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| Open AccessCUTseq is a versatile method for preparing multiplexed DNA sequencing libraries from low-input samples
Genomics DNA library preparation from formalin-fixed paraffin-embedded tissues is challenging. Here the authors describe CUTseq that uses restriction enzymes and in vitro amplification to barcode samples for reduced representation genome sequencing.
- Xiaolu Zhang
- , Silvano Garnerone
- & Nicola Crosetto
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Article
| Open AccessDe novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Large whole-exome sequencing studies have suggested that the genetic architecture of syndromic congenital heart disease (CHD) is different from sporadic forms. Here, Watkins et al. estimate the relative contribution of damaging recessive and de novo genotypes to CHD in 2391 trios and find them to be associated with different gene functions.
- W. Scott Watkins
- , E. Javier Hernandez
- & Martin Tristani-Firouzi
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Article
| Open AccessSaturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
Interpreting genetic variation in the noncoding genome remains challenging, with functional effects difficult to predict. Here, the authors perform saturation mutagenesis combined with massively parallel reporter assays for 20 disease-associated regulatory elements, quantifying the effects of over 30,000 variants.
- Martin Kircher
- , Chenling Xiong
- & Nadav Ahituv
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Article
| Open AccessFDA-ARGOS is a database with public quality-controlled reference genomes for diagnostic use and regulatory science
To be able to use infectious disease next generation sequencing as a diagnostic tool, appropriate reference datasets are required. Here, Sichtig et al. describe FDA-ARGOS, a reference database for high-quality microbial reference genomes, and demonstrate its utility on the example of two use cases.
- Heike Sichtig
- , Timothy Minogue
- & Uwe Scherf
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Article
| Open AccessAMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”
- Vincenzo Salpietro
- , Christine L. Dixon
- & Henry Houlden
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Article
| Open AccessA genome-wide scan statistic framework for whole-genome sequence data analysis
Whole-genome sequencing data reveals a large number of variants for testing their associations with phenotypic traits and diseases. Here, the authors develop WGScan, a statistical method for detecting the existence and estimating the locations of the association signal at genome-wide scale.
- Zihuai He
- , Bin Xu
- & Iuliana Ionita-Laza
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Article
| Open AccessComprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy
Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.
- Atsushi Takata
- , Mitsuko Nakashima
- & Naomichi Matsumoto
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Article
| Open AccessqDSB-Seq is a general method for genome-wide quantification of DNA double-strand breaks using sequencing
Measuring relative frequencies of DNA double-strand breaks between loci does not provide the full physiological relevance of those breaks. Here Rowicka and colleagues present qDSB-Seq method which uses spike-in double-strand breaks induced by a restriction enzyme to accurately quantify DNA damage.
- Yingjie Zhu
- , Anna Biernacka
- & Maga Rowicka
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Article
| Open AccessThe use of technical replication for detection of low-level somatic mutations in next-generation sequencing
Somatic mutations of low allele frequencies are often difficult to detect. Here, the authors develop RePlow, a computational method that leverages technical replication for detecting low-level somatic mutations using next-generation sequencing.
- Junho Kim
- , Dachan Kim
- & Sangwoo Kim
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Article
| Open AccessSingle gametophyte sequencing reveals that crossover events differ between sexes in maize
Meiotic crossover (CO) landscape differs inter- and intra-species, as well as between sexes. Here, the authors show that male meiosis produces more COs than female in maize and detect CO maturation inefficiency in some genetic backgrounds, which may help to improve breeding efficiency.
- Cheng Luo
- , Xiang Li
- & Jianbing Yan
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Article
| Open AccessNon-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function
Infection of a cell with influenza B virus (IBV) often results in cell death and the role of surviving cells in pathogenesis is unclear. Here, Dumm et al. generate a recombinant IBV that activates a host-cell reporter to permanently label infected cells, and show that surviving cells are important to preserve epithelial barrier function.
