PLoS Genet. [JOURNAL]
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200 papers
Genetic survey of biomarkers at early and mid-pregnancy identifies pregnancy-specialized immune regulation.
Cakir M, Traglia M, Alexeeff S … +12 more , Ames JL, Ashwood P, Grosvenor LP, Gunderson EP, Kim DHJ, Liang JW, Qian Y, Sahagun E, Yolken R, Van de Water J, Croen LA, Weiss LA
PLoS Genet · 2026 Jun · PMID 42378311 · Full text
Much remains unknown about the genetics of immune system changes during pregnancy. We used SNP data in a pregnancy cohort to genetically investigate 47 immune biomarkers at two timepoints, along with change between timep...
Much remains unknown about the genetics of immune system changes during pregnancy. We used SNP data in a pregnancy cohort to genetically investigate 47 immune biomarkers at two timepoints, along with change between timepoints (Δ). We identified 19 biomarkers with significant SNP-based heritability and 34 with genome-wide significant signals, demonstrating genetic regulation. The same biomarkers measured in early- and mid-pregnancy shared about half of significant associations across timepoints, with enrichment for immune pathways. In contrast, Δ showed enrichment in transcription factors and developmental processes. About half of suggestive associations overlapped with non-pregnancy associations. However, these data leave a substantial fraction of potentially timepoint-specific and pregnancy-unique findings. Nearby genes were enriched for high expression in decidual cells at the maternal-fetal interface, reinforcing the novelty of our results. We additionally explored the relationship between immune genetic associations and prior GWAS of pregnancy complications. Overall, we present the first two-timepoint genetic study of immune profile in pregnancy.
Argonaute proteins orchestrate Meiotic Sex Chromosome Inactivation and timing of the spermatogenic transcriptional program.
de Las Mercedes Carro M, Dziubek A, Touey-May A … +8 more , Popkowski EA, Abdelmassih M, Simon LE, Tanis SL, Ahmed F, Grenier JK, Grimson A, Cohen PE
PLoS Genet · 2026 Jun · PMID 42371982 · Full text
Argonaute proteins (AGO) are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we demonstrate that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatoc...
Argonaute proteins (AGO) are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we demonstrate that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatocytes, where they are required for the transcriptional silencing of XY-linked genes that characterizes Meiotic Sex Chromosome Inactivation (MSCI). Previous findings showed that deletion of Ago4 (Ago4-/-) mildly impairs MSCI and normal spermatozoa production. By contrast, loss of Ago3 (Ago3-/-) does not produce these defects, while combined deletion of Ago1, Ago3, and Ago4 (Ago413-/-) leads to severely reduced fertility, accompanied by disrupted autosomal and sex chromosome gene regulation and altered chromatin accessibility in spermatocytes. In Ago413-/- mice, premature overexpression of spermiogenesis genes during prophase I results in reduced sperm production, abnormal sperm morphology, and impaired fertilization capacity. Together, AGO3 and AGO4 act during prophase I to ensure the timely expression of meiosis-related genes during prophase I while maintaining repression of spermiogenesis-associated genes. These results indicate that AGO3 and AGO4 act in a coordinated fashion in the male germline to orchestrate cell progression in spermatogenesis through temporal regulation of autosomal and sex chromosome genes.
Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer's disease and related dementias in a multi-site autopsy cohort.
Cholerton B, Godrich D, Pasteris J … +28 more , Rivero J, Martin ER, Kunkle BW, Naj AC, Hamilton-Nelson KL, Wang H, Lee WP, Dumitrescu L, Hohman TJ, Mayeux R, Larson EB, Crane PK, Keene CD, Latimer CS, Mukherjee S, Kofler JK, Kamboh MI, Bennett DA, Molina-Porcel L, Cuccaro M, Pericak-Vance MA, Rundek T, Scott WK, Kukull W, Schellenberg G, Alzheimer’s Disease Genetics Consortium, Beecham GW, Montine TJ
PLoS Genet · 2026 Jun · PMID 42371968 · Full text
Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple...
Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n = 12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with APOE across AD and ADRDs but not cerebrovascular disease and vascular brain injury. We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on BIN1, PICALM/ EED, TMEM106B, GRN, and SNCA/ SNCA-AS1) and 7 novel genome-wide associations (variants on EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4 and SLAIN2/ SLC10A4). Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases. Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features. This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.
Microtubule stiffening by the doublecortin-domain protein ZYG-8 contributes to mitotic spindle orientation during zygote division in Caenorhabditis elegans.
