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| Open AccessCaenorhabditis elegans is a useful model for anthelmintic discovery
Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.
- Andrew R. Burns
- , Genna M. Luciani
- & Peter J. Roy
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Article
| Open AccessDigital microfluidic immunocytochemistry in single cells
The ability to measure signalling responses in single cells following short pulses of stimulus would shed insight into temporal thresholds for cell activation. Here the authors introduce a microfluidic platform that allows downstream phosphorylation cascades to be observed following as little as one second of stimulus exposure.
- Alphonsus H. C. Ng
- , M. Dean Chamberlain
- & Aaron R. Wheeler
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| Open AccessA genome-wide association study identifies multiple loci for variation in human ear morphology
The shape of the pinna varies widely in the general human population but the genetic basis of this variation is unknown. Here Adhikari et al. conduct a genome-wide association study in Latin Americans and discover seven gene regions influencing pinna morphology, including EDAR and TBX15.
- Kaustubh Adhikari
- , Guillermo Reales
- & Andrés Ruiz-Linares
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Article
| Open AccessThe impact of DNA intercalators on DNA and DNA-processing enzymes elucidated through force-dependent binding kinetics
DNA intercalators, a type of fluorescent probes widely used to visualize DNA, can perturb DNA structure and stability. Here, the authors show how DNA-binding affinity can be tuned using DNA tension, ionic strength and dye species, and how this can be used to minimize DNA structural perturbations.
- Andreas S. Biebricher
- , Iddo Heller
- & Gijs J. L. Wuite
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Article
| Open AccessCharacterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours
Despite methodological improvements, it remains extremely difficult to routinely establish cell lines from human primary tumours. Here, the authors develop a culture medium that allows efficient cell line establishment and use this to generate 25 ovarian cancer cell lines.
- Tan A. Ince
- , Aurea D. Sousa
- & Gordon B. Mills
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| Open AccessRh D blood group conversion using transcription activator-like effector nucleases
Group O/RhD− blood can be safely transfused to any recipient and methods for converting other blood groups into this group hold therapeutic potential. By using programmable nucleases, here the authors edit the gene that determines the RhD blood group and convert the RhD+ into RhD− erythroid progenitor cells.
- Young-Hoon Kim
- , Hyun O. Kim
- & Hyongbum Kim
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Article
| Open AccessDirect wavefront sensing for high-resolution in vivo imaging in scattering tissue
Direct wavefront sensing with laser ‘guide stars’ is used in astronomy and microscopy to correct for optical aberrations. Wang et al.use near-infrared guide stars to extend this approach to the highly scattering mouse brain, allowing high-resolution fluorescence imaging at 700μm depth.
- Kai Wang
- , Wenzhi Sun
- & Na Ji
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| Open AccessSingle molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes
Bacterial DNA methylation is involved in many processes, from host defense to antibiotic resistance, however current methods for examining methylated genomes lack single-cell resolution. Here Beaulaurier et al. present Single Molecule Modification Analysis of Long Reads, a new tool for de novodetection of epigenetic heterogeneity.
- John Beaulaurier
- , Xue-Song Zhang
- & Gang Fang
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Article
| Open AccessSalicylic acid biosynthesis is enhanced and contributes to increased biotrophic pathogen resistance in Arabidopsis hybrids
The molecular basis for heterosis, the phenomenon whereby hybrid plants show phenotypic superiority to their parents, remains poorly understood. Here, Yanget al. show that salicylic acid biosynthesis is enhanced in hybrids of Arabidopsis thalianaand correlates with heterosis for pathogen defence.
- Li Yang
- , Bosheng Li
- & Xing Wang Deng
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Article
| Open AccessSteady-state cross-correlations for live two-colour super-resolution localization data sets
Quantitative live cell super-resolution microscopy is currently limited by the time it takes to acquire a well sampled image. Here Stone and Veatch develop a cross-correlation analysis that does not rely on image reconstruction and apply this method to quantify the co-distribution of Lyn kinase and the B-cell receptor during antigen stimulation.
- Matthew B. Stone
- & Sarah L. Veatch
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Article
| Open AccessSomatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling
Gene transfer is a powerful technique to investigate the mechanistic basis of tumorigenesis. Here Zuckermann et al. adapt CRISPR/Cas9 genome editing to target potential oncogenes somatically in vivo, establishing a fast and convenient system for validating novel genetic candidates.
- Marc Zuckermann
- , Volker Hovestadt
- & Jan Gronych
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Article
| Open AccessContext influences on TALE–DNA binding revealed by quantitative profiling
TALE proteins are popular tools for genome engineering because they can recognize specific DNA sequences, however off-target effects are a routine problem. Here Rogers and Barrera et al. comprehensively map TALE–DNA interactions to develop a computational model to predict binding specificity.
