Current Biology

Patterns of locus coeruleus (LC) activity and norepinephrine (NE) release during non-rapid-eye-movement (NREM) sleep suggest a critical role for the LC-NE system in offline modulation of forebrain circuits. NE transmission promotes synaptic plasticity and is required for memory consolidation, but the field has only begun to uncover how LC activity contributes to coordinated forebrain network dynamics. Hippocampal ripples, a hallmark of memory replay, are temporally coupled with thalamocortical oscillations; however, the circuit mechanisms underlying systems-level consolidation across larger brain networks remain incompletely understood. Here, using multi-site electrophysiology, we examined LC firing in relation to hippocampal ripples in freely behaving rats. LC activity and ripple occurrence were state-dependent and inversely related: heightened arousal was associated with increased LC firing and reduced ripple rates. At finer timescales, LC spiking decreased {approx}1-2 seconds before ripple onset, with the strongest modulation during awake ripples but minimal change during ripple- spindle coupling. These findings reveal state-dependent dynamics of LC-hippocampal interactions, positioning the LC as a key component of a cortical-subcortical network supporting systems-level memory consolidation.

Neuronal migration is a vital process that positions billions of neurons to create a functional brain. To navigate the constrained microenvironments within the cortex, precise control over the nuclear mechanics in migrating neurons is indispensable. Here, we show that Lamin B1 (LB1) regulates neuronal migration by modulating nuclear deformability. Excess LB1 in neurons halted migration without altering laminar identity or overall gene expressions in vivo, while in vitro, it elevated nuclear stiffness and impaired neuronal motility in confined spaces. Moreover, mispositioned neurons resulted in electrophysiological defects in the brain. Computational modeling predicted a temporal relationship between nuclear deformation and enhanced migration velocity, which was validated experimentally through live imaging. Notably, cerebral organoid assays using iPS cells established from patients with LMNB1 duplication exhibited impaired neuronal migration in a human model. Collectively, these findings demonstrate that LB1 is a critical regulator of nuclear mechanics, ensuring the accurate spatiotemporal positioning of neurons.

How embryonic cells generate large clones of cells in the adult represents a fundamental question in biology. Here, using melanocyte stem cells (McSCs) in the zebrafish as a model, we explore the function of the master melanocyte transcription factor (MITF) in safeguarding McSCs in embryonic development and their potential to pigment large clones in the adult. MITF is well known is for its role in the specification of melanoblasts from the neural crest (NC) and their differentiation into melanocytes, yet little is known about how this activity shapes the stem cell lineages. Here, we use live imaging coupled with single-cell transcriptomics and lineage tracing to show that MITF (mitfa in zebrafish) protects the melanocyte stem cell (McSC) fate in zebrafish. Utilizing a temperature sensitive mitfavc7 mutant, we show loss of Mitfa leads to a surprising premature and aberrant expansion of McSC progeny at the niche during embryogenesis, coupled with novel emergent transcriptional cell states. Linage tracing of McSCs from the embryonic to juvenile stages reveals Mitfa activity is subsequently required in regeneration by Schwann cell-like and melanocyte stem cell progenitors that serve as a reservoir for fast-responding pigment progenitors. Thus, the impact of Mitfa loss on the melanocyte lineage is cell-state and stage-specific. The emergent cell states upon mitfa loss may have important implications for our understanding the loss of MITF activity in human genetic disease and melanoma.

Orphan genes, lacking homologs in other species, are systematically found across genomes. Their presence may result from extensive divergence from pre-existing genes or from de novo gene birth, which occurs when a gene emerges from a previously non-genic region. In this study, we identified orphan genes in the genomes of globally distributed plant-parasitic nematodes of the genus Meloidogyne and investigated their origins, evolution, and characteristics. Using a comparative genomics framework across 85 nematode species, we found that 18% of Meloidogyne genes are genus-specific, transcriptionally supported orphans. By combining ancestral sequence reconstruction and synteny-based approaches, we inferred that 20% of these orphan genes originated through high divergence, while 18% likely emerged de novo. Proteomic and translatomic evidence confirmed the translation of a subset of these genes, and feature analyses revealed distinctive molecular signatures, including shorter length, signal peptide enrichment, and a tendency for extracellular localization. These findings highlight orphan genes as a substantial and previously underexplored component of the Meloidogyne genome, with potential roles in their worldwide parasitism.

