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Article
| Open AccessPervasive epistasis exposes intramolecular networks in adaptive enzyme evolution
Here, the authors perform statistical analyses to demonstrate that epistasis is highly pervasive in adaptive evolutionary trajectories of enzymes. Using epistatic data, they expose higher-order rewiring of intramolecular amino acid networks.
- Karol Buda
- , Charlotte M. Miton
- & Nobuhiko Tokuriki
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Article
| Open AccessUnraveling the causal genes and transcriptomic determinants of human telomere length
Variation in human telomere length has been well studied, but most previous studies have used adult telomere length. Here, the authors explore the genetic basis of telomere length in the placenta and find suggestive causal genes modulating human telomere length.
- Ying Chang
- , Yao Zhou
- & Dandan Huang
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Article
| Open AccessMultiple independent losses of the biosynthetic pathway for two tropane alkaloids in the Solanaceae family
Hyoscyamine and scopolamine (HS) are two tropane alkaloids with medicinal significance produced by distantly related lineages in the Solanaceae family. Here, the authors assemble the genome of three HS-producing and one non-HS-producing species within Solanaceae, and reveal the evolution of the biosynthetic pathway.
- Jiao Yang
- , Ying Wu
- & Jianquan Liu
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Article
| Open AccessA unique sigma/anti-sigma system in the actinomycete Actinoplanes missouriensis
Bacteria of the genus Actinoplanes form sporangia which, upon contact with water, release motile spores. Here, the authors study the mechanisms behind sporangium dehiscence and discover a sigma/anti-sigma system with unique features.
- Takeaki Tezuka
- , Kyota Mitsuyama
- & Yasuo Ohnishi
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Article
| Open AccessA histone demethylase links the loss of plasticity to nongenetic inheritance and morphological change
A challenge for understanding plasticity is connecting macroevolutionary patterns to molecular mechanisms. Using a nematode model, this study identifies a mediator of nongenetic inheritance which is linked to multigenerational shifts in plasticity and morphology.
- Nicholas A. Levis
- & Erik J. Ragsdale
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Article
| Open AccessiMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis
DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
- Aldo S. Bader
- & Martin Bushell
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Article
| Open AccessPotent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir
Reactivating latent HIV reservoirs could be beneficial towards a functional cure. Here, the authors show that Tat-LNP effectively reactivates HIV while preserving the cell transcriptome. Upon reactivation, p24+ cells exhibit distinct genes and pathways potentially contributing to their persistence.
- Marion Pardons
- , Basiel Cole
- & Linos Vandekerckhove
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Article
| Open AccessDissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
To overcome challenges posted by vast number of GPCR genes and redundancy, the authors disrupted nearly all GPCR-encoding genes in C. elegans, enabling effective examination of GPCR signaling and offering a valuable resource for the research community.
- Longjun Pu
- , Jing Wang
- & Changchun Chen
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Article
| Open AccessGenomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort
Renal cell carcinoma (RCC) subtypes are associated with different molecular alterations and clinical outcomes, but they need to be characterised in diverse cohorts. Here, the authors perform genomic, transcriptomic, and epigenomic profiling in a large cohort of Japanese RCC cases, and identify epi-subtypes associated with a particular immune environment.
- Akihiko Fukagawa
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessGenome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study
Hypertension is a major risk factor for cardiovascular disease prevalent in Africa. Here the authors report a genome-wide study providing insights into the genetics and physiology of blood pressure variation in African populations.
- Surina Singh
- , Ananyo Choudhury
- & Michèle Ramsay
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Article
| Open AccessMaternal dominance contributes to subgenome differentiation in allopolyploid fishes
Cyprinids fish species contain multiple subgenomes as a result of past duplications. Here, Xu et al. report new genomes of 21 cyprinid fish and conclude that observed subgenome dominance patterns are likely due to both maternal dominance and transposable element densities in each polyploid.
- Min-Rui-Xuan Xu
- , Zhen-Yang Liao
- & Hua-Hao Zhang
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Article
| Open AccessEssential transcription factors for induced neuron differentiation
Using integrative multi-omics and CRISPR knock-out of all ~1,900 transcription factors, the authors identify essential transcription factors required for Neurogenin-driven differentiation of human cortical neurons.
