopsis arenosa</i>
Genetic variation underpins evolutionary change, but mutation accumulation increases genetic load. Various factors affect the extent of load, such as population size and breeding system, but other important determinants remain unexplored. In particular, whole-genome duplication (WGD)—a pervasive macromutation occurring broadly across Eukaryotes—remains poorly understood in terms of its impact on neutral and selective processes within populations. Using iterative forward simulations and empirical analysis of 632 short- and 16 long-read sequenced individuals of Arabidopsis arenosa (in 23 diploid and 42 natural autotetraploid populations), we measure the effects of WGD on genome-wide diversity and mutation load. Our simulations show how genetic variation gradually rises in autotetraploids due to increased mutational target size. Moreover, mutation load increases due to relaxed purifying selection as ploidies rise, when deleterious mutations are masked by additional chromosome copies. Empirical data confirm these patterns, showing significant increases in nucleotide diversity, ratios of nonsynonymous to synonymous SNPs, and numbers of indels and large structural variants in A. arenosa autotetraploids. However, a rather modest increase in load proxies together with a broad distribution and niche of autotetraploids suggests load accumulation has not yet limited their successful expansion. Overall, we demonstrate a complex interplay between neutral processes and purifying selection in shaping genetic variation following WGD and highlight ploidy as an important determinant of mutation load, genetic diversity, and therefore adaptive potential in natural populations.