Featured
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Article
| Open AccessThe dynamic genetic determinants of increased transcriptional divergence in spermatids
Here the authors show that genetic changes between species often alter gene expression in a cell type-specific manner. Most of this variability is driven by locally functioning cis-acting variation, and this contributes to the speed at which cell types accumulate expression changes.
- Jasper Panten
- , Tobias Heinen
- & Duncan T. Odom
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Article
| Open AccessMatrin3 mediates differentiation through stabilizing chromatin loop-domain interactions and YY1 mediated enhancer-promoter interactions
Alterations in proteins within nuclear compartments often lead to changes in chromosomal architecture. Here, using acute targeted protein degradation, the authors reveal that the nuclear complex protein Matrin3 directly mediates differentiation through stabilizing chromatin loop domain interactions.
- Tianxin Liu
- , Qian Zhu
- & Stuart H. Orkin
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Article
| Open AccessA method to estimate the contribution of rare coding variants to complex trait heritability
The contribution of rare variants to complex traits has not been well studied. Here, the authors present RARity, a method to assess rare variant heritability without assuming a particular genetic architecture and enabling both gene-level and exome-wide heritability estimation of continuous traits.
- Nazia Pathan
- , Wei Q. Deng
- & Guillaume Paré
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Article
| Open AccessMechanistic characterization of a Drosophila model of paraneoplastic nephrotic syndrome
The fruit fly Drosophila melanogaster has emerged as a model to characterize the mechanisms of tumor-induced host organ dysfunction. Here, Xu, Liu et al. describe a mechanism of tumor-induced kidney dysfunction through hyper-activation of the PvR/JNK/Jra pathway in the Principal cells of the fly kidney/Malpighian tubules.
- Jun Xu
- , Ying Liu
- & Norbert Perrimon
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Article
| Open AccessT-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms
Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.
- Eileen Rauch
- , Timm Amendt
- & Philipp Yu
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Article
| Open AccessChildren born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight
Assisted reproduction increases low birthweight risk in children. This study finds a mitochondrial DNA genotype that is more common in ART children, associates to birthweight and that is linked to maternal ageing and to ovarian stimulation.
- Joke Mertens
- , Florence Belva
- & Claudia Spits
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Article
| Open AccessCompromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
THOC2 is an essential subunit of Transcription mRNA Export complex of eukaryotic cells and its compromise causes adverse (neuro)development. Using mouse model and patient cells the authors unravel molecular pathology of the syndrome, from R-loops dysregulation, to altered transcriptome and DNA damage triggered cell death.
- Rudrarup Bhattacharjee
- , Lachlan A. Jolly
- & Jozef Gecz
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Article
| Open AccessA mediator of OsbZIP46 deactivation and degradation negatively regulates seed dormancy in rice
Seed dormancy is the preferred trait in rice production as it can prevent preharvest sprouting. Here, the authors report that MODD (mediator of OsbZIP46 deactivation and degradation) negatively regulates seed dormancy by inhibiting the transcriptional activity of ABSCISIC ACID INSENSITIVES (ABIs).
- Naihui Guo
- , Shengjia Tang
- & Peisong Hu
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Article
| Open AccessUnraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine
Congenital vertebral malformation has a complex genetic architecture that isn’t fully understood. Here, the authors explore the genetic architecture of congenital vertebral malformation through case-control rare variant genetic analyses and embryonic transcriptome analyses of the developing spine.
- Sen Zhao
- , Hengqiang Zhao
- & Nan Wu
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Article
| Open AccessPredicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy
Resistance to chemotherapy for soil-transmitted helminth infection has been detected in veterinary settings but not yet in human infections. Here, the authors investigate the risk of resistance in humans and how it may change as a result of scaling-up preventative deworming programs.
- Luc E. Coffeng
- , Wilma A. Stolk
- & Sake J. de Vlas
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Article
| Open AccessRepeated upslope biome shifts in Saxifraga during late-Cenozoic climate cooling
The origins of alpine plant diversity are unclear. Here, the authors provide a time-calibrated molecular phylogenetic tree for Saxifraga, a diverse alpine plant clade, and show that upslope biome shifts into the alpine zone occurred more often than dispersal between alpine regions.
- Tom Carruthers
- , Michelangelo S. Moerland
- & Wolf L. Eiserhardt
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Article
| Open AccessSynchrony of Bird Migration with Global Dispersal of Avian Influenza Reveals Exposed Bird Orders
Highly pathogenic avian influenza virus subtype H5 is an important pathogen of wild birds and poultry that has also caused infection in humans and other mammals. Here the authors use wild bird movement tracking data and virus genome sequences to quantify how seasonal bird migration facilitates global dispersal of the virus.
