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Article
| Open AccessThe gene “degrees of kevin bacon” (dokb) regulates a social network behaviour in Drosophila melanogaster
The structure of a social network is thought to be heritable in many animals, including humans. Here, Rooke and colleagues identify a gene, which they name “degrees of kevin bacon (dokb)”, that is expressed in the central nervous system of Drosophila melanogaster and regulates the structure of social networks.
- Rebecca Rooke
- , Joshua J. Krupp
- & Joel D. Levine
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Article
| Open AccessUnraveling the mechanisms of PAMless DNA interrogation by SpRY-Cas9
CRISPR-Cas9 is a powerful tool, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence limits the number of editable genes. Here the authors combine enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognises target sites for cleavage.
- Grace N. Hibshman
- , Jack P. K. Bravo
- & David W. Taylor
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Article
| Open AccessA case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID
Leukaemia development has been reported as an associated risk of haematopoietic stem cell gene therapy (HSPC-GT) using retroviral vectors in different diseases. Here, the authors show a case of T-cell acute lymphoid leukaemia in a patient with Adenosine Deaminase-deficient Severe Combined Immunodeficiency (ADA-SCID) treated with retroviral gene therapy.
- Daniela Cesana
- , Maria Pia Cicalese
- & Alessandro Aiuti
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Article
| Open AccessDopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo
Here, the authors report that schizophrenia risk variants mapping to a striatal dopamine-related gene set are associated with increased striatal dopamine synthesis capacity and increased striatal activity during reward anticipation in humans.
- Leonardo Sportelli
- , Daniel P. Eisenberg
- & Giulio Pergola
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Article
| Open AccessPositive selection in the genomes of two Papua New Guinean populations at distinct altitude levels
This study explores selection signals of Papua New Guinean highlanders and lowlanders using 128 new whole genome sequences. It highlights two genetic variants associated with blood traits that also influence the heart rate of these populations.
- Mathilde André
- , Nicolas Brucato
- & François-Xavier Ricaut
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Article
| Open AccessHIV transmission dynamics and population-wide drug resistance in rural South Africa
There is limited data on drug resistance in South African communities strongly affected by HIV. In this study, the authors observed low levels of resistance to newer drugs but widespread resistance to older HIV medications in a South African community. Resistance to rilpivirine was detected even in untreated individuals.
- Steven A. Kemp
- , Kimia Kamelian
- & Ravindra K. Gupta
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Article
| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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Article
| Open AccessLinear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters
In neural progenitor cells, recurrent DNA break clusters (RDCs) occur to genes crucial for brain function. Here the authors find that most RDCs emerge at long-traveling unidirectional replication forks, and often unrelated to R-loops.
- Lorenzo Corazzi
- , Vivien S. Ionasz
- & Pei-Chi Wei
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Article
| Open AccessDiphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
Rare disease DEDSSH1-associated DPH1 mutations impair eEF2 diphthamide modification that leads to eEF2 as a transcriptional coactivator for p53 to enhance expression of the cell proliferation inhibitor p21, resulting in birth defects.
- Yu Shi
- , Daochao Huang
- & Weihong Song
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Article
| Open AccessDeep learning the cis-regulatory code for gene expression in selected model plants
This study explores the variation in gene regulation across plant species and genotypes using interpretable deep learning on DNA sequence and RNA-seq data, demonstrating the models’ utility in functional genomics and phenotypic trait prediction.
- Fritz Forbang Peleke
- , Simon Maria Zumkeller
- & Jędrzej Szymański
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Article
| Open AccessPatrilineal segmentary systems provide a peaceful explanation for the post-Neolithic Y-chromosome bottleneck
Prior work has identified a male-only effective population size bottleneck 3-5000 years ago. While violent competition has been proposed as a cause, the authors here show that a segmentary patrilineal system with lineal fission provides a peaceful alternative explanation.
- Léa Guyon
- , Jérémy Guez
- & Raphaëlle Chaix
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Article
| Open AccessEmergence of enhancers at late DNA replicating regions
Here the authors report that enhancers appear more often in late-replicating DNA regions and are enriched for mutations affecting TF binding. This relationship with DNA replication time is seen in species evolution and cancer, suggesting a fundamental principle of genome evolution.
- Paola Cornejo-Páramo
- , Veronika Petrova
- & Emily S. Wong
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Article
| Open AccessEZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition
Cells carrying EZH2 mutations found in lymphoma show a specific transcriptional response to PRC2 inhibition. A longitudinal study reveals unexpected genetic heterogeneity in follicular lymphomas, with implications for therapeutic strategies.