- Congyi Lu
- , Görkem Garipler
- & Neville E. Sanjana
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Article
| Open AccessBRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state
BRD9 is a core non-canonical BAF component. Here the authors show that BRD9 plays a pivotal role in regulating the disease-related cell fate of hematopoietic stem cells. Its loss promotes myeloid skewing while impairing B cell development by altering CTCF-mediated chromatin states.
- Muran Xiao
- , Shinji Kondo
- & Daichi Inoue
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Article
| Open AccessDiversity and dissemination of viruses in pathogenic protozoa
Heeren et al study the evolutionary genomics of leishmaniasis in Peru and Bolivia to show that parasite hybridization increases the prevalence, diversity and spread of viruses that have been previously associated with disease severity and treatment failure.
- Senne Heeren
- , Ilse Maes
- & Frederik Van den Broeck
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Article
| Open AccessImmune-response 3′UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases
Alternative polyadenylation (APA) has a key role in the post-transcriptional regulation of most human genes but is understudied in cells of the immune system. Here, the authors construct an atlas of cell type-specific APA events in various immune cell-types and stimulation conditions, providing evidence of widespread stimulation-responsiveness and association with immune-related traits.
- Lei Li
- , Xuelian Ma
- & Wei Li
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Article
| Open AccessPrediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors
Many people who never smoke develop COPD. Here, the authors derive and validate the Socioeconomic and Environmental Risk Score (SERS) which captures cumulative exposure risks beyond tobacco smoking to predict and stratify risk of COPD.
- Yixuan He
- , David C. Qian
- & Chirag J. Patel
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Article
| Open AccessUbiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers
Meiotic drivers of the wtf family kill progeny lacking the driver by producing a toxin and an antidote. Here, authors reveal that ubiquitination-mediated sorting of the antidote prevents it from becoming toxic and enables it to neutralize the toxin.
- Jin-Xin Zheng
- , Tong-Yang Du
- & Li-Lin Du
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Article
| Open AccessOn the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging
Tryptophan metabolism through the kynurenine pathway changes with age and represents a potential intervention target for age associated disease. Here, the authors show that elevating physiological levels of the kynurenine pathway metabolite 3- hydroxyanthranilic acid can promote healthy aging.
- Hope Dang
- , Raul Castro-Portuguez
- & George L. Sutphin
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Article
| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessStructural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing
Here, the authors use single-molecule long-read sequencing to decipher the role of structural variations in high-altitude adaptation, finding evidence that an intergenic deletion down-regulates EPAS1 by disrupting a super-enhancer.
- Jinlong Shi
- , Zhilong Jia
- & Kunlun He
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Article
| Open AccessTopological structures and syntenic conservation in sea anemone genomes
Slowly evolving cnidarians are useful models to study genome architecture. This study shows that sea anemones have a high degree of chromosomal macrosynteny, but poor microsynteny conservation. This is correlated with a small genome size and short distances of cis-regulatory elements to genes.
- Bob Zimmermann
- , Juan D. Montenegro
- & Ulrich Technau
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Article
| Open AccessGenes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
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Article
| Open AccessDissecting the basis for differential substrate specificity of ADAR1 and ADAR2
Human ADAR1 and ADAR2 edit millions of adenosines transcriptome-wide, altering RNA structure. Here the authors show that variations in RNA binding domains influence site-specific editing, enhancing ADAR2-targeted therapeutics.
- Marlon S. Zambrano-Mila
- , Monika Witzenberger
- & Schraga Schwartz
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Article
| Open AccessThe Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes
The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.
- Kaisa Thorell
- , Zilia Y. Muñoz-Ramírez
- & Charles S. Rabkin
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Article
| Open AccessDispersal from the Qinghai-Tibet plateau by a high-altitude butterfly is associated with rapid expansion and reorganization of its genome
The butterfly Parnassius glacialis experienced vast environmental transition when it dispersed out of the Qinghai-Tibet plateau. Here, the authors find that P. glacialis has an unusually large genome with rapid accumulation of transposable elements possibly facilitating its evolutionary adaptation.