Cueff L, Schmitt L, Huet E … +6 more , Pastezeur S, Coquil M, Savary T, Sénard A, Pécréaux J, Bouvrais H
PLoS Genet · 2026 Jun · PMID 42371962 · Full text
In the Caenorhabditis elegans zygote, mutations in zyg-8DCLK1, the sole Doublecortin-family member, disrupt mitotic spindle positioning, as seen by immunofluorescence. Doublecortin proteins bind microtubules and are thou...
In the Caenorhabditis elegans zygote, mutations in zyg-8DCLK1, the sole Doublecortin-family member, disrupt mitotic spindle positioning, as seen by immunofluorescence. Doublecortin proteins bind microtubules and are thought to stabilise or rigidify them. In the zygote, ZYG-8 only modestly affects microtubule growth and nucleation. We thus investigated whether these moderate dynamic perturbations alone could explain the spindle mispositioning observed in zyg-8 mutants. Using three complementary genetic perturbations-RNAi-mediated depletion of ZYG-8, its overexpression, and the thermosensitive zyg-8(or484ts) mutant (that disrupts microtubule binding)-we observed altered spindle pole oscillations and changes in microtubule cortical-contact behaviour, indicative of impaired cortical forces. Importantly, these phenotypes could not be fully explained by previously reported alterations in microtubule dynamics, suggesting an additional mechanism. Our findings indicate that ZYG-8 increases microtubule rigidity: ZYG-8 depletion or mutation led to more frequent microtubule bending and higher curvature and tortuosity. Simulations confirmed that reduced rigidity prolongs cortical contact lifetimes, an effect we experimentally observed in zyg-8(RNAi) embryos. Using custom biophysical assays, we showed that microtubule softening in zyg-8(RNAi) embryos and zyg-8 mutants reduced the efficiency of centring forces, leading to exaggerated spindle-pole oscillations. In mutants, the largest oscillations caused spindle poles to move closer to the cell periphery, preventing re-centring and resulting in spindle mispositioning and misorientation during late anaphase. Importantly, reducing cortical pulling forces rescued orientation defects, highlighting the importance of balanced pulling-pushing forces for proper spindle positioning. We propose that sufficient microtubule rigidity is essential for generating effective cortical pushing forces, potentially in synergy with other microtubule properties, which contribute to centring mechanisms that ensure accurate spindle orientation in late mitosis. Given that DCLK1 is frequently deregulated in human cancers and that accurate spindle positioning is essential for maintaining cell proliferation-differentiation balance, these findings may have implications for understanding how disruptions in microtubule mechanics contribute to carcinogenesis.
Multiple instance fine-mapping: Predicting causal regulatory variants with a deep sequence model.
Rakowski A, Lippert C
PLoS Genet · 2026 Jun · PMID 42371957 · Full text
Identifying causal genetic variants in a computational manner remains an open problem. Training end-to-end prediction models is not possible without large ground-truth datasets, while results of genome-wide association s...
Identifying causal genetic variants in a computational manner remains an open problem. Training end-to-end prediction models is not possible without large ground-truth datasets, while results of genome-wide association studies (GWAS) are entangled by linkage disequilibrium (LD), and gene expression datasets do not contain genetic variation at individual-level. Here, we propose Multiple Instance Fine-mapping (MIFM) - a multiple instance learning (MIL) objective to overcome the lack of strong labels by grouping putatively causal variants together based on their LD scores. Using MIFM, we trained a deep classifier on a dataset aggregating over 13,000 GWAS to predict causal variants based on their underlying DNA sequences. We validated variants prioritized by MIFM by constructing polygenic risk scores which transferred better to different target ancestries. Furthermore, we demonstrated how MIFM can be used to disentangle effect sizes of highly-correlated variants to better fine-map GWAS results.
Nuclear ubiquitin-conjugating enzyme TrUbc4 and F-box protein TrFwd1-mediated modification of Cre1 in Trichoderma reesei establishes a regulatory mechanism for carbon catabolite repression.
Xu G, Cao Y, Xia Y … +4 more , Jiang S, Zhang W, Meng X, Liu W
PLoS Genet · 2026 Jun · PMID 42361156 · Full text
Carbon catabolite repression (CCR) mediated by the transcriptional repressor Cre1 represents a major mechanism ensuring the energy-efficient cellulase production in the model cellulolytic fungus Trichoderma reesei. Howev...