- Rebekah E. Dumm
- , Jessica K. Fiege
- & Nicholas S. Heaton
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Article
| Open AccessLoss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella
Multiple morphological abnormalities of the sperm flagella (MMAF) is a cause of male infertility. Here the authors identify homozygous nonsense mutations of the glutamine rich 2 (QRICH2) gene in two MMAF patients from 2 consanguineous families and show using QRICH2 knockout mice that the protein is required for sperm flagellar formation and motility.
- Ying Shen
- , Feng Zhang
- & Wenming Xu
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Article
| Open AccessChromatin conformation analysis of primary patient tissue using a low input Hi-C method
Chromatin conformation studies are limited by the large amounts of starting material required to perform current protocols. Here the authors present Low-C, a Hi-C method for low amounts of input material and produce Low-C maps from primary B-cells of a diffuse large B-cell lymphoma patient, demonstrating the suitability of Low-C to analyse rare cell populations.
- Noelia Díaz
- , Kai Kruse
- & Juan M. Vaquerizas
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Article
| Open AccessExpansive microbial metabolic versatility and biodiversity in dynamic Guaymas Basin hydrothermal sediments
The diversity and function of microbes inhabiting hydrothermal areas is a topic of active interest in marine microbiology. Here, the authors assemble genomes from Guaymas Basin hydrothermal sediments and describe the metabolic roles of the bacterial community, which includes five new bacterial candidate phyla
- Nina Dombrowski
- , Andreas P. Teske
- & Brett J. Baker
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Article
| Open AccessSingle cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant
The function of the Retinoblastoma (Rb) protein is regulated by its cellular environment. Here, the authors perform single cell RNA-sequencing during Drosophila eye development and identify the impact of an Rbf mutation, which sensitises specific cells to apoptosis by changing metabolism.
- Majd M. Ariss
- , Abul B. M. M. K. Islam
- & Maxim V. Frolov
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Article
| Open AccessAncient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe
Populations from North-eastern Europe, in particular those speaking Uralic languages, carry additional ancestry in similarity with modern East Asian populations. Here, the authors analyse ancient genomic data from 11 individuals from Finland and Northwest Russia, and identify genomic signals of migrations from Siberia that began at least 3500 years ago.
- Thiseas C. Lamnidis
- , Kerttu Majander
- & Stephan Schiffels
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Article
| Open AccessCohort-wide deep whole genome sequencing and the allelic architecture of complex traits
Rare genetic variants can contribute to complex traits but this contribution is not well understood. Here, the authors analyse deep whole genome sequencing data across 1457 individuals from an isolated Greek population and find association of rare variant burdens with cardiometabolic traits.
- Arthur Gilly
- , Daniel Suveges
- & Eleftheria Zeggini
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Article
| Open AccessJoint single-cell DNA accessibility and protein epitope profiling reveals environmental regulation of epigenomic heterogeneity
Cellular heterogeneity in cancer is complex and difficult to study. Here, the authors introduce Protein-indexed Assay of Transposase Accessible Chromatin (Pi-ATAC), which combines single cell chromatin and proteomic profiling to provide deep insight into the tumor microenvironment, and reveal the role of hypoxia in shaping the regulome of a subset of breast cancer cells in vivo.
- Xingqi Chen
- , Ulrike M. Litzenburger
- & Howard Y. Chang
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Article
| Open AccessMapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries
Characterizing the binding selectivity landscape of interacting proteins is crucial in protein engineering. Here the authors use multi-target selective library screening and in silico next-generation sequencing to map the binding landscape of proteins and produce improved proteases inhibitors.
- Si Naftaly
- , Itay Cohen
- & Niv Papo
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Article
| Open AccessDistinct epigenomic patterns are associated with haploinsufficiency and predict risk genes of developmental disorders
Predicting haploinsufficient genes helps to understand the genetic risk underlying developmental disorders. Here, the authors develop a Random Forest-based method that uses epigenomic data to predict haploinsufficiency, Episcore, which is complementary to methods based on mutation intolerance scores.