Drug-tolerant persisters (DTPs) represent a major obstacle to durable responses in targeted cancer therapy. DTPs are commonly described as distinct single-cell states that survive drug treatment via reversible, non-genetic mechanisms and drive tumor recurrence. Recent work demonstrates that multiple DTPs can coexist, reflecting diversity in lineage, signaling programs, or stress responses. However, each DTP is still generally viewed as a uniform cellular phenotype. Building on our prior work describing a population-level DTP termed "idling" [Paudel et al., Biophys. J. (2018) 114, 1499-1511], here we present evidence supporting a fundamentally different view: that DTPs are not single-cell states, but rather heterogeneous populations composed of multiple sub-states with distinct division and death rates that balance to produce near-zero net population growth. Using single-cell transcriptomics and lineage barcoding, we identify multiple phenotypic states within idling DTP populations, with reduced heterogeneity compared to untreated populations, and find that idling DTP cells emerge from nearly all lineages. Transcriptomic and functional analyses further reveal altered ion-channel activity in idling DTPs, which we confirm experimentally. Moreover, drug-response assays reveal increased susceptibility of idling DTPs to ferroptosis, a non-apoptotic form of regulated cell death, indicating the emergence of vulnerabilities associated with drug tolerance. Altogether, our results support a population-level view of tumor drug tolerance in which DTPs comprise stable collections of phenotypic states, shaped by treatment-defined phenotypic landscapes, which are potentially vulnerable to subsequent interventions. This perspective implies that eradicating DTPs will require a fundamental shift away from cell-type-centric strategies toward sequential treatments that progressively reduce phenotypic heterogeneity by modulating the molecular and cellular processes that establish the DTP landscape, an approach previously termed "targeted landscaping."

Study ObjectivesIdiopathic hypersomnia (IH) is a central nervous system hypersomnia frequently accompanied by autonomic symptoms, yet objective physiological data are limited. We sought to characterize autonomic nervous system (ANS) dysfunction in IH using nocturnal heart rate variability (HRV) and diurnal autonomic reflex testing (ART), compared to individuals with type 1 narcolepsy (NT1) and healthy controls (HCs). MethodsTwenty-four adults with IH, 10 with NT1, and 14 HCs underwent overnight video polysomnography with HRV analyses in time and frequency domains during stable slow-wave sleep and REM sleep. Comprehensive ART included sympathetic adrenergic (head-up tilt (HUT), Valsalva BP responses), parasympathetic cardiovagal (HRV to deep breathing, Valsalva ratio), and sudomotor (Q-Sweat) measures. ResultsIH participants were predominantly female, with over half reporting long sleep duration. Compared to NT1 and HC, participants with IH demonstrated a greater magnitude of orthostatic tachycardia on tilt ({Delta}HR 41.0 {+/-} 16.3 vs. 26.3 {+/-} 9.3 vs. 30.8 {+/-} 9.3 bpm, p = 0.0086), as well as frequent sudomotor dysfunction (64.3%). IH participants demonstrated greater nocturnal and REM HR with reduced parasympathetic indices during REM, indicating diminished vagal modulation compared with HCs ConclusionsIH is characterized by a distinct pattern of autonomic dysfunction, including pronounced orthostatic tachycardia, frequent sudomotor abnormalities, and reduced parasympathetic activity during sleep. These findings provide objective physiological evidence of ANS involvement in IH and delineate features that distinguish IH from NT1 and HCs.

Our understanding of human mucosal T cell clonotype distribution in health and disease has centered on immunodominant antigens. We performed single cell T cell receptor (TCR) and RNA sequencing as an untargeted approach to define distributions of T cell clonal groups in health and ulcerative colitis (UC) across 333,088 T cells in colon and peripheral blood. Healthy donor-specific TCR repertoires had limited blood-colon clonal sharing, which was highest in cytotoxic T effector memory (Tem) populations and lowest in regulatory T cells (Tregs), reflecting tissue-based compartmentalization. Within healthy colon, TCR repertoires showed high T cell clonal sharing independent of anatomic distance, associated with high intra-clonal phenotypic diversity. Colon cytotoxic and Th17 populations showed high dispersion across sites, while Tregs were compartmentalized. Clonal lineages dispersed across blood and colon upregulated trafficking markers, suggesting active movement between tissues, while those dispersed across colon sites upregulated residency markers, suggesting intra-colon repertoire sharing is mediated by long-term, slow moving clonal groups. In UC, Tregs were expanded across inflamed sites, and increased CD8 Tem clonal groups showed increased dispersion regardless of inflammation. These findings reveal principles of T cell clonal organization in the human colon during health and disease, identifying opposing patterns of clonal dispersion among Treg and Th17 clonal groups, high phenotypic diversity within dispersed clonal groups, and elevated cross-colon dispersion of CD8 Tem clonotypes in UC.