Carbon catabolite repression (CCR) mediated by the transcriptional repressor Cre1 represents a major mechanism ensuring the energy-efficient cellulase production in the model cellulolytic fungus Trichoderma reesei. However, largely unknown is the regulatory pathway governing CCR. In this study, we identified a nuclear ubiquitination system targeting Cre1 to facilitate the induced cellulase gene expression. Either repression of Trubc4 encoding an E2 (ubiquitin-conjugating enzyme) or deletion of Trfwd1 encoding an F-box protein significantly compromised the induced cellulase biosynthesis. However, combinatorial repression of cre1 suppressed the phenotypic defects resultant from mutations of Trubc4 or Trfwd1. Further analyses demonstrated that TrUbc4 and TrFwd1 collaboratively mediated the ubiquitination of Cre1. Impaired ubiquitination of Cre1 at K361 resulted in its enhanced binding to cellulase gene promoters even under cellulose inducing conditions. This persistent Cre1 binding in turn competitively excluded the functional promoter occupancy of the transcriptional activator Xyr1 required for full cellulase gene expression. These results thus support that Cre1 ubiquitination constitutes a primary mechanism to relieve CCR to ensure the efficient cellulase induction. The present work also highlights the importance of protein ubiquitination for control of carbohydrate utilization and biotechnologically relevant enzyme production in industrial filamentous fungi including Trichoderma reesei.
Cold-responsive interaction between MdRAD23D1 and MdMYB15 confers cold stress tolerance via the CBF pathway in apple (Malus domestica).
Zhang X, Zhao B, Li X … +4 more , Xia H, Ma F, Liang D, Gong X
PLoS Genet · 2026 Jun · PMID 42348517 · Full text
Low temperature is a major environmental factor that impairs plant growth and development, posing a significant threat to crop yield and quality. RAD23 (RADIATION SENSITIVE23) proteins belong to the UBL-UBA (Uiquitin-lik...
Low temperature is a major environmental factor that impairs plant growth and development, posing a significant threat to crop yield and quality. RAD23 (RADIATION SENSITIVE23) proteins belong to the UBL-UBA (Uiquitin-like-ubiquitin associated) family and function as shuttle factors in the UPS (ubiquitin proteasome system). Although UBL-UBA proteins are known regulators of plant stress responses, the function and mechanism of RAD23 in apple under cold stress are poorly understood. Here, we demonstrated that MdRAD23D1 is induced by 4 °C and positively regulates cold tolerance. Silencing MdRAD23D1 impaired cold tolerance in both apple plants and calli. Conversely, its overexpression enhanced cold tolerance in transgenic tobacco, and apple calli and plants. We further demonstrated that MdRAD23D1 interacted with MdMYB15 protein via in vivo and in vitro assays. MdMYB15 functions as a negative regulator of cold stress tolerance. This is evidenced by the enhanced cold tolerance in apple calli and plants in which MdMYB15 expression was silenced, contrasted with the reduced tolerance in materials of overexpressing MdMYB15. Furthermore, yeast one-hybrid (Y1H), dual-luciferase (Dual-LUC), and electrophoretic mobility shift assays (EMSA) showed that MdMYB15 could bind to the promoters of CBF1, CBF2, and CBF3 and inhibit the expressions of the corresponding genes. In addition, MdRAD23D1 promoted MdMYB15 degradation under cold stress, thus enhancing the cold tolerance of apple. In summary, we proposed a mechanism for the response of apple to cold stress that is mediated by the 'MdRAD23D1-MdMYB15-MdCBFs' modula, which enhances our understanding of the regulation of cold tolerance in apple by UBL-UBA protein.
Exploring mechanisms of scar-free skin wound healing in adult zebrafish in comparison to mouse.
Küçükaylak İ, Halwas K, Martínez Morcillo FJ … +7 more , Reiche N, Metzger M, Comelli P, Voigt B, Brinckmann J, Eming S, Hammerschmidt M
PLoS Genet · 2026 Jun · PMID 42341061 · Full text
Adult zebrafish have the ability to perfectly regenerate their skin after injury without leaving a scar behind. Yet, they intermediately form a collagen-rich granulation tissue that later fully regresses. In contrast, ad...