- Xinwei Han
- , Siying Chen
- & Yufeng Shen
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Article
| Open AccessThe human Vδ2+ T-cell compartment comprises distinct innate-like Vγ9+ and adaptive Vγ9- subsets
Human Vδ2+ γδ T cells are thought to be an innate-like T-cell population. Here the authors show the Vδ2+ compartment contains both innate-like Vγ9+ and an adaptive Vγ9- subset that undergoes clonal expansion during viral infection and can infiltrate liver tissue.
- Martin S. Davey
- , Carrie R. Willcox
- & Benjamin E. Willcox
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Article
| Open AccessDeep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese
Recent natural selection left signals in human genomes. Here, Okada et al. generate high-depth whole-genome sequence (WGS) data (25.9×) from 2,234 Japanese people of the BioBank Japan Project (BBJ), and identify signals of recent natural selection which overlap variants associated with human traits.
- Yukinori Okada
- , Yukihide Momozawa
- & Yoichiro Kamatani
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Article
| Open AccessHistone H3.3 sub-variant H3mm7 is required for normal skeletal muscle regeneration
Incorporation of histone H3 variant H3.3 into chromatin regulates transcription. Here the authors find that H3.3 sub-variant H3mm7 is required for skeletal muscle regeneration and that H3mm7 nucleosomes are unstable and exhibit higher mobility, with H3mm7 promoting open chromatin around promoters.
- Akihito Harada
- , Kazumitsu Maehara
- & Yasuyuki Ohkawa
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Article
| Open AccessGenome-wide identification of natural RNA aptamers in prokaryotes and eukaryotes
Riboswitches recognize and respond to specific metabolites by altering gene expression. Here, the authors developed a high-throughput method (PARCEL) to experimentally identify RNA aptamers across transcriptomes.
- Sidika Tapsin
- , Miao Sun
- & Yue Wan
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Article
| Open AccessA complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site
The receptor-binding site (RBS) of influenza A viruses evolves to evade immune pressure, while maintaining efficient attachment to the host receptor. Wu et al. here identify the complex epistatic network in RBS of H3N2 viruses that limits reversibility of naturally occurring mutations to retain infectivity.
- Nicholas C. Wu
- , Andrew J. Thompson
- & Ian A. Wilson
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Article
| Open AccessSomatic mutagenesis in satellite cells associates with human skeletal muscle aging
Aging skeletal muscle shows declining numbers and activity of satellite cells. Here, Franco et al. show that in satellite cells of the human leg muscle vastus lateralis, somatic mutations accumulate with age and that these mutations become enriched in exons and promoters of genes involved in muscle function.
- Irene Franco
- , Anna Johansson
- & Maria Eriksson
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Article
| Open AccessCellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.
- Terrence N. Wong
- , Christopher A. Miller
- & Daniel C. Link
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Article
| Open AccessNucleotide resolution mapping of influenza A virus nucleoprotein-RNA interactions reveals RNA features required for replication
Influenza A virus packaging depends on interactions between nucleoprotein (NP) and viral RNA (vRNA), but the pattern of NP binding is unclear. Using PAR-CLIP, Williams et al. here show that NP binds vRNA non-uniformly and that RNA structures in low-NP binding regions are important for packaging.
- Graham D. Williams
- , Dana Townsend
- & Adrianus C. M. Boon
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Article
| Open AccessReading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration
The Iberian ribbed newt Pleurodeles waltl has a wide spectrum of regeneration abilities. Here, Elewa et al. sequence its ~20 Gb genome and transcriptome to investigate the molecular features underlying its regenerative capacities.
- Ahmed Elewa
- , Heng Wang
- & András Simon
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Article
| Open AccessEfficient transgenesis and annotated genome sequence of the regenerative flatworm model Macrostomum lignano
Regeneration capable flatworms have emerged as powerful models for studying stem cell biology and patterning, however their study has been hindered by the lack of transgenesis methods. Here, the authors describe a transgenesis method for Macrostomum lignano, as well as a new annotated genome sequence.