- Julia M. Rogers
- , Luis A. Barrera
- & Martha L. Bulyk
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Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons
Abnormal accumulation of TDP-43 and FUS proteins is found in a neurodegenerative disease amyotrophic lateral sclerosis. Here the authors show by modelling the disease in worms that these proteins activate local and distal immune responses, and blocking this pathway in neurons ameliorates the disease.
- Julie Vérièpe
- , Lucresse Fossouo
- & J Alex Parker
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Article
| Open AccessLigand regulation of a constitutively dimeric EGF receptor
Whereas epidermal growth factor-induced dimerization is considered essential for EGFR signalling, the structurally related insulin receptor is a disulfide-linked dimer. Here the authors show that C. elegansEGFR is constitutively dimeric and undergoes subtle structural changes upon ligand binding that likely underlie allosteric activation.
- Daniel M. Freed
- , Diego Alvarado
- & Mark A. Lemmon
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Article
| Open AccessEffective heritable gene knockdown in zebrafish using synthetic microRNAs
Zebrafish is a model system for which for no reliable heritable gene silencing method is available. Here the authors provide a system for heritable miRNA-mediated knockdown and demonstrate tunable silencing of the smn1gene that recapitulate different forms of spinal muscular atrophy.
- Jean Giacomotto
- , Silke Rinkwitz
- & Thomas S. Becker
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Article
| Open AccessMolecular architecture of native fibronectin fibrils
Fibronectin fibres are an important component of the extracellular matrix, supporting cell adhesion, growth and migration. Here the authors combine site-specific protein labelling with single-molecule localization microscopy to provide detailed insights into the molecular organization of native fibronectin fibrils.
- Susanna Maria Früh
- , Ingmar Schoen
- & Viola Vogel
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CUL4 forms an E3 ligase with COP1 and SPA to promote light-induced degradation of PIF1
Light exposure to plants initiates a developmental programme known as photomorphogenesis, which is triggered by repression of PIF transcription factors. Here Zhu et al. identify an E3 ubiquitin ligase complex that contributes to photomorphogenesis and is required for the degradation of PIF1.
- Ling Zhu
- , Qingyun Bu
- & Enamul Huq
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| Open AccessOptogenetic control of contractile function in skeletal muscle
Nerve damage can lead to skeletal muscle paralysis. The authors show that localized photostimulation of skeletal muscle expressing the light-sensitive channel Channelrhodopsin-2 generates contraction in the absence of neural impulses and prove that this strategy can be used for optogenetic opening of explanted murine vocal cords.
- Tobias Bruegmann
- , Tobias van Bremen
- & Philipp Sasse
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Coordination and fine motor control depend on Drosophila TRPγ
Perception of mechanical tension is important for coordinated locomotion, and in Drosophila, mutations in stretch-sensitive TRPV channels grossly impair locomotor behaviour. Akitake et al. show that the Drosophila TRPC channel TRPγis, in contrast, specifically required for fine motor control.
- Bradley Akitake
- , Qiuting Ren
- & Craig Montell
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| Open AccessPlatelet actin nodules are podosome-like structures dependent on Wiskott–Aldrich syndrome protein and ARP2/3 complex
During early platelet spreading a novel F-actin structure forms, called the actin nodule. Here Poulter et al.demonstrate that actin nodule formation depends on WASp and the Arp2/3 complex, and using super-resolution microscopy they show that nodules bear a structural resemblance to podosomes.
- Natalie S. Poulter
- , Alice Y. Pollitt
- & Steven G. Thomas
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| Open AccessTemporal regulation of kin recognition maintains recognition-cue diversity and suppresses cheating
It is unclear how variation in cues that enable recognition of kin and facilitate cooperation is maintained. Here, the authors show that rare variants of Dictyostelium discoideumare excluded from aggregates when the potential for social cheating is high, but subsequently rejoin the aggregate and produce spores.
- Hsing-I Ho
- & Gad Shaulsky
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Article
| Open AccessMultiparametric AFM reveals turgor-responsive net-like peptidoglycan architecture in live streptococci
The peptidoglycan (PG) layer of the Gram-positive bacteria cell wall resists turgor pressure, but the architecture of this layer is largely unknown. Here the authors use high resolution atomic force microscopy to image the PG layer from live Streptococcusto reveal a net-like arrangement that resists osmotic challenge by stretching and stiffening.
- Ron Saar Dover
- , Arkady Bitler
- & Yechiel Shai
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Article
| Open AccessComprehensive survey of condition-specific reproductive isolation reveals genetic incompatibility in yeast
Chromosomal rearrangements may hamper intraspecific hybrid fertility. Here the authors show that environment-specific genetic incompatibility segregates readily within intermating populations and leads to intrinsic reproductive isolation within a yeast species.