Adult zebrafish have the ability to perfectly regenerate their skin after injury without leaving a scar behind. Yet, they intermediately form a collagen-rich granulation tissue that later fully regresses. In contrast, adult mammals lose this ability, resulting in persistent tissue fibrosis and scarring. We performed single-cell RNA sequencing and first HCR-based spatial transcriptomics to characterize the dynamics and heterogeneity of involved cell types during different stages of zebrafish cutaneous wound healing, focusing on macrophages and fibroblasts. Macrophage subclusters display pro-inflammatory and/or anti-inflammatory/pro-repair characteristics, and fibroblast subclusters characteristics of extracellular matrix formation and degradation, which largely co-exist during all stages of wound healing. Some wound-specific cells have a signature similar to that of myofibroblasts implicated in fibrotic healing in mammals. However, in contrast to mammalian myofibroblasts, they lack collagen expression, suggesting that they might only share the beneficial, but not the detrimental roles of their mammalian counterparts. Strikingly, zebrafish fibroblasts, in addition to expressing anti-fibrotic genes, express multiple genes with described pro-fibrotic effects in mammalian models. One of them is plod2, which encodes lysylhydroxylase 2. In cutaneous mouse wounds, Plod2 is induced in fibroblasts by the macrophage-released Resistin-like molecule RELMα encoded by the Retlna gene, promoting the formation of DHLNL collagen crosslinks and thereby less resolvable fibrotic tissue. retln genes are absent from the zebrafish genome; nevertheless, plod2 expression is initiated in zebrafish dermal fibroblasts upon wounding, in this case via TGFβ signaling, accompanied by increased collagen DHLNL crosslinking. Yet, both transgenic overexpression and genetic knock-out of plod2 do not interfere with granulation tissue formation and regression, pointing to additional pathways assuring the resolution of temporary fibrosis in zebrafish skin wounds even in the presence of strong collagen crosslinking.
Correlated protein-RNA associations and a requirement for HNRNPU in the long-range recruitment of Polycomb Repressive Complexes by the lncRNAs Airn and Kcnq1ot1.
Murvin MM, Li S, Abrash EW … +5 more , Peck BA, Boyson SP, Zhang Z, Cherney RE, Calabrese JM
PLoS Genet · 2026 Jun · PMID 42335169 · Full text
The lncRNAs Airn and Kcnq1ot1 recruit Polycomb Repressive Complexes (PRCs) and repress genes over multi-megabase genomic intervals, but how they interact with proteins to direct repression remains poorly understood. We c...
The lncRNAs Airn and Kcnq1ot1 recruit Polycomb Repressive Complexes (PRCs) and repress genes over multi-megabase genomic intervals, but how they interact with proteins to direct repression remains poorly understood. We conducted formaldehyde-based RNA-immunoprecipitations (RIPs) of 27 proteins from mouse trophoblast stem cells (TSCs), using a protocol exhibiting similar signal-to-non-specific signal and post-lysis reassociation ratios as crosslinking immunoprecipitation (CLIP) and crosslinking affinity purification (CLAP). Patterns of protein associations across Airn and Kcnq1ot1 were more similar to each other than to nearly all other transcripts and partitioned to extents that mirrored the degree of repression each lncRNA induced, implying connections to mechanism. Indeed, HNRNPU, a factor essential for Xist's localization to chromatin, was enriched over Airn and Kcnq1ot1 and required to maintain normal levels of PRC1- and PRC2-directed chromatin modifications across the Airn and Kcnq1ot1 target domains, yet was dispensable for both lncRNAs' localization to chromatin and for their association with PRC1. HNRNPU depletion caused a greater reduction in PRC-directed chromatin modifications and gene repression across the inactive X and the ~ 15 Mb Airn target domain than across the ~ 3 Mb Kcnq1ot1 domain. Perhaps relatedly, HNRNPU depletion significantly reduced the overall levels of Xist and Airn but not Kcnq1ot1. Our study reports architectures of protein association along Airn and Kcnq1ot1 compared to the transcriptome at large, highlights shared and distinct features between the two lncRNAs, and provides new perspective on the role of HNRNPU in long-range chromatin regulation by lncRNAs.
A point mutation in the FAT domain constitutively increases the kinase activity of Rad3ATR and bypasses the requirement for 9-1-1 phosphorylation to activate the DNA replication checkpoint.
Dev K, Rider SD, Singh B … +2 more , Saini A, Xu YJ
PLoS Genet · 2026 Jun · PMID 42330073 · Full text
Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoin...
Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoint initiation remains incompletely understood. The canonical model suggests that binding of an ATR-activator protein relieves the autoinhibitory PIKK regulatory domain (PRD) within the kinase domain, thereby activating ATR by granting substrate access to the catalytic centre. To better understand the checkpoint initiation mechanism, we conducted a genetic screen in fission yeast that identified a charge-reversal mutation, E1369K, in the conserved FRAP-ATM-TRRAP (FAT) domain of Rad3, the ortholog of ATR. In vitro kinase assays show that the mutation converts Rad3 into a constitutively active form. This allows rescue of the Rad3 kinase signaling defect in cells lacking the phosphorylation of the Rad9-Rad1-Hus1 (9-1-1) complex specifically in the DNA replication checkpoint, not the damage checkpoint pathway. Since the mutation is not in the kinase domain and is away from the PRD, these findings show that, in addition to the canonical mechanism, Rad3 may also be activated allosterically via the FAT domain, a mechanism likely conserved in higher eukaryotes.
