Linking genetic data with electronic health records in hospital biobanks promises to advance precision medicine, but limited ancestral diversity constrains discovery and generalizability. We analyzed 93,936 participants from the UCLA ATLAS Community Health Initiative to inform disease prevalence and genetic risk across five continental and 36 fine-scale ancestry groups. We discovered numerous unreported gene-phenotype associations, including FN3K with intestinal disaccharidase deficiency in Europeans and admixed Americans. Polygenic scores (PGS) robustly predicted common diseases, with effects markedly diminished in non-Europeans. Furthermore, we reduced the pronounced European bias in curated clinical variants using computational predictors, uncovering unreported disease-gene associations, including ANKZF1 and peripheral vascular disease in African Americans. Longitudinal data revealed that semaglutide efficacy varies across ancestries, is associated with PGS for type 2 diabetes, and is modulated by genetic variation in PTPRU. These findings illustrate how ancestrally diverse biobanks from a single health system yield robust disease associations and pharmacogenomic insights.

Piaget's theory posits that children develop structured knowledge schemas for inferring and assimilating new information, yet the underlying neural mechanisms remain unclear. In 203 participants aged 8-25 years, we investigated how maturation of a two-dimensional (2D) knowledge map underpins inferential reasoning and knowledge assimilation. Grid-cell-like codes in the entorhinal cortex (EC) strengthened with age, reflecting schema representations in non-spatial conceptual spaces, and predicted improved inferential reasoning. These grid-like codes also supported the medial prefrontal cortex (mPFC) in encoding distance relationships between objects on the 2D map. As participants assimilated new information, they integrated it into existing grid patterns in the EC. Moreover, the maturation of these neural codes tracked real-world intelligence measures, particularly reasoning abilities. Our findings demonstrate that the development of non-spatial grid-like neural codes offers a mechanistic account of cognitive development, bridging psychological theory with a fundamental cellular representation of the cognitive map.

Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole proteome, detergent-insoluble proteome, and posttranslational modifications (phosphorylation and ubiquitination), enabling intra- and inter-disease comparisons. Intra-disease analyses uncover distinct molecular subtypes (e.g., three in AD and four in LBD), reveal dysregulated pathways, and prioritize top-ranked proteins. Inter-disease comparisons identify shared alterations in NDs, such as GPNMB in microglial and lysosomal activation and NPTX2 in synaptic regulation, alongside disease-specific changes and hub regulators within protein networks. Overall, PanNDA provides a systems-level framework for understanding ND mechanisms and serves as a foundational resource that is accessible via an interactive website: https://penglab.shinyapps.io/pannda.

Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration-restoring diverse cell types across lineages-remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered that three PWF-enriched genes-Timp1, Cxcl12, and Ccl7-inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation in postnatal wounds through the depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of diverse lineages after injury. Our study identifies mechanisms that transition an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates that removing this barrier unlocks organ-level regeneration.

To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.

Nucleotide-binding, leucine-rich repeat (NLR) receptors are widespread intracellular immune sensors across kingdoms. Plant G10-type coiled-coil (CCG10)-NLRs constitute a distinct phylogenetic clade that remains poorly characterized. Here, we identified a gain-of-function mutant of wheat autoimmunity 3 (WAI3GOF), which encodes a constitutively active CCG10-NLR resulting from a residue substitution in the leucine-rich repeat (LRR) domain. Cryo-electron microscopy (cryo-EM) analysis reveals that activated WAI3 assembles into a distinctive octameric resistosome. Arabidopsis RPS2, another CCG10-NLR, also forms an octamer, indicating a conserved structural property across monocot and dicot plants. The WAI3 resistosome induces a prolonged and sustained increase in cytosolic calcium, likely facilitated by a unique channel architecture arising from its divergent coiled-coil (CC) domain configuration. Notably, this domain arrangement may be shared by plant NLRs that lack the conserved EDVID (Glu-Asp-Val-Ile-Asp) motif in their CC domains. Together, our findings uncover a conserved yet previously uncharacterized NLR resistosome structure and provide insights into the plant immune receptor plasticity.