- Jakub Wudarski
- , Daniil Simanov
- & Eugene Berezikov
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Article
| Open AccessScallop genome reveals molecular adaptations to semi-sessile life and neurotoxins
Bivalve molluscs have evolved various characteristics to adapt to benthic filter-feeding. Here, Li et al investigate the genome, transcriptomes and proteomes of scallop Chlamys farreri, revealing evidences of molecular adaptations to semi-sessile life and neurotoxins.
- Yuli Li
- , Xiaoqing Sun
- & Zhenmin Bao
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Article
| Open AccessLoss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
Mutations in potassium and calcium channel genes have been associated with cardiac arrhythmias. Here, Jensen et al. show that an anion transporter chloride-bicarbonate exchanger AE3 is also responsible for the genetically-induced mechanism of cardiac arrhythmia, suggesting new therapeutic targets for this disease
- Kasper Thorsen
- , Vibeke S. Dam
- & Henrik K. Jensen
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Article
| Open AccessTracing the origin and evolution of supergene mimicry in butterflies
Wing pattern mimicry in the butterfly Papilio polytes is controlled by a single Mendelian locus, the mimicry supergene doublesex. Here, Zhang and colleagues reconstruct the complex evolutionary history of the doublesex supergene and mimicry in the Papilio polytes species group.
- Wei Zhang
- , Erica Westerman
- & Marcus R. Kronforst
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Article
| Open AccessDemographic history and biologically relevant genetic variation of Native Mexicans inferred from whole-genome sequencing
People of Mexico have diverse historical and genetic background. Here, Romero-Hidalgo and colleagues sequence whole genomes of Native Americans of Mexico, and show demographic history and genetic variation shared among subgroups of Native Americans.
- Sandra Romero-Hidalgo
- , Adrián Ochoa-Leyva
- & Xavier Soberón
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Article
| Open AccessCross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.
- Beben Benyamin
- , Ji He
- & Dongsheng Fan
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Article
| Open AccessIdentifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer
Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I hypersensitive sites in breast cancer and experimentally demonstrate they are regulatory elements of known cancer genes.
- Matteo D′Antonio
- , Donate Weghorn
- & Kelly A Frazer
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Article
| Open AccessNanopore long-read RNAseq reveals widespread transcriptional variation among the surface receptors of individual B cells
Short-read RNA-seq is limited in its ability to resolve complex transcript isoforms since it cannot sequence full-length cDNA. Here the authors use Oxford Nanopore MinION and their Mandalorion analysis pipeline to measure complex isoforms in B1a cells.
- Ashley Byrne
- , Anna E. Beaudin
- & Christopher Vollmers
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Article
| Open AccessGeneration and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma
Site-specific recombination and CRISPR-Cas9 have been used to generate genetically engineered mouse models of cancer. Here the authors compare sarcomas generated using both systems and see similar genetic and cellular phenotypes, suggesting CRISPR-Cas9 can be used to rapidly generate sarcoma models.
- Jianguo Huang
- , Mark Chen
- & David G. Kirsch
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Article
| Open AccessUltrasensitive and high-efficiency screen of de novo low-frequency mutations by o2n-seq
Detection ofde novo, low frequency mutations is important for characterising heterogeneous cell populations, such as those found in cancer cell populations. Here the authors present o2n-seq, an ultrasensitive method with highly efficient data usage for detection of rare mutations.
- Kaile Wang
- , Shujuan Lai
- & Jue Ruan
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Article
| Open AccessBLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks
Double-strand breaks are a major DNA lesion that can occur by endogenous and exogenous processes. Here the authors present BLISS—Breaks LabellingIn Situand Sequencing—to map breaks across the genome.