- Pierre Romero
- , Laia Richart
- & Raphaël Margueron
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Article
| Open AccessLarge-scale cross-ancestry genome-wide meta-analysis of serum urate
This large-scale cross-ancestry genome-wide association study reveals the genetic architecture of serum urate across ancestries and identifies urate-associated diseases and potential targets of urate-lowering drugs.
- Chamlee Cho
- , Beomsu Kim
- & Hong-Hee Won
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Article
| Open AccessA genomic basis of vocal rhythm in birds
Little is known about the genetic basis of the rhythmic component of bird song, an important trait in sexual selection and species recognition. By studying a system with innate vocalizations, the Pogoniulus tinkerbirds, this study finds candidate genes that underlie differences in speed in vocal rhythm in this system.
- Matteo Sebastianelli
- , Sifiso M. Lukhele
- & Alexander N. G. Kirschel
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Article
| Open AccessClinical associations with a polygenic predisposition to benign lower white blood cell counts
Here, the authors find that a benign polygenic predisposition to lower white blood cell counts is associated with multiple clinical endpoints, suggesting that predisposed individuals are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
- Jonathan D. Mosley
- , John P. Shelley
- & Vivian K. Kawai
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Article
| Open AccessAn approach to identify gene-environment interactions and reveal new biological insight in complex traits
Here, the authors report 5 loci interacting with smoking/alcohol for serum lipids using a new method akin to Mendelian randomization. They unveil significant heritability through gene-environment interaction and mediation, enhancing understanding of complex trait genetics.
- Xiaofeng Zhu
- , Yihe Yang
- & Hugues Aschard
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Article
| Open AccessTAD boundary deletion causes PITX2-related cardiac electrical and structural defects
This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.
- Manon Baudic
- , Hiroshige Murata
- & Julien Barc
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Article
| Open AccessMassively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes
The function of rare non-coding variants remains challenging to decipher. Here, the authors developed MapUTR to uncover 10,524 functional rare 3’ UTR variants regulating mRNA abundance, many of which reside in cancer driver genes.
- Ting Fu
- , Kofi Amoah
- & Xinshu Xiao
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Article
| Open AccessLKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes
Age has an impact on circadian rhythm. Here, the authors report that LKRSDH-dependent H3R17me2 and H3K27me3 at insulin-like peptide sites contribute to age-related circadian rhythm change in Drosophila.
- Pengfei Lv
- , Xingzhuo Yang
- & Juan Du
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Article
| Open AccessTracing genetic diversity captures the molecular basis of misfolding disease
Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management.
- Pei Zhao
- , Chao Wang
- & William E. Balch
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Article
| Open AccessThe genetic landscape of a metabolic interaction
Reynolds and colleagues examine a biochemically-mediated epistatic interaction between metabolic enzymes involved in folate metabolism and show that biochemical coupling shapes the range of enzyme activities sufficient to rescue cell growth.
- Thuy N. Nguyen
- , Christine Ingle
- & Kimberly A. Reynolds
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Matters Arising
| Open AccessThe wheat stripe rust resistance gene YrNAM is Yr10
- Katherine Dibley
- , Matthias Jost
- & Peng Zhang
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Article
| Open AccessA pair of atypical NLR-encoding genes confers Asian soybean rust resistance in soybean
Asian soybean rust (ASR) is a devastating disease of soybean. Here, the author report the identification of an atypical pair of nucleotide-binding leucine-rich repeat (NLR) encoding genes and how they function together to confer broad-spectrum resistance to ASR.
- Qingnan Hao
- , Hongli Yang
- & Xinan Zhou
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Article
| Open AccessPhylogenomic profiles of whole-genome duplications in Poaceae and landscape of differential duplicate retention and losses among major Poaceae lineages
Grasses share a whole-genome duplication called rho, but the adaptive implications are unclear. Here, the authors conduct phylogenomic and phylotranscriptomic analyses of 363 grasses, identifying additional whole-genome duplications and finding that duplicates are implicated in environmental adaptations or morphogenesis.