Lysosome-related organelles employ divergent mechanisms to modulate cytosolic zinc homeostasis.
Xie C, Luo Y, Zheng Y … +5 more , Liu B, Song S, Wei J, Shi A, Yan Y
PLoS Genet · 2026 Jun · PMID 42329921 · Full text
Elevated environmental zinc levels pose significant toxicity to biological systems, necessitating adaptive responses to mitigate excessive zinc exposure. In C. elegans, a specific lysosome-related organelle, the gut gran...
Elevated environmental zinc levels pose significant toxicity to biological systems, necessitating adaptive responses to mitigate excessive zinc exposure. In C. elegans, a specific lysosome-related organelle, the gut granule, may increase in number and volume with high dietary zinc, thereby lowering cytosolic zinc concentration, though the mechanisms remain unclear. Our results suggest that GLO-1 predominantly controls granule biogenesis, whereas zinc-induced granule expansion involves distinct mechanisms. Further study revealed that high zinc upregulated GLO-1 activity through its GEF complex GLO-3-CCZ-1, by enhancing transcription of GLO-3 and post-translational modification of CCZ-1. Zinc transporter CDF-2 has been identified to mediate zinc influx into gut granules. In this study, analysis of 14 C. elegans CDFs reveals that ZK185.5 (CDF-3) and F19C6.5 (CDF-4) also localize in gut granules. Functional studies suggest that CDF-3, not CDF-4, complements CDF-2 in facilitating zinc influx into gut granules. Unlike CDF-2, the expression of CDF-3 is downregulated in a high zinc diet. These results suggest a modulation in the composition of CDFs within gut granules in response to environmental zinc. Together, our study reveals a sophisticated zinc detoxification mechanism of C. elegans gut granule to uphold cytosolic zinc homeostasis amidst fluctuating environments.
Genetic analysis and mapping of adult plant stripe rust resistance loci in CIMMYT wheat 'Kijil' under Mexican and Chinese field environments.
Yan S, Teng L, Xi M … +7 more , Yuan C, Wang L, Li S, Huerta-Espino J, Bhavani S, Singh RP, Lan C
PLoS Genet · 2026 Jun · PMID 42313875 · Full text
Stripe rust, caused by Puccinia striiformis f. sp. tritici, can cause severe yield losses in wheat (Triticum aestivum L.) during epidemics. Breeding resistant wheat varieties remains the most cost-effective approach to m...
Stripe rust, caused by Puccinia striiformis f. sp. tritici, can cause severe yield losses in wheat (Triticum aestivum L.) during epidemics. Breeding resistant wheat varieties remains the most cost-effective approach to manage this disease; and the identification of new resistance loci is essential for maintaining genetic diversity. The CIMMYT-derived wheat line 'Kijil' was highly resistant to stripe rust in both Mexican and Chinese environments. A population of 153 F₅ recombinant inbred lines (RILs) was derived from a cross between Kijil and the susceptible parent 'Apav#1'. The population was phenotyped for stripe rust resistance across seven environments in two countries and genotyped using a genotyping-by-sequencing (GBS) platform. Inclusive composite interval mapping (ICIM) was used to construct a genetic map and identify significant resistance quantitative trait loci (QTLs) using 5,468 polymorphic markers. Mapping revealed the known resistance loci Yr29, Yr30 and QYr.hzau-3AS, along with two novel loci, QYr.hzau-2BS and QYr.hzau-5DL, across both Chinese and Mexican rust environments. Among these, QYr.hzau-2BS accounted for 11.75% to 19.19% of the phenotypic variance. A corresponding KASP marker, KASP_2BS, was developed to facilitate marker-assisted selection. Based on the mapping interval, two candidate genes underlying this locus were predicted. Further analysis revealed that Yr29 showed significant additive effects with other stripe rust resistance genes/loci, and the combination of Yr29, Yr30, and QYr.hzau-2BS reduced disease severity by up to 67.8%. Our findings suggest that Kijil and RILs carrying Yr29, Yr30, and QYr.hzau-2BS can serve as valuable donors for breeding wheat varieties with improved stripe rust resistance.
Towards a unified model of aneuploid karyotype dynamics.
Hénault M, Wood LM, Heasley LR
PLoS Genet · 2026 Jun · PMID 42313851 · Full text
Aneuploidies-whole-chromosome copy number imbalances arising from nondisjunction-underlie numerous congenital and somatic disorders, but unlike many other disease-causing variants, they can revert back to euploidy throug...