- Jing Hou
- , Anne Friedrich
- & Joseph Schacherer
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Article
| Open AccessDrosophila glucome screening identifies Ck1alpha as a regulator of mammalian glucose metabolism
Diabetes is associated with aberrations in glucose metabolism. Here the authors perform a genomic screen in fruit flies to identify new regulators of fly glucose metabolism, and show that mice lacking the murine homologue of one of their hits, the protein kinase CK1alpha, in the adipose lineage develop diabetes.
- Rupali Ugrankar
- , Eric Berglund
- & Jonathan M. Graff
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Article
| Open AccessSingle-molecule imaging of a three-component ordered actin disassembly mechanism
The roles of Coronin, Cofilin and AIP1 in promoting actin disassembly have not been well understood. Here using single-molecule fluorescence imaging, Jansen et al. show that the three proteins act together in a coordinated, temporal pathway to induce rapid severing and disassembly of actin filaments.
- Silvia Jansen
- , Agnieszka Collins
- & Bruce L. Goode
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Article
| Open AccessProteins that bind regulatory regions identified by histone modification chromatin immunoprecipitations and mass spectrometry
The protein factors that bind to regulatory regions in the genome have not been systematically mapped. Here the authors performed chromatin immunoprecipitations for histone modifications associated with promoters, enhancers or heterochromatin in mouse embryonic stem cells and assigned a genome location to many factors important for pluripotency.
- Erik Engelen
- , Johannes H. Brandsma
- & Raymond A. Poot
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| Open AccessThe fission yeast MTREC complex targets CUTs and unspliced pre-mRNAs to the nuclear exosome
The evolutionarily conserved MTREC complex promotes degradation of meiotic mRNAs and regulatory ncRNAs. Here the authors show that MTREC also targets cryptic unstable transcripts and unspliced pre-mRNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process.
- Yang Zhou
- , Jianguo Zhu
- & Tamás Fischer
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Article
| Open AccessTargeted DNA degradation using a CRISPR device stably carried in the host genome
The ability to contain and destroy synthetically engineered microorganisms is an important consideration with environmental, industrial and intellectual property implications. Here Caliando et al. design and demonstrate a stably integrated CRISPR-based system for targeted DNA destruction.
- Brian J. Caliando
- & Christopher A. Voigt
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Article
| Open AccessAtomistic design of microbial opsin-based blue-shifted optogenetics tools
Retinal-bound opsins are widely used tools for optical control of neuronal activity in vivo, so called optogenetics. Here, using molecular simulations, biochemistry, electrophysiology and X-ray crystallography, the authors present new molecular design principles for the generation of blue-shifted variants of microbial rhodopsins.
- Hideaki E. Kato
- , Motoshi Kamiya
- & Osamu Nureki
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| Open AccessGreen fluorescent protein nanopolygons as monodisperse supramolecular assemblies of functional proteins with defined valency
Supramolecular protein assemblies can provide novel nano-architectures with diverse structures and functions. Here, the authors report a fabrication strategy for a series of monodisperse protein oligomers, which allows valency-controlled display of various functional proteins.
- Young Eun Kim
- , Yu-na Kim
- & Yongwon Jung
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Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin
Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.
- Beeke Wienert
- , Alister P. W. Funnell
- & Merlin Crossley
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Article
| Open AccessContrasting host–pathogen interactions and genome evolution in two generalist and specialist microsporidian pathogens of mosquitoes
Microsporidia are intracellular parasitic fungi that infect diverse animal hosts including humans. Here, Desjardins et al.present genomic and transcriptomic data for two microsporidia that infect disease-transmitting mosquitoes, highlighting differences in potential host interplay mechanisms.
- Christopher A. Desjardins
- , Neil D. Sanscrainte
- & Christina A Cuomo
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Article
| Open AccessVisualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters
Extracellular vesicles (EVs) act as a conduit for intercellular communication through the exchange of cellular materials without direct cell-to-cell contacts. Here the authors develop a multiplexed reporter system that allows monitoring of EV exchange, cargo delivery and protein translation between different cell populations.
- Charles P. Lai
- , Edward Y. Kim
- & Xandra O. Breakefield
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Article
| Open AccessSingle-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes
The spatial organization of the genome within the nucleus impacts many processes. Here the authors combine oligo-based DNA FISH with single-molecule super-resolution microscopy to image single-copy genomic regions and, taking advantage of SNPs, distinguish allelic regions of homologous chromosomes.
- Brian J. Beliveau
- , Alistair N. Boettiger
- & Chao-ting Wu
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MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis
Compromised function of regulatory T cells can lead to autoimmunity. Here the authors show that miR-125a stabilizes regulatory T-cell function and is downregulated in lupus and Crohn’s disease, as well as autoimmune mouse models, and that a chemical miR-125a analogue reverts established disease in a mouse model of multiple sclerosis.