How morphological diversity arises from variations in biomechanical processes remains an open question. Although forces shape tissues, how force-generating systems differ across species to create diverse forms is unclear. Here, we combine comparative morphogenesis and active matter theory across six cnidarian species spanning 500 million years of divergence to identify the mechanical basis of larval shape diversity. We define species-specific configurations of mechanical modules-termed mechanotypes-that quantitatively predict larval shapes across taxa. We find that shape elongation is a simple trait at the mesoscale level, as its variation depends on one mechanical module, whereas shape polarity is a complex trait dependent on several modules. Perturbations mimicking interspecies regulatory differences reshape these modules, reprogramming larval morphology into forms resembling sister species. By establishing a mesoscale mechanical framework for cross-species comparison, this work reveals how variations in a limited set of tissue-scale parameters generate morphological diversity.

Bowhead whales were heavily exploited during commercial whaling between the 16th and 20th centuries. Current and near-future climate warming poses a new threat. Assessing bowhead vulnerability to climatic change remains challenging due to insufficient knowledge regarding responses to past climates and pre-whaling population dynamics. We integrate paleogenomics and stable isotopes (δ13C and δ15N) from 206 bowhead fossils from the Atlantic Arctic with paleoclimate and ecological modeling based on 823 radiocarbon-dated fossils, including 140 from this study. We find long-term resilience of bowheads to Holocene environmental perturbations, with no detectable changes in genetic diversity or population structure. Simulated commercial-whaling-driven genetic and fitness changes indicate that population subdivision and loss of genetic diversity are unlikely to be fully realized, despite nearly a century since whaling ceased. Furthermore, even in simulated complete population recovery scenarios, overall fitness did not return to pre-whaling levels, potentially compromising the future resilience of bowhead whales.

Identifying drugs that reverse disease-associated transcriptomic features has been widely explored for drug repurposing, but its potential for de novo drug discovery remains underexplored. Here, we present gene expression profile predictor on chemical structures (GPS), a deep-learning-based drug discovery platform, guided by transcriptomic features, that screens large compound libraries and optimizes lead molecules. We first develop a model that captures transcriptomic perturbation signatures solely from chemical structures and deploy it to library compounds. We refine scoring methods and employ a tree-search method for optimization. By incorporating structure-gene-activity relationships, we uncover drug mechanisms from transcriptomic data. We evaluate GPS across multiple diseases and conduct extensive validation in two cases. In hepatocellular carcinoma, we discover two unique compound series with favorable cellular selectivity and in vivo efficacy. In idiopathic pulmonary fibrosis, we identify one repurposing candidate and one novel anti-fibrotic compound by reversing gene expression of multiple distinct cell types derived from single-cell transcriptomics.

Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.

Aging is a major risk factor for neurodegenerative diseases, yet the underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that transposable element (TE) methylation alone distinguished age groups, showing cell-type-specific genome-wide demethylation. Chromatin conformation analysis demonstrated age-related increases in topologically associated domain (TAD) boundary strength with enhanced accessibility at CCCTC-binding factor (CTCF) binding sites. Spatial transcriptomics across 895,296 cells revealed regional heterogeneity during aging within identical cell types. Finally, we developed deep-learning models that reliably predict age-related gene expression changes using multi-modal epigenetic features, providing mechanistic insights into gene regulation. Age-related comparisons use a 2-month baseline reflecting the late-adolescent/early-young adult stage. This dataset advances our understanding of brain aging and offers potential translational applications.

Understanding the unique features of the human brain compared with non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells (GCs). Experimental data show that ZP2 expression in human GCs is induced by pontine mossy fibers, reducing synaptic proteins at the pontocerebellar glomerular synapses and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

The first people reached Remote Oceania 3,000 years before present (BP), arriving roughly simultaneously in the southwest Pacific, the Marianas Archipelago, and Palau. However, no genome-wide ancient DNA data have been available from Palau, a gap we address by reporting 21 individuals from four archaeological sites dating between 2,900 and 500 BP. All had approximately 60% ancestry related to East Asians and 40% to Papuans, similar to present-day Palauans, the longest stretch of population continuity anywhere in Remote Oceania. The lengths of contiguous Papuan ancestry segments in the oldest individuals show that major admixture between Papuans and East Asians in the ancestors of all sampled Palauans began prior to first settlement. This differs from the pattern in the southwest Pacific, where sampled individuals of the Lapita archaeological culture from three different islands had almost entirely East Asian ancestry, with large amounts of Papuan admixture observed only hundreds of years later.

Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Longitudinal data spanning more than a year indicated the significant stability of these parameters within individuals over time. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.

