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| Open AccessmRIN for direct assessment of genome-wide and gene-specific mRNA integrity from large-scale RNA-sequencing data
With the rapid increase in the volume of publically available RNA-seq data, quality control is an increasingly important consideration. Here Feng et al. develop mRIN, a method to directly assess mRNA integrity, and show that RNA degradation in post-mortem samples has a strong impact on global expression profiles.
- Huijuan Feng
- , Xuegong Zhang
- & Chaolin Zhang
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| Open AccessThe iBeetle large-scale RNAi screen reveals gene functions for insect development and physiology
Unbiased screening for insect gene function has been largely restricted to Drosophila. Here, Schmitt-Engel et al. perform an unbiased large-scale RNAi screen in the red flour beetle Tribolium castaneumto identify putative gene functions.
- Christian Schmitt-Engel
- , Dorothea Schultheis
- & Gregor Bucher
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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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| Open AccessTCF12 is mutated in anaplastic oligodendroglioma
Anaplastic oligodendrogliomas are rare and incurable primary brain tumours with few treatment options. Here Labrecheet al. perform whole-exome sequencing and identify recurring mutations in transcription factor TCF12, which are associated with aggressive tumours.
- Karim Labreche
- , Iva Simeonova
- & Michel Wager
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| 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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| Open AccessPhasing of single DNA molecules by massively parallel barcoding
DNA phasing information — the determination of which specific sequences belong to the same DNA molecule—is not easily obtained from sequencing applications that rely on short reads. Here the authors develop a phasing method based on massively parallel barcoding of single DNA molecules.
- Erik Borgström
- , David Redin
- & Afshin Ahmadian
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| Open AccessCharacterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
Currently, genome-wide methylation studies are limited to using targeted arrays or enrichment to assess large sample sizes. Here, Allum et al. demonstrate MethylC-Capture Sequencing, a cost-effective method for investigating genetic and epigenetic variation.
- Fiona Allum
- , Xiaojian Shao
- & Elin Grundberg
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| Open AccessTranslational regulation shapes the molecular landscape of complex disease phenotypes
To what extent translational control can contribute to global gene expression patterns in the disease state is poorly defined. Here the authors conduct genome-wide RNA-seq and ribosome profiling in a rat model of hypertension and uncover altered translation patterns in disease associated genes.
- Sebastian Schafer
- , Eleonora Adami
- & Norbert Hubner
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| Open AccessWidespread disruption of host transcription termination in HSV-1 infection
Herpes simplex virus 1 (HSV-1) efficiently shuts down host gene expression in infected cells. Here Rutkowski et al. analyse the genome-wide changes in transcription and translation in infected cells, and show that HSV-1 triggers an extensive disruption of transcription termination of cellular genes.
- Andrzej J. Rutkowski
- , Florian Erhard
- & Lars Dölken
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| Open AccessLarge-scale recent expansion of European patrilineages shown by population resequencing
The origins and antiquity of the people of Europe has been much debated. Here, the authors sequence 3.7 Mb of the Y chromosome in over 300 Europeans and Middle Easterners and show a recent, continent-wide and male-specific expansion dating back to the Bronze Age.
- Chiara Batini
- , Pille Hallast
- & Mark A. Jobling
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| Open AccessCharacterization of genome-wide ordered sequence-tagged Mycobacterium mutant libraries by Cartesian Pooling-Coordinate Sequencing
The generation of characterized panels of specific mutants is an essential but time-consuming step of reverse genetic studies. Here Vandewalle et al. describe CP-CSeq, an easy to implement parallel sequencing method for rapid library construction.
- Kristof Vandewalle
- , Nele Festjens
- & Nico Callewaert
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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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| 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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High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq
Characterizing mammalian gene expression regulation by enhancer elements is complicated by the size and complexity of the genome. Here Vanhille et al.demonstrate CapStarr-Seq, a novel high-throughput method for assessing potential enhancers and deciphering the mechanisms regulating transcription
- Laurent Vanhille
- , Aurélien Griffon
- & Salvatore Spicuglia
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Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
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| Open AccessmiR-26a and miR-384-5p are required for LTP maintenance and spine enlargement
Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength. Here, the authors demonstrate that miR-26a and miR-384-5p affect the maintenance, but not induction, of LTP as well as spine enlargement by regulating the expression of RSK3.