- Qiqi Yang
- , Ben Wang
- & Bryan Grenfell
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Article
| Open AccessLogical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Descriptive data in biomedical research are expanding rapidly, but functional validation methods lag behind. Here, authors present Logical Synthetic cis-regulatory DNA, a framework to design reporters that mark cellular states and pathways, showcasing its applicability to complex phenotypic states.
- Carlos Company
- , Matthias Jürgen Schmitt
- & Gaetano Gargiulo
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Article
| Open AccessUnzipped genome assemblies of polyploid root-knot nematodes reveal unusual and clade-specific telomeric repeats
Telomeres protect the extremities of linear chromosomes and are involved in ageing, senescence and genome stability. Here, the authors have identified peculiar and specific telomeric DNA repeats in the genomes of devastating plant-parasitic nematodes, opening new perspectives for their control.
- Ana Paula Zotta Mota
- , Georgios D. Koutsovoulos
- & Etienne G. J. Danchin
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Article
| Open AccessOrchestrating chromosome conformation capture analysis with Bioconductor
The Bioconductor project aims to develop R packages for analysis of genomic datasets. Here the authors show the HiCExperiment package suite and its companion online book (https://bioconductor.org/books/OHCA/) which present data structures, computational methods and visualization tools available in Bioconductor to investigate chromatin conformation capture (3C) data in R.
- Jacques Serizay
- , Cyril Matthey-Doret
- & Romain Koszul
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Article
| Open AccessShort-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21
Surgery poses significant risks for patients, with attempts to mitigate these risks using multimodal perioperative care pathways. Here, the authors show that preoperative hypercaloric carbohydrate drinks not only alleviate surgical stress but also demonstrates the replicability of this protection using FGF21 treatment alone.
- Thomas Agius
- , Raffaella Emsley
- & Alban Longchamp
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Article
| Open AccessImproving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI
Most polygenic risk score (PRS) methods focus only on individuals with distinct primary continental ancestry, without accommodating recently-admixed individuals. Here, the authors develop a novel penalized regression-based PRS method specifically designed for admixed individuals.
- Quan Sun
- , Bryce T. Rowland
- & Yun Li
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Article
| Open AccessA sequence-aware merger of genomic structural variations at population scale
Existing tools for structural variations (SVs) calling and merging often lead to fragmented SVs and the potential of introducing unnecessary errors. Here, the authors report the PanPop pipeline to address these issues by implementing sequence-aware SV merging algorithm to efficiently merge SVs of various types.
- Zeyu Zheng
- , Mingjia Zhu
- & Yongzhi Yang
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Article
| Open AccessDysfunction of duplicated pair rice histone acetyltransferases causes segregation distortion and an interspecific reproductive barrier
Loss of function alleles of two genetically interacting loci mediate both segregation distortion and interspecific hybrid incompatible via epigenetic regulation in rice.
- Ben Liao
- , You-Huang Xiang
- & Hong-Xuan Lin
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Article
| Open AccessNanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping
Genetic association studies with affinity proteomics face challenges when dealing with protein altering variants. Suhre et al. show that nanoparticle enrichment mass-spectrometry can distinguish between epitope effects and bona fide protein quantitative traits.
- Karsten Suhre
- , Guhan Ram Venkataraman
- & Frank Schmidt
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Article
| Open AccessAnti-CRISPR Anopheles mosquitoes inhibit gene drive spread under challenging behavioural conditions in large cages
CRISPR-based gene drives have the potential to spread within populations and are considered as promising vector control tools. Here the authors show an anti-drive mosquito strain that prevents the spread and collapse of a population suppression gene drive in laboratory Anopheles mosquito large cage trials in complex ecological and behavioral conditions.
- Rocco D’Amato
- , Chrysanthi Taxiarchi
- & Ruth Müller
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Article
| Open AccessHRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1
Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.
- Shihui Chen
- & Carolyn M. Phillips
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Article
| Open AccessMultiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo
Dysregulation of alternative polyadenylation (APA) is associated with poor prognosis in cancer but its functional role is less clear. Here, the authors develop a CRISPR-Cas9- based screen to determine the effects of different APA events on melanoma growth in mouse models.
- Austin M. Gabel
- , Andrea E. Belleville
- & Robert K. Bradley
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Comment
| Open AccessImplementing community-engaged pharmacogenomics in Indigenous communities
Innovative pharmacogenomic approaches (genetic variation related to medication response) are needed to reduce disease and disparities in Indigenous communities. We support community-based pharmacogenomics research, inclusive of Indigenous values and priorities, to improve the health and well-being of Indigenous peoples.