- Winston X. Yan
- , Reza Mirzazadeh
- & Nicola Crosetto
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Article
| Open AccessSequencing and de novo assembly of a near complete indica rice genome
High-quality reference genomes facilitate analysis of genome structure and variation. Here Duet al. create a near-complete assembly of the indicarice genome by combining single molecule sequencing with mapping data and fosmid sequences and identify genetic variants by comparison with other rice genomes.
- Huilong Du
- , Ying Yu
- & Chengzhi Liang
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Article
| Open AccessGenome assembly with in vitro proximity ligation data and whole-genome triplication in lettuce
Genome assembly for many plant species can be challenging due to large size and high repeat content. Here, the authors usein vitroproximity ligation to assemble the genome of lettuce, revealing a family-specific triplication event and providing a comprehensive reference genome for a member of the Compositae.
- Sebastian Reyes-Chin-Wo
- , Zhiwen Wang
- & Richard W. Michelmore
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Article
| Open AccessBarcode extension for analysis and reconstruction of structures
Techniques for structural characterization and quantification of DNA origami are still poorly developed, despite advances in other aspects of DNA nanotechnology. Here, the authors combine barcoding and next generation sequencing to simultaneously image and quantify self-assembled DNA nanostructures.
- Cameron Myhrvold
- , Michael Baym
- & Peng Yin
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Article
| Open AccessHigh-throughput automated microfluidic sample preparation for accurate microbial genomics
Shotgun DNA sequencing experiments for microbial genomic analysis are often impractical due to minimum sample input requirements. Here the authors develop a microfluidic sample preparation platform that reduces sample input requirements 100-fold and enables high throughput sequencing from low numbers of cells.
- Soohong Kim
- , Joachim De Jonghe
- & Paul C. Blainey
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Article
| Open AccessRapid construction of a whole-genome transposon insertion collection for Shewanella oneidensis by Knockout Sudoku
Knockout collections provide a valuable tool to explore gene function, yet are expensive and technically challenging to produce at a genome-wide scale. Here Baym et al. devise a cost-effective transposon-based method to quickly develop a knockout collection for the electroactive microbe Shewanella oneidensis.
- Michael Baym
- , Lev Shaket
- & Buz Barstow
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Article
| Open AccessDe novo genic mutations among a Chinese autism spectrum disorder cohort
Recurrent sporadic mutations are important risk factors for autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, Eichler, Xia and colleagues analyse risk genes in a large Chinese ASD cohort and find novel recurrences of potential pathogenic significance.
- Tianyun Wang
- , Hui Guo
- & Evan E. Eichler
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Article
| Open AccessA high-quality human reference panel reveals the complexity and distribution of genomic structural variants
Structural variants (SVs) are prevalent in genomes of the general population. Here, Guryev and The Genome of the Netherlands Consortium describe the reference panel of haplotype-resolved SVs from 769 individuals from 250 Dutch families and show its utility for studying heritable traits.
- Jayne Y. Hehir-Kwa
- , Tobias Marschall
- & Victor Guryev
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Article
| Open AccessRapid construction of metabolite biosensors using domain-insertion profiling
In the construction of single fluorescent protein biosensors, selection of the insertion point of a fluorescent protein into a ligand-binding domain is a rate-limiting step. Here, the authors develop an unbiased, high-throughput approach, called domain insertion profiling with DNA sequencing (DIP-seq), to generate a novel trehalose biosensor.
- Dana C. Nadler
- , Stacy-Anne Morgan
- & David F. Savage
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Article
| Open AccessDe novo assembly and next-generation sequencing to analyse full-length gene variants from codon-barcoded libraries
This paper described a new and efficient method for de novoassembly of multiple DNA sequence information from mutagenized clone libraries. Using codon-barcoded libraries and calling the method JigsawSeq, the authors overcome limitations of short-read sequencing assembly from next-generation sequencing.
- Namjin Cho
- , Byungjin Hwang
- & Duhee Bang