Aneuploidies-whole-chromosome copy number imbalances arising from nondisjunction-underlie numerous congenital and somatic disorders, but unlike many other disease-causing variants, they can revert back to euploidy through subsequent errors of the same type. The extent to which this inherent plasticity impacts the stability and persistence of aneuploid karyotypes in populations remains poorly understood, a gap in knowledge that continues to limit our understanding of aneuploidy-driven disease incidence, penetrance, and progression. To assess how reversion shapes aneuploid population dynamics, we developed a budding yeast system to systematically measure the rates at which aneuploidies arise and revert and quantify the relative fitness differences between these karyotypic states. We integrated these data into a computational framework encompassing the broad physiological range of aneuploid karyotype dynamics captured in our experiments. The resulting models reveal that canonical reversion (i.e., subsequent secondary nondisjunction) occurs rarely, conferring a negligible effect on the population dynamics of most chromosomal aneuploidies. However, our models also identified that the reversion dynamics of some chromosomes-those displaying extremely high apparent rates of reversion-were more consistent with a coupled mutational process involving a transient aneuploid state. Whole-genome sequencing and live-cell microscopy demonstrates one such mechanism is facilitated by unresolved intermolecular linkages that disrupt chromosome segregation, leading to chromosome breakage and recombination-mediated repair over subsequent cell divisions. Collectively, this work advances a model of aneuploid population genetics and expands our perspective of the diverse, and chromosome-specific, mutational mechanisms shaping genome architecture.
Genetic risk for high body mass index before and amidst the obesity epidemic: Cross-cohort analysis of four british birth cohort studies.
Wright L, Davies NM, Shireby G … +3 more , Williams DM, Morris TT, Bann D
PLoS Genet · 2026 Jun · PMID 42313719 · Full text
Obesity is a highly heritable trait, but rising obesity rates suggest environmental change is also of profound importance. We conducted a cross-cohort analysis to examine how associations between genetic risk for high BM...
Obesity is a highly heritable trait, but rising obesity rates suggest environmental change is also of profound importance. We conducted a cross-cohort analysis to examine how associations between genetic risk for high BMI and observed BMI differed in four British birth cohorts born before and amidst the obesity epidemic (1946, 1958, 1970 and ~2001; N = 19,379). BMI (kg/m2) was measured at multiple time points between ages 3 and 69 years. We used polygenic indices (PGI) derived from GWAS of adulthood and childhood BMI, respectively, with mixed effects models used to estimate associations with mean BMI and quantile regression used to assess associations across the distribution of BMI. We further used linear regression to estimate PGI-heritability (PGI-h2; incremental variance explained by the PGI) and Genomic Relatedness Restricted Maximum Likelihood (GREML) to calculate SNP-heritability (SNP-h2) by cohort and age. Adulthood BMI PGI was associated with BMI in all cohorts and ages but was more strongly associated with BMI in more recently born generations, e.g., at age 16y, a 1 SD increase in the adulthood PGI was associated with 0.46 kg/m2 (0.37, 0.55) higher BMI in the 1946c and 0.90 kg/m2 (0.83, 0.97) higher BMI in the 2001c. Cross-cohort differences widened with age and were larger at the upper end of the BMI distribution, indicating disproportionate increases in obesity in more recent generations for those with higher PGIs. Differences were also observed when using the childhood PGI. There were no clear, consistent differences in PGI-h2 or SNP-h2, possibly due to limited statistical power, except that PGI-h2 was highest in the most recently born cohort (2001c) when using the most predictive PGI for adulthood BMI. Findings highlight how the environment can modify genetic associations; genetic associations with BMI differed by birth cohort, age, and outcome centile.
Ultra-fast genetic colocalisation across millions of association signals.
Jesse M, Riet AE, Alasoo K
PLoS Genet · 2026 Jun · PMID 42308237 · Full text
Co localisation is a powerful approach to assess if two genetic association signals are likely to share a causal variant. However, association analyses in large bio banks and molecular quantitative trait loci (molmol) st...