- Katrina G. Claw
- , Casey R. Dorr
- & Erica L. Woodahl
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Article
| Open AccessGWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Article
| Open AccessEffect of aging on the human myometrium at single-cell resolution
Age-associated myometrial dysfunction can cause complications during pregnancy and labor. Here, the authors report that aging myometrium is characterized by diminished contractile capillary cells, altered gene expression, and disrupted cellular communication leading to impaired angiogenesis, increased fibrosis and inflammation.
- Paula Punzon-Jimenez
- , Alba Machado-Lopez
- & Aymara Mas
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Article
| Open AccessBCL7A and BCL7B potentiate SWI/SNF-complex-mediated chromatin accessibility to regulate gene expression and vegetative phase transition in plants
This study uncovers the specialized function of previously elusive BCL7 subunits of SWI/SNF complexes in eukaryotes and reveals the mechanism whereby plants memorize the juvenile identity through SWI/SNF-mediated control of chromatin accessibility.
- Yawen Lei
- , Yaoguang Yu
- & Chenlong Li
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Article
| Open AccessMulti-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Thyroid dysfunction is involved in many diseases. Here, the authors provide insights into the genetics and biological pathways influencing important thyroid function parameters, showing potential causal effects on many clinical outcomes.
- Rosalie B. T. M. Sterenborg
- , Inga Steinbrenner
- & Marco Medici
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Article
| Open AccessTransgenic expression of cif genes from Wolbachia strain wAlbB recapitulates cytoplasmic incompatibility in Aedes aegypti
The Wolbachia cifA and cifB genes generate cytoplasmic incompatibility (CI) in insect hosts but the role of cifA is still debated. Here, the authors report the transgenic recapitulation of CI in the major arbovirus vector Aedes aegypti and provide evidence for cifA inhibiting cifB toxicity in the male germline.
- Cameron J. McNamara
- , Thomas H. Ant
- & Steven P. Sinkins
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Article
| Open AccessBacPE: a versatile prime-editing platform in bacteria by inhibiting DNA exonucleases
Prime editing in bacteria is currently inefficient. Here the authors report BacPE, a versatile prime editing platform in Escherichia coli that works by inhibiting 3′→5′ DNA exonucleases, highlighting the intrinsic genetic factors that are adverse to efficient prime editing.
- Hongyuan Zhang
- , Jiacheng Ma
- & Quanjiang Ji
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Article
| Open AccessThe origin and structural evolution of de novo genes in Drosophila
It is unclear whether naturally evolved de novo proteins have stable, folded structures. Here, through systematic identification and structural modeling of de novo genes, this study reveals that a small subset of these proteins may have well-folded structures, and were likely born with these structures.
- Junhui Peng
- & Li Zhao
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Article
| Open AccessLarge-scale genomic rearrangements boost SCRaMbLE in Saccharomyces cerevisiae
Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution (SCRaMbLE) is a promising tool to study genomic rearrangements. Here the authors present an engineered yeast strain with 83 sparsely distributed loxPsym sites across the genome can genrerate large-scale genomic rearrangements, which benefits cell fitness under stress and boosts the SCRaMbLE system when combined with synthetic chromosomes.
- Li Cheng
- , Shijun Zhao
- & Junbiao Dai
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Article
| Open AccessTransposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
It has been suggested that transposable elements (TE) play a role in tumourigenesis, but the associated mechanisms remain unclear. Here, the authors show, using colorectal cancer data and Bayesian Networks, that TEs can mediate the effect of expression quantitative trait loci and contribute to the regulation of cancer-related genes.
- Nikolaos M. R. Lykoskoufis
- , Evarist Planet
- & Emmanouil T. Dermitzakis
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Article
| Open AccessA multiplexed, confinable CRISPR/Cas9 gene drive can propagate in caged Aedes aegypti populations
Aedes aegypti is the main vector of several major pathogens including dengue, Zika and chikungunya viruses. Here the authors find that a CRISPR/Cas9 based split gene drive in Aedes aegypti could successfully bias inheritance up to 89% over successive generations in a multi-cage trial with further deep sequencing suggesting that the multiplexing design could mitigate resistance allele formation.
- Michelle A. E. Anderson
- , Estela Gonzalez
- & Luke Alphey
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Article
| Open AccessInvestigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing
Non-malarial febrile illnesses have a range of potential aetiologies which are difficult to diagnose and therefore treat. Here, the authors investigate the causes of acute febrile illness in a peri-urban area of Senegal with low malaria incidence using untargeted and targeted sequencing methods.