A central question in psycholinguistics in visual word recognition is whether morphologically complex words are obligatorily decomposed into stems and affixes during visual word recognition or whether whole-word access can occur when forms are frequent and familiar. The present study investigated how morphological complexity and lexical frequency jointly shape neural responses by leveraging Korean nominal inflection, whose transparent stem-suffix structure permits a clean dissociation between base (stem) frequency and surface (whole-word) frequency. Twenty-five native Korean speakers completed a rapid event-related fMRI lexical decision task involving simple and inflected nouns that varied parametrically in both frequency measures. Representational similarity analysis (RSA) revealed robust encoding of surface frequency--but not base frequency--in the inferior frontal gyrus (IFG) pars opercularis and supramarginal gyrus (SMG), with significantly stronger correlations for inflected than simple nouns. Univariate analyses converged with this result: surface frequency selectively increased activation for inflected nouns in inferior parietal regions, whereas base frequency showed no reliable effects in any ROI. These findings challenge models positing obligatory pre-lexical decomposition, instead supporting accounts in which morphological processing is shaped by post-lexical, usage-driven lexical statistics. Taken together, our findings shed light on a distributed perspective on morphological processing, suggesting that structural and statistical factors jointly constrain access to morphologically complex forms.

Ewing sarcoma (EwS) is an aggressive, human-exclusive tumor typically driven by the EWS::FLI1 fusion protein. To assess whether the neomorphic functions of EWS::FLI1 are fundamentally dependent on evolutionarily recent cofactors such as ETS transcription factors (ETS-TFs), Plycomb group (PcG) proteins, CBP/p300, or specific subunits of the BAF complex, we expressed EWS::FLI1 in the model organism Saccharomyces cerevisiae. This minimal system was chosen because several key EWS::FLI 's cofactors possess greatly reduced sequence homology (e.g., BAF) or are lacking altogether (e.g., ETS-TFs, PcG, or CBP/p300). We used co-IP/MS to map the yeast interactome, Chip-Seq to identify gDNA binding sequences, RNA-Seq for global gene expression, and engineered reporters to test conversion of (GGAA) tandem repeats (GGAASat) into neoenhancers. We found that the yeast EWS::FLI1 interactome was more limited and qualitatively distinct from its human counterpart, sharing core machinery (e.g. RNA Polymerase II, FACT) but lacking the BAF/SWI-SNF and spliceosome complexes, and showing strong enrichment for the SAGA chromatin remodeling complex. We also found that EWS::FLI1 binds to hundreds of sites in the yeast genome with a clear preference for putative ETS-TF consensus sequences and (CA) dinucleotide repeats. Yet, EWS::FLI1 expressing cells presented only minimal transcriptional dysregulation, a stark contrast to the extensive changes observed in humans and Drosophila cells. Finally, we found that EWS::FLI1 successfully converted silent GGAASat sequences into active enhancers in yeast. This remarkable result occurs despite the absence of homologs for key human activators, such as CBP/p300, strongly suggesting that EWS::FLI1 can mobilize functionally related, non-homologous pathways to establish neoenhancers at GGAASat sites. Altogether, our results indicate that EWS::FLI1's core ability to drive GGAASat-dependent gene expression is a conserved, ancient property, while GGAASat-independent extensive transcriptome reprogramming is dependent on co-factors and pathways specific to animal cells.

We used 2492 whole genome sequences from Laos to investigate the molecular epidemiology of SARS-CoV-2 from 2021 through 2024, covering the major waves of COVID-19 disease in Laos including time periods of travel restrictions and after relaxation of travel across international borders. We identify successive waves of COVID-19 caused by shifts in the dominant lineage, beginning with the Alpha variant in April 2021 and continuing through the Delta and Omicron variants. We quantify a shift from a small number of viral introductions responsible for widespread transmission in early waves to a larger number of introductions for each variant after travel restrictions were lifted, and identify potential routes of introduction into the country. Our study underscores the importance of genomic surveillance to public health responses to characterize viral transmission dynamics during pandemics.