Co localisation is a powerful approach to assess if two genetic association signals are likely to share a causal variant. However, association analyses in large bio banks and molecular quantitative trait loci (molmol) studies now routinely identify millions of association signals across thousands of traits, making it infeasible to test for colocalization between all pairs of signals. Here we introduce gpu-coloc, a GPU-accelerated re-implementation of the coloc algorithm that combines efficient data storage with parallelisation to achieve a 1000-fold speed increase while maintaining near-identical results. As a result, the run time of gpu-coloc now approaches the colocalisation posterior probability (CLPP) method, a competing method that only uses information from fine mapped credible sets to detect colocalisations. Using summary statistics from UK Biobank, FinnGen, and eQTL Catalogue, we demonstrate that gpu-coloc and CLPP detect highly concordant results, especially when restricting the analysis to confidently fine mapped signals. We introduce the colocalisation collider metric to quantify spurious colocalisations in large-scale colocalisation graphs and use it to choose decision thresholds that provide a reasonable trade-off between sensitivity and specificity. Finally, we demonstrate how gpu-coloc can also be applied to marginal GWAS summary statistics from studies that lack fine mapping, where it is still able to recover molQTL colocalisations for ~80% of the GWAS loci. Our efficient software and comprehensive analyses provide practical guidelines for future large-scale colocalisation analyses.
Functional profiling of 2,193 ASS1 missense variants: Insights into variant pathogenicity and epistatic interactions in citrullinemia type I.
Lo RS, Cromie GA, Tang M … +6 more , Sirr A, Caldovic L, Morizono H, Ah Mew N, Gropman A, Dudley AM
PLoS Genet · 2026 Jun · PMID 42308225 · Full text
Sequence variants in the urea cycle gene argininosuccinate synthase (ASS1) cause Citrullinemia type 1 (CTLN1), a rare autosomal recessive disease. Mechanistically, reduction in argininosuccinate synthetase (ASS) enzyme a...
Sequence variants in the urea cycle gene argininosuccinate synthase (ASS1) cause Citrullinemia type 1 (CTLN1), a rare autosomal recessive disease. Mechanistically, reduction in argininosuccinate synthetase (ASS) enzyme activity impairs the urea cycle, leading to an accumulation of citrulline and neurotoxic ammonia. Disease severity varies according to the degree of enzyme impairment, ranging from severe neonatal forms (classic citrullinemia) to milder, late-onset forms that may manifest in childhood or adulthood. We established a high-throughput yeast functional assay of human ASS and individually measured the impact of 2,193 amino acid substitutions, representing 90% of all single nucleotide variant (SNV)-accessible substitutions. When benchmarked against existing clinical variant annotation, our assay distinguishes known benign variants from strong loss of function pathogenic variants, enabling identification of a functional score threshold below which variants show clinically relevant impairment of ASS activity. Using the ACMG OddsPath framework, our assay meets PS3_supporting criteria for pathogenicity classification and achieves full PS3-level strength when variants observed as homozygotes in other primates are used as benign proxies for calibration. These results provide direct functional evidence to inform reclassification of ASS1 missense variants. Under the current ACMG guidelines, inclusion of our data yielded definitive classifications (pathogenic or likely pathogenic) for all 25 ClinVar VUS falling in the functionally impaired range of our assay. Mapping functional scores onto the protein structure, we confirmed that residues involved in catalysis are highly sensitive to substitution. In addition, we identified residues from adjacent subunits of the ASS homotetramer that form compound active sites. Assaying these positions revealed a capacity for intragenic complementation consistent with a variant sequestration model: a form of positive epistasis in which deleterious variants from different subunits are sequestered into only a subset of active sites, restoring function in the remaining variant-free sites. The discovery of intragenic complementation in ASS reveals a novel mode of functional interaction with clinical implications for interpreting variant combinations in heterozygous individuals.
Retraction: Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence.
PLOS Genetics Editors
PLoS Genet · 2026 Jun · PMID 42301994 · Full text
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CsmR controls both, motility and cell shape, in Haloferax volcanii.
Nußbaum P, Grünberger F, Neuschütz F … +10 more , Chou K, Sivabalasarma S, Eulitz A, Sailer AL, Vogl K, Exterkate M, He W, Marchfelder A, Grohmann D, Albers SV
PLoS Genet · 2026 Jun · PMID 42284368 · Full text
Archaea rely on motility and morphological plasticity to navigate their environments, yet the transcriptional regulation of these processes remains poorly understood. In Haloferax volcanii, archaellum-dependent motility...