We present a whole-cell spatial and kinetic model for the ∼100 min cell cycle of the genetically minimal bacterium JCVI-syn3A. We simulate the complete cell cycle in 4D (space and time), including all genetic information processes, metabolic networks, growth, and cell division. By integrating hybrid computational methods, we model the dynamics of morphological transformations. Growth is driven by insertion of lipids and membrane proteins and constrained by fluorescence imaging data. Chromosome replication and segregation are controlled by the essential structural maintenance of chromosome proteins, analogous to condensin (SMC) and topoisomerase proteins in Brownian dynamics simulations, with replication rates responding to deoxyribonucleotide triphosphate (dNTP) pools from metabolism. The model captures the origin-to-terminus ratio measured in our DNA sequencing and recovers other experimental measurements, such as doubling time, mRNA half-lives, protein distributions, and ribosome counts. Because of stochasticity, each replicate cell is unique. We predict not only the average behavior of partitioning to daughter cells but also the heterogeneity among them.

Somatic mutations, or genetic changes occurring in cells after conception, are widespread in healthy tissues but are conventionally viewed as signs of pre-cancer or simply a consequence of aging. However, an emerging body of work has shown that somatic mutations can drive or protect against disease, which could inspire novel therapeutic strategies. The unexpected depth of genetic diversity within individuals also provides a massive substrate for discovering mutant genes selected for by disease. For instance, mutant hematopoietic cells can exacerbate inflammatory disease, and mutant hepatocytes can protect against liver disease. This suggests that somatic mutations, whether maladaptive or beneficial, could provide crucial insights into disease mechanisms, history, and reversal strategies. Somatic genetics offers a powerful, complementary approach to traditional germline genetics, which has had an enormous impact on biomedicine and drug development. This review explores the factors that shape the landscape of somatic mosaicism and discusses somatic mutations that cause or protect from disease. We highlight how somatic mutations are becoming a key discovery engine for disease genetics, moving rapidly toward drug target identification and clinical translation.

Hepatitis D-like satellite viruses, known as deltaviruses, have been recently discovered in a wide range of animals. These viruses are thought to expropriate glycoproteins from helper viruses to form infectious particles. Here, we challenge this paradigm and demonstrate that deltaviruses are packaged within helper virus particles, using them as viral Trojan Horses for cell entry. By leveraging orthogonal electron and optical super-resolution microscopy, we visualize deltaviruses enclosed within virions from rhabdo-, herpes-, and arenavirus families. We show that this conserved hitchhiking mechanism ensures concomitant deltavirus-helper virus spread, thereby promoting the dissemination of deltaviruses, broadening their host range, and expanding their tropism. Our findings reveal a previously unrecognized mode of viral transmission, providing a framework to investigate overlooked deltavirus infections outside of the human liver.

Using a phylogenetic framework to characterize natural selection, we investigate the hypothesis that zoonotic viruses require adaptation prior to zoonosis to sustain human-to-human transmission. Examining the zoonotic emergence of Ebola virus, Marburg virus, mpox virus, influenza A virus, and SARS-CoV-2, we find no evidence of a change in selection intensity immediately prior to outbreaks in humans compared with typical selection within reservoir hosts. We found a change in selection on SARS-CoV in an intermediate host. We conclude that extensive pre-zoonotic adaptation is not necessary for human-to-human transmission of zoonotic viruses. In contrast, the reemergence of H1N1 influenza A virus in 1977 was preceded by a shift in selection intensity, consistent with the hypothesis of passage in a laboratory setting. Holistic phylogenetic analysis of selection regimes can be used to detect evolutionary signals of host switching or laboratory passage, providing insight into the circumstances of past and future viral emergence.

Evolving dynamic, multi-state, and computational protein functionalities is challenging because it requires selection pressure on all the states of a protein of interest (POI) and the transitions between them. To create a continuous directed evolution paradigm for such properties, we genetically engineered budding yeast for optogenetic input to switch a POI "on" and "off," which, in turn, controls a Cdk1 cyclin that is essential for one cell-cycle stage but detrimental for another. The method, "optovolution," generates dynamic selection pressure on POI cycling at the timescale of tens of minutes. We used it to evolve 19 new variants of the LOV transcription factor El222, including in vivo green-light-responsive variants allowing LOV color-multiplexing. Evolving the PhyB-Pif3 optogenetic system, we discovered that loss of YOR1 makes supplementing phycocyanobilin (PCB) unnecessary. Finally, we demonstrated the generality of the method by evolving a non-light-responsive AND gate (PEST-rtTA). Optovolution makes difficult-to-engineer protein functionalities continuously evolvable.