Zoos may serve as sentinel sites for zoonotic vector-borne diseases. West Nile virus (WNV) and Usutu virus (USUV) are closely related orthoflaviviruses transmitted between Culex mosquitoes and a bird reservoir. Both viruses can also infect mammals, including humans, where they may cause symptoms and, more rarely, hospitalization and death. However, serological cross-reactivity between WNV and USUV complicates their differential diagnosis. Here, we aimed to reconstruct the dynamics of emergence of WNV in a zoo located in a newly affected area in Europe, using ELISA and Virus Neutralization Test (VNT) serological analysis of 1707 animal sera collected between 2015 and 2024. Combining this data in a model accounting for cross-reactivity with USUV, we estimated yearly forces of infection (FOI) by both viruses, and thus found that WNV likely circulated in the area one year prior to the first cases reported to the passive surveillance system. Our results also showed that, in the zoo, mammals and reptiles had a lower risk of infection than birds (relative risk of 0.14 [0.05; 0.28]), and that the exposure of birds to water (aquatic lifestyle or proximity to stagnant water) affected the risk. Finally, we estimated diagnosis parameters, including the sensitivity of the VNT (80.4% [76.5%; 84.3%]), the expected VNT titer value, and the level of serological cross-reactivity between viruses during the VNT. To conclude, our modelling framework allowed to disentangle the co-circulation of two closely related viruses, a crucial point in ensuring the reliable sentinel surveillance of these vector-borne zoonotic pathogens.

Human papillomavirus (HPV) testing is the primary method for cervical cancer screening, and a negative HPV test is associated with a very low subsequent risk of invasive cancer. Nevertheless, a small number of cervical cancers are diagnosed following an HPV-negative testing result, posing challenges within HPV-based screening pathways. Using nationwide Swedish registry data of HPV testing, we identified women diagnosed with invasive cervical cancer between 2019 and 2024 and reconstructed HPV testing histories from the National Cervical Screening Registry (NKCx). The most recent HPV test prior to diagnosis was defined as the index test, and longitudinal HPV testing trajectories were classified among women with an HPV-negative index test. Of 3,000 women diagnosed with invasive cancer, 243 (8.1%) had an HPV-negative index test. These women were older at diagnosis and more frequently diagnosed at advanced stages compared with women with an HPV-positive index test. Most HPV-negative index tests (66.3%) were performed in the peri-diagnostic period (+/- 30 days). Among women with an HPV-negative index test, 52.7% (128/243) had no prior HPV testing recorded, while the remainder had consistently HPV-negative histories (33.3%, 83/243) or evidence of prior HPV positivity before the index negative test (14%, 32/243). Possible recurrent HPV positivity following an intervening negative test was rare (0.4%, 1/243). HPV-negative screening results preceding invasive cancer reflect heterogeneous screening histories and cannot be explained solely by test failure. Findings highlighting the importance of reaching women earlier in screening programs and show that fluctuating HPV detectability is rare.

Osteoarthritis (OA) is a prevalent musculoskeletal disorder and a leading cause of global disability. Although meniscal damage is a major risk factor of OA pathogenesis, genetic regulatory studies have remained largely confined to articular cartilage. Here, we establish the first comprehensive expression quantitative trait locus (eQTL) map integrating whole-genome sequencing and bulk transcriptomics from human meniscus (n=112) and cartilage (n=113). Supported by single-nucleus multiomics (cartilage: 56,549 nuclei; meniscus: 34,343 nuclei), we uncovered highly tissue-specific genetic risk architectures. Colocalization with OA GWAS identified 27 meniscus-specific, 28 shared, and 20 cartilage-specific causal genes. Chromatin-informed fine-mapping and deconvolution elucidated distinct pathogenic mechanisms; notably, meniscus-specific signals converged on VEGFA via rare promoter variants and an enhancer in fibrochondrocyte progenitors, alongside a shared eQTL for CLEC18A. Exploratory analysis suggested candidate compounds to reverse pathogenic gene expression. Our findings underscore the meniscus as a distinct genetic driver, molecularly reinforcing OA as an entire joint organ failure.