- Wen Pan
- , Shu Zhu
- & Nan Shen
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Article
| Open AccessConformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy
Cyclic nucleotide gated channels are activated after binding cyclic nucleotides. Here, using single molecule force spectroscopy, the authors reveal that cyclic nucleotide binding causes conformational changes and tighter coupling of the S4 helix to the pore forming domain.
- Sourav Maity
- , Monica Mazzolini
- & Vincent Torre
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Article
| Open AccessPigment cell movement is not required for generation of Turing patterns in zebrafish skin
Pigment pattern formation in zebrafish depends on the interactions between the pigment cells. Here the authors present a mathematical model based on mutual interaction of pigment cells in the absence of cell motion, revising the current model of the pattern formation that relies on reaction–diffusion Turing patterns.
- D. Bullara
- & Y. De Decker
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Article
| Open AccessRNA structure determination by solid-state NMR spectroscopy
The determination of RNA structures within high-molecular weight protein-RNA complexes in non-crystalline state is technically challenging. Here, the authors describe a solid-state NMR protocol for the determination of RNA structures at high resolution.
- Alexander Marchanka
- , Bernd Simon
- & Teresa Carlomagno
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Article
| Open AccessChip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma
Predicting and monitoring chemotherapy response remains a challenge for glioma treatment. Here the authors show that a microfluidic device can isolate glioma-derived exosomes from patient blood and accurately determine the levels of mRNA of key enzymes important for chemoresponsiveness.
- Huilin Shao
- , Jaehoon Chung
- & Ralph Weissleder
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eQTL mapping identifies insertion- and deletion-specific eQTLs in multiple tissues
Expression quantitative trait loci (eQTLs) may provide insight into the functional mechanisms underlying disease risk variants. Here the authors characterize INDEL-specific eQTLs in several tissues and show that these can have both tissue-specific and tissue-consistent effects.
- Jinyan Huang
- , Jun Chen
- & Liming Liang
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Article |
Two susceptibility loci identified for prostate cancer aggressiveness
Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.
- Sonja I. Berndt
- , Zhaoming Wang
- & Stephen J. Chanock
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Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium
Cystic fibrosis is a lethal genetic disorder commonly caused by the F508del mutation which is not amenable to gene therapy. Here, the authors use triplex-forming PNA molecules and donor DNA in biodegradable polymer nanoparticles to correct F508del and achieve clinically relevant levels of gene editing.
- Nicole Ali McNeer
- , Kavitha Anandalingam
- & Marie E. Egan
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Article
| Open AccessReal-time submillisecond single-molecule FRET dynamics of freely diffusing molecules with liposome tethering
Single-molecule fluorescence resonance energy transfer is widely used to probe biomolecular dynamics, but is limited by its temporal resolution. Here, Kim et al. push the limit to submillisecond for the duration of tens of milliseconds by tethering target molecules to liposomes in buffer solutions.
- Jae-Yeol Kim
- , Cheolhee Kim
- & Nam Ki Lee
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Article
| Open AccessGenome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.
- Xianyong Yin
- , Hui Qi Low
- & Jianjun Liu
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Article |
Regulation of endogenous transmembrane receptors through optogenetic Cry2 clustering
Signaling through transmembrane receptors regulates diverse biological processes including cell proliferation, motility and differentiation. Here, the authors demonstrate the optogenetic control of endogenous transmembrane receptor activity through clustering using a new modular strategy.
- L. J. Bugaj
- , D. P. Spelke
- & D. V. Schaffer
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Article
| Open AccessDesigner diatom episomes delivered by bacterial conjugation
Algae hold great promise for biofuel and chemical production but their use as model systems is hampered by the absence of suitable genetic tools. Here Karas et al. present a nuclear episomal vector for diatoms that is maintained in the absence of antibiotics, and a plasmid delivery method via conjugation with E. coli.
- Bogumil J. Karas
- , Rachel E. Diner
- & Philip D. Weyman
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Calibrating genomic and allelic coverage bias in single-cell sequencing
Artifacts caused by whole-genome amplification bias are a recurrent challenge in single-cell sequencing analysis. Here, the authors develop statistical models and demonstrate an efficient strategy for controlling amplification errors by a joint analysis of single cell genomes.
- Cheng-Zhong Zhang
- , Viktor A. Adalsteinsson
- & J. Christopher Love
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Article
| Open AccessHigh-resolution genetic mapping of maize pan-genome sequence anchors
Structural variations in crop genomes are thought to be responsible for significant differences in phenotype and they can be well-represented by a ‘pan-genome’. Here, Lu et al.develop an approach to genetically map pan-genome sequence anchors using 14,129 inbred lines of maize, showing structural variation is a significant source of adaptive variation.
- Fei Lu
- , Maria C. Romay
- & Edward S. Buckler
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Article
| Open AccessIncreased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension
Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al.use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.
- John H. Newman
- , Timothy N. Holt
- & Rizwan Hamid
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