- Qin-Hua Gu
- , Danni Yu
- & Zheng Li
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| Open AccessWhole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
Diagnosis of pancreatic ductal adenocarcinoma (PDA) has poor long-term survival rates with limited therapy options. Here Witkiewicz et al.use microdissection and whole-exome sequencing to identify novel recurrent PDA mutations, highlighting the genetic diversity of this aggressive cancer.
- Agnieszka K. Witkiewicz
- , Elizabeth A. McMillan
- & Erik S. Knudsen
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Metal ion-directed dynamic splicing of DNA through global conformational change by intramolecular complexation
Higher-order structured DNA molecules can be manipulated to carry out specific enzymatic functions. Here the authors demonstrate the metal ion-directed global conformational control of DNA structure, using intramolecular coordination chemistry to manipulate the DNAzyme activity.
- Toshihiro Ihara
- , Hiroyuki Ohura
- & Yusuke Kitamura
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| Open AccessDissecting meiotic recombination based on tetrad analysis by single-microspore sequencing in maize
The crossovers and gene conversions that occur during meiotic recombination contribute to genome diversity in eukaryotes. Here Li et al. describe a method of isolating individual microspores for whole-genome sequencing, providing new insights into the generation of genome diversity through sexual reproduction.
- Xiang Li
- , Lin Li
- & Jianbing Yan
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| Open AccessRecurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution
Papillary renal cell carcinoma (pRCC) is a subtype of kidney cancer characterized by highly variable clinical behaviour. Here the authors sequence either the genomes or exomes of 31 pRCCs and identify several genes in sub-clones and large copy number variants in major clones that may be important drivers of pRCC.
- Michal Kovac
- , Carolina Navas
- & Ian Tomlinson
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| Open AccessGenetic blueprint of the zoonotic pathogen Toxocara canis
Toxocara canis is a zoonotic parasite of major worldwide socioeconomic importance. Here, the authors sequence the genome and transcriptome of T. canis, and highlight potential mechanisms involved in development and host–parasite interactions that could support the pursuit of new drug interventions.
- Xing-Quan Zhu
- , Pasi K. Korhonen
- & Robin B. Gasser
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| Open AccessA high-throughput optomechanical retrieval method for sequence-verified clonal DNA from the NGS platform
One of the biggest bottlenecks in large-scale DNA synthesis is the retrieval of target clonal DNA from high-density sequencing platforms. Here, the authors present a method called ‘Sniper Cloning’ that allows for precise mapping of target clone features and rapid retrieval of targets for full utilization of DNA clones.
- Howon Lee
- , Hyoki Kim
- & Sunghoon Kwon
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Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value
Triple-negative breast cancers (TNBCs) are a heterogeneous group of cancers with varying prognoses. Here, the authors carry out whole-genome methylation capture sequencing from TNBC samples and matched normal samples, and identify differentially methylated regions that define a potentially novel TNBC signature.
- Clare Stirzaker
- , Elena Zotenko
- & Susan J. Clark
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| Open AccessDNA sequencing using polymerase substrate-binding kinetics
Next-generation sequencing technologies vary in performance, which is often measured by metrics such as sequencing speed, accuracy and read length. Here, the authors present a new sequencing by synthesis method that monitors polymerase binding to DNA, and suggest that this method has the potential to generate longer and faster reads.
- Michael John Robert Previte
- , Chunhong Zhou
- & Molly Min He
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| Open AccessWhole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here, the authors sequence the whole exomes of 42 TGCTs, and characterize the mutational profile of this tumour type.
- Kevin Litchfield
- , Brenda Summersgill
- & Clare Turnbull
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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al. show a novel FGFR2–PPHLN1 fusion and ARAFmutations that may represent future potential therapeutic targets.
- Daniela Sia
- , Bojan Losic
- & Josep M. Llovet
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Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas
Pheochromocytomas and paragangliomas (PCC/PGL) are tumours of the autonomic nervous system. Here, the authors identify ATRX mutations in PCC/PGL and suggest that ATRXloss is important for tumorigenesis in a subset of PCC/PGL.