- Youjie Zhao
- , Chengyong Su
- & Jiasheng Hao
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Article
| Open AccessRIF1 regulates early replication timing in murine B cells
Here the authors show that in activated B cells, RIF1 primarily binds early-replicating active chromatin and promotes early replication. RIF1 and MCM proteins establish early replication timing signatures genome-wide and ensure early replication of highly transcribed genes.
- Daniel Malzl
- , Mihaela Peycheva
- & Rushad Pavri
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Article
| Open AccessSingle cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines
Intra-cell line heterogeneity remains to be characterized. Here, the use of single multi-omics on a large panel of human cell lines identifies copy number variation, epigenetic variation and extrachromosomal DNA distribution as the main contributors to intra-cell line heterogeneity.
- Qionghua Zhu
- , Xin Zhao
- & Liang Wu
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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Article
| Open Accessvcfdist: accurately benchmarking phased small variant calls in human genomes
Accurately benchmarking small variant calling accuracy is critical for the continued improvement of human genome sequencing. Here, the authors show that current approaches are biased towards certain variant representations and develop a new approach to ensure consistent and accurate benchmarking, regardless of the original variant representations.
- Tim Dunn
- & Satish Narayanasamy
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Article
| Open AccessSTalign: Alignment of spatial transcriptomics data using diffeomorphic metric mapping
Spatial transcriptomics (ST) enables gene expression characterisation within tissue sections, but comparing across sections and technologies remains challenging. Here, authors develop STalign to spatially align ST data and demonstrate applications including aligning to common coordinate frameworks.
- Kalen Clifton
- , Manjari Anant
- & Jean Fan
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Article
| Open AccessOutward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation
The TAD boundaries comprise clustered arrays of CTCF sites with complex orientations. Here the authors show that the outward-oriented CTCF sites within clustered TAD boundaries are central for intra-TAD chromatin spatial contacts and gene regulation.
- Xiao Ge
- , Haiyan Huang
- & Qiang Wu
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Article
| Open AccessTAD evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function
The authors show that the deletion of ultraconserved TAD boundaries affects gene expression and phenotype, highlighting TAD evolution’s function. Human-specific TAD boundaries reveal a role in brain development and disease.
- Mariam Okhovat
- , Jake VanCampen
- & Lucia Carbone
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Article
| Open AccessIn vivo RNA interactome profiling reveals 3’UTR-processed small RNA targeting a central regulatory hub
Here the authors report a new approach to profile RNA-RNA interactions in live bacterial cells. The charted RNA interaction networks unveil a key mRNA regulatory hub targeted by twelve small RNAs, including a novel RNA involved in fatty acid metabolism.
- Fang Liu
- , Ziying Chen
- & Yanjie Chao
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Article
| Open AccessSaturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation
Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.
- Elizabeth J. Radford
- , Hong-Kee Tan
- & Matthew E. Hurles
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Article
| Open AccessMosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa
Mosaic chromosomal alterations (mCAs) in peripheral blood leukocytes are associated with an increased risk of malignancy. Here, the authors use genome-wide genotyping array data to investigate the prevalence of mCAs in sub-Saharan African children with versus those without Burkitt lymphoma.
- Weiyin Zhou
- , Anja Fischer
- & Sam M. Mbulaiteye
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Article
| Open AccessRare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
Here, the authors clarify the architecture of genetic risk on chromosome X in three male-biased psychiatric disorders. Leveraging this information they identify an exome-wide significant autism risk gene, MAGEC3, and provide a path forward for future gene discovery on this chromosome.
- Sheng Wang
- , Belinda Wang
- & A. Jeremy Willsey
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Article
| Open AccessThe PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer
The authors reconstruct high fidelity networks of protein-protein interactions between promoters and enhancers in prostate cancer and demonstrate the potential of such an analytical framework to obtain actionable insights into the disease and potential therapeutic targets.