Dementia incidence has been declining in Western societies for decades, but whether this reflects higher cognitive capacity entering old age, slower cognitive decline, or both remains unresolved. Analysing ~783,000 episodic memory assessments from ~219,000 individuals across five longitudinal cohorts, we find that later-born cohorts benefit from a double dividend: higher memory levels entering old age and slower rates of decline. The projected 20-year cohort advantage at age 80 is of sufficient magnitude to plausibly account for the observed 13% per-decade decline in dementia incidence reported in meta-analyses. Generational gains are disproportionately concentrated among the fastest-declining individuals, and are reflected in lower hippocampal atrophy rates in an independent sample. A formal bounding analysis shows that the double dividend is robust across a range of plausible period assumptions, consistent with environmental conditions operating across the lifespan having reshaped the architecture of human cognitive aging.

Dietary patterns worldwide have shifted toward increased consumption of ultraprocessed foods (UPFs), which has been linked to higher disease burden. One mechanism proposed to impact both their consumption and contribution to metabolic disease is altered post-ingestive metabolic response in comparison to nutritionally similar foods. Here, we recruited 57 healthy-weight 18-45-year-old adults to examine the effects of food processing on postprandial metabolism and brain response. Despite nutritional matching, UPF meals evoked a greater insulinemic and energetic response with attenuated carbohydrate oxidation relative to non-UPF meals. Next, between-condition differences in peak carbohydrate oxidation were associated with mesolimbic and superior temporal gyrus activation in response to food cues. Finally, although food value did not differ between conditions, brain responses correlated with food valuation were positive for non-UPF but negative for UPF in visual cortex and striatum. These findings demonstrate that food processing influences post-ingestive metabolism in a way that could help explain long term health effects and differences in food reward through mechanisms beyond calories and macronutrient composition alone.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.

Intermuscular adipose tissue (IMAT) expansion is closely associated with cardiometabolic disease, yet its cellular organization and regulatory mechanisms remain poorly defined. Here, we define a human IMAT gene signature using bulk transcriptomics and identify candidate regulators for IMAT function including adipogenic transcription factor early B-cell factor 2 (EBF2). To determine how these programs are organized in situ, we mapped this signature in a mouse model of diet-induced CMD using spatial transcriptomics. We found that IMAT expansion occurs within discrete stromal niches surrounding muscle fibers, characterized by coordinated activation of adipogenic, extracellular matrix, inflammatory, and metabolic pathways. Spatial analyses showed that fibro-adipogenic progenitor (FAP) abundance does not predict adipocyte formation, supporting a model of localized and context-dependent lineage transitions. Cross-species comparison revealed partial conservation of human IMAT gene programs, validating the mouse model and highlighting species-specific features. Functional experiments in human primary myoblasts showed that EBF2 is sufficient to induce adipogenic reprogramming. Our findings establish IMAT as an active, spatially organized remodeling niche and identify lineage plasticity as a central mechanism driving its expansion in metabolic disease