- Taikui Zhang
- , Weichen Huang
- & Hong Ma
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Article
| Open AccessCombined and differential roles of ADD domains of DNMT3A and DNMT3L on DNA methylation landscapes in mouse germ cells
DNMT3A and DNMT3L form a complex to deposit DNA methylation in mammalian germ cells. Here, the authors report that loss-of-function of ADD domains of DNMT3A and/or DNMT3L has various impacts on DNA methylation landscapes in mouse oocytes and sperm.
- Naoki Kubo
- , Ryuji Uehara
- & Hiroyuki Sasaki
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Article
| Open AccessUltrasensitive single-step CRISPR detection of monkeypox virus in minutes with a vest-pocket diagnostic device
The recent monkeypox outbreak highlighted the need for rapid and accurate diagnosis of this disease. Here, authors develop an ultrasensitive and streamlined CRISPR assay using miniaturized device, which can detect monkeypox virus in rash fluid swab, oral swab, saliva, and urine within 15 minutes.
- Yunxiang Wang
- , Hong Chen
- & Shengqi Wang
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Article
| Open AccessDifferentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus
Gene-editing at the DM1 mutant locus revealed a fundamental difference between undifferentiated and differentiated cell states: abnormal epigenetic modifications cannot be repaired after differentiation.
- Tayma Handal
- , Sarah Juster
- & Rachel Eiges
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Article
| Open AccessAn ensemble penalized regression method for multi-ancestry polygenic risk prediction
Great efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However most existing PRS are primarily trained on European ancestry populations, limiting their transferability to non-European populations. Here the authors propose a new multi-ancestry PRS method, PROSPER, to reduce disparity of PRS performance across ancestry groups.
- Jingning Zhang
- , Jianan Zhan
- & Nilanjan Chatterjee
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Article
| Open AccessSplice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat
Somatic expansion of a CAG repeat in HTT drives onset of Huntington’s disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.
- Zachariah L. McLean
- , Dadi Gao
- & James F. Gusella
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Article
| Open AccessIntrogression and disruption of migration routes have shaped the genetic integrity of wildebeest populations
The evolutionary genetics of a keystone savannah species the blue wildebeest, and the related black wildebeest, remain largely unexplored. This study finds evidence for archaic introgression of black wildebeest to blue wildebeest and detrimental effects of human activities on migratory populations.
- Xiaodong Liu
- , Long Lin
- & Rasmus Heller
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Article
| Open AccessUtility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling
Here, the authors analyze polygenic scores for 457 phenotypes, finding 49 with robust polygenic score predictive models ( > 0.6 AUC). They find that population diversity and environmental factor integration are key considerations to improving the model’s performance.
- Ting-Hsuan Sun
- , Chia-Chun Wang
- & Kai-Cheng Hsu
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Article
| Open AccessAllopolyploid origin and diversification of the Hawaiian endemic mints
Hawaiian endemic mints represent the second largest plant radiation in the archipelago. Here, the authors present a reference genome and numerous resequenced individuals to uncover evidence for polyploidy, geographic speciation and localized hybridization underlying diversification in this lineage
- Crystal M. Tomlin
- , Sitaram Rajaraman
- & Charlotte Lindqvist
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Article
| Open AccessDNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues
Analysis of 92 human homeodomain mutants, including disease-associated variants and variants of uncertain significance, reveals variants with altered DNA binding affinity and/or specificity and specificity-determining positions.
- Kian Hong Kock
- , Patrick K. Kimes
- & Martha L. Bulyk
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Article
| Open AccessA membrane associated tandem kinase from wild emmer wheat confers broad-spectrum resistance to powdery mildew
Powdery mildew is a fungal leaf disease that reduces yield and grain quality in susceptible wheat varieties. Here, the authors report the cloning of the wild emmer wheat originated powdery mildew resistance gene Pm36 as a membrane associated tandem kinase and its possible resistance mechanism.
- Miaomiao Li
- , Huaizhi Zhang
- & Zhiyong Liu
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Article
| Open AccessStructure-guided functional suppression of AML-associated DNMT3A hotspot mutations
DNMT3A R882H and R882C are mutation hotspots in acute myeloid leukemia. This study describes the structural and functional consequences of the DNMT3A R882H/R882C mutations which can provide a strategy for therapy of the disease mutations.
- Jiuwei Lu
- , Yiran Guo
- & Jikui Song
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Article
| Open AccessNonlinear DNA methylation trajectories in aging male mice
DNA methylation is an age biomarker, but nonlinear aspects of its age-related dynamics are not well characterized. Here, the authors identify loci that undergo sudden methylation changes at specific life stages in the aging colon of male mice.