- Alexandros Armaos
- , François Serra
- & Gian Gaetano Tartaglia
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Article
| Open AccessEvolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle
Hyaluronic acid is believed to plays a critical role in cancer resistance and longevity of the naked mole rat. Here, Zhao and colleagues show that accumulation of high levels of hyaluronic acid has co-evolved repeatedly in mammalian clades with adaptation to subterranean habitats.
- Yang Zhao
- , Zhizhong Zheng
- & Vera Gorbunova
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessJUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease
It has recently been reported a link between Alzheimer’s disease and mobilization of transposable elements (TEs) in heterochromatic regions. Here the authors demonstrate that dysregulation of the pioneer transcription factor c-JUN (AP-1) underlies aberrant transposable element mobilization, associated innate immune 2 response, and impaired neurogenesis in Alzheimer’s disease.
- Chiara Scopa
- , Samantha M. Barnada
- & Marco Trizzino
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Article
| Open AccessNitric oxide controls shoot meristem activity via regulation of DNA methylation
The authors show that gaseous Nitric Oxide (NO) promotes transit amplifying cell fate in the Arabidopsis shoot meristem. NO acts by modifying AGO4-WUSCHEL protein interactions in stem cells, directly linking NO signaling with DNA methylation.
- Jian Zeng
- , Xin’Ai Zhao
- & Jan U. Lohmann
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Article
| Open AccessAccurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix
The authors propose “HEELS”, a new method for precise local heritability estimation. It significantly reduces the variances of summary-statistics-based heritability estimators, offering an REML-like estimator without requiring individual-level data.
- Hui Li
- , Rahul Mazumder
- & Xihong Lin
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Article
| Open AccessDynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
Off-target toxicity of antisense oligonucleotides (ASOs) poses a challenge for their clinical use. Here, authors develop a toehold-bearing ASO architecture that mitigates a broad spectrum of off-target interactions, significantly enhancing the safety profile of ASO drugs.
- Chisato Terada
- , Kaho Oh
- & Tsuyoshi Yamamoto
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Article
| Open AccessWhole genomes from Angola and Mozambique inform about the origins and dispersals of major African migrations
African human genome variation remains under-sampled. Here, the authors present a collection of 350 whole genome sequences from Angola and Mozambique and model the timing and extent of significant demographic events in African history.
- Sam Tallman
- , Maria das Dores Sungo
- & Sandra Beleza
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Article
| Open AccessSMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors
The regulatory landscape of malignant rhabdoid tumor (MRT) due to SMARCB1 loss remains to be explored. Here, the authors perform multi-omics analysis using patient-derived MRT organoids and characterise the epigenetic reprogramming events underlying SMARCB1 loss.
- Ning Qing Liu
- , Irene Paassen
- & Jarno Drost
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Article
| Open AccessSoybean reduced internode 1 determines internode length and improves grain yield at dense planting
Many cereal crops have been bred to be more compact to allow high-density planting, but soybean has remained relatively overlooked. Here, the authors describe a compact soybean mutant, reduced internode 1, that significantly enhances grain yield under high-density planting conditions compared to an elite cultivar.
- Shichen Li
- , Zhihui Sun
- & Sijia Lu
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Article
| Open AccessHaplotype-based inference of recent effective population size in modern and ancient DNA samples
The authors introduce a new computational method, HapNe, for inferring the recent effective size of human populations. HapNe does not require high-quality genotype data, making it suitable for the study of ancient DNA samples.
- Romain Fournier
- , Zoi Tsangalidou
- & Pier Francesco Palamara
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Article
| Open AccessBuilding a eukaryotic chromosome arm by de novo design and synthesis
In Saccharomyces cerevisiae, the left arm of chromosome XII only requires 12 genes to maintain cell viability, whereas 25 genes are needed for robust fitness. Here the authors demonstrate that the entire arm can be replaced by a neochromosome with completely artificial sequences.
- Shuangying Jiang
- , Zhouqing Luo
- & Junbiao Dai
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Article
| Open AccessStrong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.
- Yask Gupta
- , David J. Friedman
- & Simone Sanna-Cherchi
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