Study questionWhat are the characteristics and treatment outcomes of women who undertook planned egg freezing (PEF) in Australia and New Zealand between 2009 and 2023? Summary answerThere has been an average yearly increase in the uptake of PEF of 35%, with most women undergoing a single PEF procedure in their mid-thirties. Given ten years follow-up a little over one in four women return, with nearly half of those using donor sperm and one-third achieving a live birth. What is known alreadyPEF, where women freeze their eggs as a strategy to preserve fertility, has increased dramatically in high income countries in the last decade. Despite the rapid uptake of PEF, there remains limited information to guide women, clinicians and policy makers regarding the characteristics of women undertaking this procedure and treatment outcomes. Study design, size, durationA retrospective population-based cohort study of all women who undertook PEF in Australia and New Zealand between 2009 and 2023, including their subsequent return to thaw their eggs and treatment outcomes. Where women returned to utilise their eggs, all subsequent embryo transfer procedures were linked enabling calculation of live birth rates per woman. Participants/materials, setting, methods20,209 women who undertook PEF in Australia and New Zealand between 2009 and 2023 including 1,657 women who returned to thaw their eggs. Main results and the role of chanceThere has been a huge increase in uptake of PEF, from 55 women in 2009 to 4,919 in 2023. Women who freeze their eggs are typically aged 34-38 years (interquartile range) and nulliparous (98.6%). For women with at least 10 years follow-up (i.e. undertook PEF in 2009-13; N=514), 27.9% returned and thawed their frozen eggs (average time to return: 4.9 years). This reduced to 22.1% in those with at least 5 years follow-up (i.e. undertook PEF in 2009-2018; N=4,288). Of those who used their frozen eggs, 47% used donor sperm. After at least two years follow up, 33.9% had a live birth, rising over time to 37.8% for eggs thawed between 2019-2021. Limitations, reasons for cautionIn the timeframe 2009-2019 we did not have information on whether egg freezing occurred because of a cancer diagnosis, a cohort we wished to exclude from the study. As a result, for this timeframe we weighted observations by the probability that egg freezing occurred due to cancer, with the prediction model developed on the years 2020-2023. Wider implications of the findingsThis study provides recent and comprehensive data on PEF to guide prospective patients and clinicians and inform policy. The exponential growth in PEF in Australia and New Zealand mirrors trends in other high-income countries, suggesting a doubling time of 2-3 years. Study findings highlight the need for setting realistic expectations about the likelihood of returning to use frozen eggs and live birth rates. Study funding/competing interest(s)2020-2025 MRFF Emerging Priorities and Consumer Driven Research initiative: EPCD000014

Female genital tract (FGT) polyps are common benign growths affecting up to half of all women. However, they carry malignant potential, and their genetic architecture remains poorly defined. We conducted a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases, 477,134 controls), identifying 26 risk loci for FGT polyps, 12 of which were previously unreported. Integrative gene prioritisation highlighted 193 candidate genes, revealing a potential convergent biological mechanism: where germline variation in DNA replication and maintenance (e.g., PRIM1, TERT and HMGA1) compromises genomic stability in the context of hormone-driven proliferation (e.g., ESR1 and GREB1). This susceptibility is further modulated by metabolic drivers of estrogen biosynthesis, underscored by specific adiposity-related loci (e.g. RSPO3 and PLCE1) and the aromatase gene CYP19A1. Mendelian randomisation demonstrated bidirectional causal relationships with endometriosis and fibroids, and endometrial cancer. Leveraging the shared genetic architecture of FGT polyps and other gynaecological disorders via multi-trait analysis revealed an additional 26 loci, validating sub-threshold regions encompassing HMGA1 and GREB1. In total, 52 risk loci were identified (36 novel), 39 of which replicated in an independent cohort. These findings reframe polyps not merely as local gynaecological overgrowths but as manifestations of a systemic proliferative syndrome characterised by dysregulated genome stability and estrogen signalling, which may also impact malignant transformation.

Purpose: To determine whether spatial decomposition of longitudinal retinal nerve fiber layer (RNFL) change maps reveals distinct modes of glaucomatous progression masked by conventional averaging, and to validate these modes through structure function mapping and genetic association analysis. Methods: Pixel wise RNFL rates of change were computed from longitudinal optic disc OCT scans of 15,242 eyes (8,419 adults with primary open angle glaucoma [POAG]; Massachusetts Eye and Ear, 1998 to 2023). A loss only constraint zeroed all thickening values, reflecting the biological prior that adult RNFL does not regenerate. Nonnegative matrix factorization decomposed these maps into spatial progression components (80% training set). Components were evaluated in a heldout set (20%) for retinotopic structure function concordance, visual field (VF) progressor classification against global and quadrant RNFL rates, and enrichment of genetic association signals at established POAG loci. Results: Six anatomically distinct progression patterns emerged, including diffuse circumferential loss, focal peripapillary defects, and arcuate bundle degeneration. Pattern based models significantly outperformed global RNFL rate for classifying VF progressors (area under the curve, 0.750 [95% CI, 0.709 to 0.790] vs. 0.702; P = .0096) and explained additional variance in functional decline (Nagelkerke pseudoR2, 0.301 vs. 0.198; P = .0011). Structure function mapping confirmed retinotopic coherence. Spatial phenotypes recovered stronger genetic signals than global rates at 85.3% of established POAG loci, suggesting they capture more biologically homogeneous endophenotypes of progression. Conclusions: Glaucomatous structural progression occurs through spatially distinct modes with independent structure function and genetic signatures that conventional RNFL averaging obscures.