- Maja Olecka
- , Alena van Bömmel
- & Steve Hoffmann
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Article
| Open AccessAn Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress
In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway.
- Carlos A. Vergani-Junior
- , Raíssa De P. Moro
- & Marcelo A. Mori
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Article
| Open AccessA chromosomal-scale genome assembly of modern cultivated hybrid sugarcane provides insights into origination and evolution
Modern sugarcane cultivars have complicated genome due to interspecific crosses and multiple backcrossing. Here, the authors report the haplotype-resolved, chromosome-level genome assembly of a modern hybrid sugarcane cultivar and reveal the expansion of genes related to sugar accumulation and smut resistance.
- Yixue Bao
- , Qing Zhang
- & Muqing Zhang
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Article
| Open AccessIntegration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment
Risk prediction for prognosis in colorectal cancer is an important tool. Here, the authors utilise GWAS from 5 cohorts of colorectal cancer patients, and show a healthy lifestyle is associated with a 7.6% improvement in overall survival among patients with high pathologic and genetic risk.
- Junyi Xin
- , Dongying Gu
- & Meilin Wang
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Article
| Open AccessSingle-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.
- Amélie Roehrig
- , Theo Z. Hirsch
- & Eric Letouzé
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Article
| Open AccessSOXC are critical regulators of adult bone mass
Angelozzi et al. uncover key mechanisms involved in physiological and pathological bone mass remodeling by showing that SOXC transcription factors regulate the bone formation and resorption balance via critical roles in LepR+ mesenchymal stem cells.
- Marco Angelozzi
- , Anirudha Karvande
- & Véronique Lefebvre
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Article
| Open AccessTranslation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations
An emerging therapeutic strategy is to suppress nonsense mutations with engineered suppressor tRNAs. Here, the authors show that the mRNA translation velocity is a key parameter determining the efficacy of suppressor tRNAs.
- Nikhil Bharti
- , Leonardo Santos
- & Zoya Ignatova
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Article
| Open AccessSeeding the meiotic DNA break machinery and initiating recombination on chromosome axes
Meiotic cells deliberately break their DNA to allow chromosomes to swap genetic material. Here, authors reveal genetically separable pathways controlling the seeding and growth of chromosome-bound protein condensates responsible for DNA breaks.
- Ihsan Dereli
- , Vladyslav Telychko
- & Attila Tóth
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Article
| Open AccessA distal enhancer guides the negative selection of toxic glycoalkaloids during tomato domestication
This study identified a distal enhancer GE1, which acts as the key regulator controlling steroidal glycoalkaloids metabolism by modulating the GAME gene cluster and guides negative selection of steroidal glycoalkaloids production during tomato domestication.
- Feng Bai
- , Peng Shu
- & Mingchun Liu
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Article
| Open AccessExome-wide analysis implicates rare protein-altering variants in human handedness
Left-handedness is a common and partly heritable trait. Here, the authors perform a genome-wide screen for rare, protein-altering genetic variants associated with handedness in over 350,000 people, and implicate the tubulin gene TUBB4B.
- Dick Schijven
- , Sourena Soheili-Nezhad
- & Clyde Francks
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Article
| Open AccessEarly detection of emerging viral variants through analysis of community structure of coordinated substitution networks
Rise of new viral strains is a major public health challenge, demanding advanced detection and forecasting methods. This study shows how examining communities within networks of viral mutations enables early detection of emerging strains.
- Fatemeh Mohebbi
- , Alex Zelikovsky
- & Pavel Skums
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Article
| Open AccessArchaeological and molecular evidence for ancient chickens in Central Asia
The origin and dispersal of the chicken across Eurasia is unclear. Here, the authors examine eggshell fragments from southern Central Asia with paleoproteomics to identify chicken eggshells, suggesting that chickens may have been an important dietary component as early as 400BCE.
- Carli Peters
- , Kristine K. Richter
- & Robert N. Spengler III
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Article
| Open AccessA negative feedback loop between TET2 and leptin in adipocyte regulates body weight
The epigenetic regulation in adipocytes during obesity remains poorly understood. Here, the authors demonstrate a negative feedback loop between TET2, a DNA demethylation enzyme, and leptin, an adipokine, in adipocytes, unveiling a compensatory mechanism by which the body counteracts the metabolic dysfunction induced by obesity.
- Qin Zeng
- , Jianfeng Song
- & Tuo Deng
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