- Zoë C. Levine
- , Aita Sene
- & Katherine J. Siddle
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Article
| Open AccessA chromosome-scale assembly reveals chromosomal aberrations and exchanges generating genetic diversity in Coffea arabica germplasm
Coffea arabica is an allotetraploid hybrid of C. eugenioides and C. canephora and contributes to approximately 60% of world coffee production. Here, the authors report its chromosome-level genome assembly and identify that chromosomal abnormalities and introgression from C. canephora may contribute to diversity and pathogen resistance.
- Simone Scalabrin
- , Gabriele Magris
- & Michele Morgante
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Article
| Open AccessHuman whole-exome genotype data for Alzheimer’s disease
The heterogeneity of whole-exome sequencing (WES) data generation methods presents a challenge to joint analysis. Here, the authors present a bioinformatics strategy to generate high-quality data from processing diversely generated WES samples, as applied in the Alzheimer’s Disease Sequencing Project.
- Yuk Yee Leung
- , Adam C. Naj
- & Li-San Wang
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Article
| Open AccessThe UBP5 histone H2A deubiquitinase counteracts PRCs-mediated repression to regulate Arabidopsis development
The authors demonstrate that UBIQUITIN SPECIFIC PROTEASE 5 (UBP5) is a major H2Aub deubiquitinase that antagonises H3K27me3, leading to transcriptional de-repression and controlling development in Arabidopsis.
- James Godwin
- , Mohan Govindasamy
- & Sara Farrona
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Article
| Open AccessMolecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Investigating the genetics of male fertility requires comprehensive genotype and phenotype data. Here, the authors characterize the transcriptional complexity of bovine male reproductive tissues to identify loci associated with male fertility.
- Xena Marie Mapel
- , Naveen Kumar Kadri
- & Hubert Pausch
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Article
| Open AccessProgrammable RNA base editing with photoactivatable CRISPR-Cas13
Cas13 systems suffer from a lack of spatiotemporal control. Here the authors report paCas13, a light-inducible Cas13 system created by fusing Magnet with fragment pairs; they also report padCas13, a light-inducible base-editing system by fusing ADAR2 to catalytically inactive paCas13 fragments.
- Jeonghye Yu
- , Jongpil Shin
- & Won Do Heo
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Article
| Open AccessTwo mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality
Chiang et al. map a genetic interaction in animal mitochondrial DNA by recombination. This reveals how polymorphisms in two complex IV subunits jointly affect cardiolipin binding to impact complex stability, organismal fitness and disease expression.
- Ason C. Y. Chiang
- , Jan Ježek
- & Hansong Ma
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Article
| Open AccessGenetic architecture distinguishes tinnitus from hearing loss
The genetic basis of tinnitus and how it relates to hearing loss genetics is unknown. In a large GWAS for tinnitus, the authors discover tinnitus’ distinct genetic architecture from hearing loss and its correlation with a spectrum of psychiatric disorders.
- Royce E. Clifford
- , Adam X. Maihofer
- & Caroline M. Nievergelt
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Article
| Open AccessX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.
- Markus Scholz
- , Katrin Horn
- & Cristian Pattaro
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Article
| Open AccessAltered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Cigarette smoking is an established risk factor for inflammatory bowel disease. The authors suggest that smoking may affect the risk of Crohn’s disease and ulcerative colitis by modulating the DNA methylation status of the DNMT3A, LTA/TNF, and AHRR region, respectively.
- Han Zhang
- , Rahul Kalla
- & Xue Li
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Article
| Open AccessLeveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types
This study analyzed data from human cells assayed using single-cell technologies, together with data associating genetic variants to disease, to identify fetal and brain cell types whose biologically critically influences the etiology of disease.
- Samuel S. Kim
- , Buu Truong
- & Alkes L. Price
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Article
| Open AccessConserved chromatin and repetitive patterns reveal slow genome evolution in frogs
Frogs are an ancient and ecologically diverse group of amphibians that include important model systems. This paper reports genome sequences of multiple frog species, revealing remarkable stability of frog chromosomes and centromeres, along with highly recombinogenic extended subtelomeres.
- Jessen V. Bredeson
- , Austin B. Mudd
- & Daniel S. Rokhsar
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Article
| Open AccessNAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD+ depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.
- Liang Yang
- , Zifeng Ruan
- & Xingguo Liu
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Article
| Open AccessHaplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data
Genetic variants that influence gene expression play a major role in human phenotypic variability and disease susceptibility. Here, the authors introduce a computational method to estimate the regulatory effect size in genes with multiple conditionally independent regulatory variants.
- Nava Ehsan
- , Bence M. Kotis
- & Pejman Mohammadi
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Article
| Open AccessLarge scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development
The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.
- Amil M. Shah
- , Peder L. Myhre
- & Bing Yu
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