- Lauren Fishbein
- , Sanika Khare
- & Katherine L. Nathanson
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An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations
Standard ChIP-seq protocols require large numbers of cells for high-quality datasets, limiting the application of this technique on rare cell types. Here, Brind’Amour et al. introduce an ultra-low-input ChIP-seq protocol to generate maps of covalent histone marks from as few as 1,000 cells.
- Julie Brind’Amour
- , Sheng Liu
- & Matthew C. Lorincz
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Sequencing of first-strand cDNA library reveals full-length transcriptomes
Strand-specific RNA-seq (ssRNA-seq) data often lack information on 5′ and 3′ ends of transcripts. Here the authors present a novel method for ssRNA-seq that enables the simultaneous profiling of gene expression, TSSs and polyadenylation sites at near-base resolution with a single library.
- Saurabh Agarwal
- , Todd S. Macfarlan
- & Shigeki Iwase
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| Open AccessAn integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.
- Wei Yuan
- , Yudong Xia
- & Tim D. Spector
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| Open AccessIdentification of the remains of King Richard III
King Richard III was a controversial English King whose remains are presumably deposited in Grey Friars in Leicester. Here the authors sequence the mitochondrial genome and Y-chromosome DNA of the skeletal remains and living relatives of Richard III and confirm that the remains belong to King Richard III.
- Turi E. King
- , Gloria Gonzalez Fortes
- & Kevin Schürer
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| Open AccessTargeted and genome-wide sequencing reveal single nucleotide variations impacting specificity of Cas9 in human stem cells
The microbial RNA-guided CRISPR/Cas9 system has robust genome-editing activities, but the off-target effects of the Cas9 nuclease have only recently begun to be analysed. Here the authors provide evidence for high specificity of the Cas9 nuclease on targeting of the Tafazzin gene in human-induced pluripotent stem cells and demonstrate the impact of single-nucleotide variations of the human genome on Cas9 specificity.
- Luhan Yang
- , Dennis Grishin
- & George Church
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Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing
Gastric cancer has two distinct morphologic subtypes, intestinal and diffuse, that differ in genetic composition and clinical manifestation. Here, the authors carry out whole-genome sequencing of diffuse and intestinal gastric cancer samples and characterize the mutational landscape of these different subtypes.
- Swee Seong Wong
- , Kyoung-Mee Kim
- & Amit Aggarwal
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| Open AccessGenome sequencing of chimpanzee malaria parasites reveals possible pathways of adaptation to human hosts
Plasmodium falciparum, known to cause malaria in humans, evolved from parasites of African Great Apes. Here, the authors compare the genome of the human parasite, P. falciparum, with those of two related chimpanzee parasites, P. reichenowi and P. gaboni, and provide insight into the genetic basis of P. falciparumadaptation to human hosts.
- Thomas D. Otto
- , Julian C. Rayner
- & Matthew Berriman
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| Open AccessSequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins
Ashkenazi Jews are a genetically isolated population with distinct patterns of genetic diversity. Here, the authors sequence the genomes of 128 Ashkenazi Jewish individuals and use the sequence information to provide insight into the population's European and Middle Eastern origins.
- Shai Carmi
- , Ken Y. Hui
- & Itsik Pe’er
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| Open AccessA genome-wide map of hyper-edited RNA reveals numerous new sites
Common methods to detect adenosine-to-inosine RNA editing sites rely on mapping short RNA reads to the genome while allowing only a limited number of mismatches. Here, Porath et al. present a novel RNA-seq based approach to identify hyper-edited reads that significantly expands the RNA editome.
- Hagit T. Porath
- , Shai Carmi
- & Erez Y. Levanon
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Sequencing-based approach identified three new susceptibility loci for psoriasis
Although psoriasis is a chronic disorder affecting approximately 2% of the population, little is known about the underlying genetic architecture. Here, the authors carry out exome sequencing in a large Han Chinese cohort of psoriasis patients and healthy controls, and identify three new genes that may increase risk of developing the disease.
- Yujun Sheng
- , Xin Jin
- & Xuejun Zhang
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An RNA-seq method for defining endoribonuclease cleavage specificity identifies dual rRNA substrates for toxin MazF-mt3
MazF toxins inhibit bacterial growth by cleaving single-stranded RNA at specific sequences. Here, the authors describe a new genome-wide approach, MORE RNA-seq, for defining MazF cleavage specificity, and show that MazF-mt3 cleaves 23S and 16S ribosomal RNAs.