Archaea rely on motility and morphological plasticity to navigate their environments, yet the transcriptional regulation of these processes remains poorly understood. In Haloferax volcanii, archaellum-dependent motility is transcriptionally regulated, but an EarA-like central regulator for transcription of archaellum genes that is found in other Euryarchaeota like Methanococcus maripaludis or Pyrococcus furiosus, is absent. Here, we identify CsmR as a transcriptional regulator that controls archaellum biogenesis and cell-shape transitions in H. volcanii. Deletion of csmR abolished detectable motility, whereas overexpression increased motility and promoted a sustained rod-like morphology. Comparative transcriptomics defined a CsmR-associated regulon that includes archaellum and chemotaxis genes as well as cell-shape determinants (e.g., Sph3 and RdfA), and ChIP-seq identified promoter-proximal binding sites consistent with direct transcriptional control. Furthermore, csmR and cirA, a KaiC-like regulator, share extensive transcriptional overlap, with CirA potentially fine-tuning CsmR-mediated regulation through post-translational modification. These findings establish CsmR as a key regulator of archaellum gene expression and cell shape regulation in Haloferax volcanii, suggesting that haloarchaea coordinate these fundamental processes through an unidentified transcriptional network. Moreover, Northern blotting and cell shape observation suggest that transcription factor RosR is involved in the regulation of an regulatory RNA that shares extensive overlap with the cirA gene, possibly fine-tuning the effect of CirA on the regulation of the archaellum cluster and the rod shape determinants sph3 and rdfA. Understanding this interplay provides new insights into archaeal adaptability and may reveal broader regulatory principles in prokaryotic cell biology.
Metabolism fine tuning and cardiokines secretion represent adaptative responses of the heart to High Fat and High Sugar Diets in flies.
Khamvongsa-Charbonnier L, Kremmer L, Torres M … +7 more , Krifa S, Aubert C, Corbet A, Crespo L, Roder L, Perrin L, Arquier N
PLoS Genet · 2026 Jun · PMID 42275457 · Full text
Cardiopathies are one of the leading causes of death in obese diabetics. Diabetic cardiomyopathies are notably characterized by contractile dysfunctions. Using the Drosophila model for cardiac function in pathophysiologi...
Cardiopathies are one of the leading causes of death in obese diabetics. Diabetic cardiomyopathies are notably characterized by contractile dysfunctions. Using the Drosophila model for cardiac function in pathophysiological context, we identified a set of candidate genes whose cardiac expression is modulated by High Sugar and High Fat regimes. Genes encoding core components of key homeostatic pathways - such as 1C-metabolism homeostasis, the galactose metabolism pathway and metabolites transporters - were identified and characterized as adaptative factors of cardiac function under nutritional stresses. In addition, putative secreted proteins were found dysregulated, highlighting the heart as a secretory organ in hyperglycemia and hyperlipidemia. In particular, we characterized the Fit satiety hormone as a new fly cardiokine, which autonomously modulates the cardiac function and remotely affects feeding behavior. Overall, our study uncovered autonomous and systemic adjustable responses of the heart to nutritional stresses.
FEMA-Long: Modeling unstructured covariances for discovery of time-dependent effects in large-scale longitudinal datasets.
Parekh P, Parker N, Pecheva D … +23 more , Frei E, Vaudel M, Smith DM, Rigby A, Jahołkowski P, Sønderby IE, Birkenæs V, Bakken NR, Fan CC, Makowski C, Kopal J, Loughnan R, Hagler DJ, van der Meer D, Johansson S, Njølstad PR, Jernigan TL, Thompson WK, Frei O, Shadrin AA, Nichols TE, Andreassen OA, Dale AM
PLoS Genet · 2026 Jun · PMID 42275417 · Full text
While linear mixed-effects (LME) models are common for analyzing longitudinal data, most users rely on random intercepts or simple stationary covariance, due to unavailability of computationally tractable solutions. Here...
While linear mixed-effects (LME) models are common for analyzing longitudinal data, most users rely on random intercepts or simple stationary covariance, due to unavailability of computationally tractable solutions. Here, we extend the Fast and Efficient Mixed-Effects Algorithm (FEMA) and present FEMA-Long, a computationally tractable approach to flexibly modeling longitudinal covariance suitable for high-dimensional data. FEMA-Long can: i) model unstructured covariance, ii) model covariates as smooth functions using splines, iii) discover time-dependent effects of covariates with spline interactions, and iv) use these flexible longitudinal modeling strategies to perform longitudinal genome-wide association studies and discover time-dependent genetic effects, in a computationally scalable manner, suitable for high-dimensional data. Through extensive simulations, we show that estimates from FEMA-Long are accurate, while being up to several thousand times faster and with minimal carbon footprint. To show the utility of FEMA-Long for discovering novel biological signal, using data from the Norwegian Mother, Father and Child Cohort Study (MoBa), we performed a longitudinal genome-wide association study with non-linear SNP-by-time interaction on length, weight, and BMI of 68,273 infants with up to six measurements in the first year of life. We found dynamic patterns of random effects including time-varying heritability and genetic correlations, as well as several genetic variants showing time-dependent effects, highlighting the applicability of FEMA-Long to enable novel discoveries.
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