- Jason M. Schifano
- , Irina O. Vvedenskaya
- & Nancy A Woychik
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| Open AccessDrawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing
Adeno-associated viruses (AAV) are promising gene transfer vectors for human gene therapy. Here, the authors report a high-throughput, sequencing-based method for characterizing amino acid function in AAV capsids and highlight the potential of this method for improving capsid design.
- Kei Adachi
- , Tatsuji Enoki
- & Hiroyuki Nakai
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RNA sequencing reveals the complex regulatory network in the maize kernel
Determining the link between gene polymorphisms and phenotypic traits is the subject of intense research in agricultural plant science. In this study, Fu et al. conduct RNA sequencing in maize kernels to determine gene polymorphisms, which may aid future research aiming to improve the nutritional value of maize.
- Junjie Fu
- , Yanbing Cheng
- & Guoying Wang
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Semiconductor-based DNA sequencing of histone modification states
Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.
- Christine S. Cheng
- , Kunal Rai
- & Ido Amit
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Genome-scale proteome quantification by DEEP SEQ mass spectrometry
The complexity and dynamic range of mammalian proteomes has stymied comprehensive protein quantification for the past twenty years. Zhou et al. develop DEEP SEQ mass spectrometry and use it to quantify a murine stem cell proteome to a depth equivalent to RNA-seq-based ribosome profiling.
- Feng Zhou
- , Yu Lu
- & Jarrod A. Marto
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| Open AccessWhole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genome evolution
The wild rice species can be used as germplasm resources for this crop’s genetic improvement. Here Chen and colleagues report the de novo sequencing of the O. brachyanthagenome, and identify the origin of genome size variation, the role of gene movement and its implications on heterochromatin evolution in the rice genome.
- Jinfeng Chen
- , Quanfei Huang
- & Mingsheng Chen
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Tet-mediated covalent labelling of 5-methylcytosine for its genome-wide detection and sequencing
A number of methylome sequencing technologies depend on affinity purification of methylated DNA. Zhang et al. demonstrate a click-chemistry-based protocol for covalently labelling 5-methylcytosine residues with biotin, providing enhanced sensitivity and specificity compared with antibody-based enrichment.
- Liang Zhang
- , Keith E. Szulwach
- & Chuan He
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| Open AccessThe genome of Prunus mume
The Prunus mume was domesticated in China over 3,000 years ago and is an important ornamental plant and fruit. Here Qixiang Zhang et al.obtain the first assembly of its genome with a combination of next-generation sequencing, whole-genome mapping and restriction-site-associated DNA.
- Qixiang Zhang
- , Wenbin Chen
- & Jun Wang
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A fast and accurate SNP detection algorithm for next-generation sequencing data
The amount of data supplied by next-generation sequencing technologies presents a challenge for traditional algorithms to detect single-nucleotide polymorphisms. Xu et al.develop an efficient detection program and demonstrate its utility by identifying polymorphisms in cancer genomes and human populations.
- Feng Xu
- , Weixin Wang
- & Junwen Wang
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| Open AccessGenome sequences of wild and domestic bactrian camels
Camels are essential means of transport in deserts, but we know little about the biology of these extraordinary mammals. This study reports the genome sequences of the wild and domestic bactrian camel, offering a glimpse into the camels’ genetic adaptation to harsh environments.
- Jirimutu
- , Zhen Wang
- & He Meng
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| Open AccessGenome sequence of the model medicinal mushroom Ganoderma lucidum
Ganoderma lucidumis a macrofungus in traditional Chinese medicine known to produce different bioactive compounds. In this study, the genome ofG. lucidumis sequenced, making this organism a potential model system for future studies of secondary metabolic pathways and their regulation in medicinal fungi.
- Shilin Chen
- , Jiang Xu
- & Chao Sun
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Mapping of H3N2 influenza antigenic evolution in China reveals a strategy for vaccine strain recommendation
Influenza vaccines are updated frequently to accommodate changing influenza antigenicity. Here, the authors develop a new computational method for predicting the antigenicity of H3N2 influenza strains based on the HA sequence.
- Xiangjun Du
- , Libo Dong
- & Taijiao Jiang