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| Open AccessFunctional testing of thousands of osteoarthritis-associated variants for regulatory activity
GWAS have identified risk loci for osteoarthritis (OA), but the causal variants still have to be determined. Here, the authors apply a massively-parallel reporter assay to screen 1,605 candidate SNPs in 35 OA loci, which prioritizes six SNPs in four loci, one of which, rs4730222, is characterized in more detail.
- Jason C. Klein
- , Aidan Keith
- & Jay Shendure
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Article
| Open AccessFunctional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening
Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.
- Gabriele Picco
- , Elisabeth D. Chen
- & Mathew J. Garnett
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Article
| Open AccessInterferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.
- Christopher A. Odhams
- , Amy L. Roberts
- & Timothy J. Vyse
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Article
| Open AccessGenome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density
GWAS have identified numerous genetic loci for bone mineral density (BMD) and fracture risk. Here, the authors map these variants to putative target genes using ATAC-seq and Capture C of human osteoblasts and confirm ING3 and EPDR1 as BMD genes in in vitro osteoblast differentiation experiments.
- Alessandra Chesi
- , Yadav Wagley
- & Struan F. A. Grant
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Article
| Open AccessPervasive function and evidence for selection across standing genetic variation in S. cerevisiae
Genetic architecture underlies the complexity of heritable traits. Here, the authors perform high-resolution genetic mapping of metabolic traits in S. cerevisiae and show evidence for selection across standing genetic variation.
- Christopher M. Jakobson
- , Richard She
- & Daniel F. Jarosz
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Article
| Open AccessPrioritizing Parkinson’s disease genes using population-scale transcriptomic data
GWAS have identified over 41 susceptibility loci for Parkinson’s disease (PD). Here, the authors integrate PD GWAS summary statistics with transcriptome data from monocytes and DLFPC tissue in a TWAS approach and find 66 significant associations with PD risk highlighting lysosomal and innate immune functions.
- Yang I. Li
- , Garrett Wong
- & Towfique Raj
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Article
| Open AccessFunctional genomics reveal gene regulatory mechanisms underlying schizophrenia risk
We know a large number of risk SNPs for schizophrenia, but little about how these SNPs contribute to the disorder. Here, the authors use functional genomics to identify risk SNPs that disrupt transcription factor binding and validate the regulatory effects of the transcription factor binding-disrupting SNPs.
- Yongxia Huo
- , Shiwu Li
- & Xiong-Jian Luo
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Article
| Open AccessHydrogen-based metabolism as an ancestral trait in lineages sibling to the Cyanobacteria
Most cyanobacteria are oxygenic photoautotrophs, and fermenters under dark anoxic conditions. Here, the authors analyse genomic sequences of related uncultivated bacteria, inferring their metabolic potential, and supporting that their common ancestor was an anaerobe capable of fermentation and H2 metabolism.
- Paula B. Matheus Carnevali
- , Frederik Schulz
- & Jillian F. Banfield
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Article
| Open AccessPenaeid shrimp genome provides insights into benthic adaptation and frequent molting
The Pacific white shrimp Litopenaeus vannamei is an important aquaculture species and a promising model for crustacean biology. Here, the authors provide a reference genome assembly, and show that gene expansion is involved in the regulation of frequent molting as well as benthic adaptation of the shrimp.
- Xiaojun Zhang
- , Jianbo Yuan
- & Jianhai Xiang
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Article
| Open AccessDual-barcoded shotgun expression library sequencing for high-throughput characterization of functional traits in bacteria
Gain of function methods based on gene overexpression are not easily applied to high-throughput screening across different experimental conditions. Here, the authors present Dub-seq, which separates overexpression library characterization from functional screening and uses random DNA barcodes to increase the experimental throughput.
- Vivek K. Mutalik
- , Pavel S. Novichkov
- & Adam P. Arkin
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Article
| Open AccessHigh-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human
Millions of enhancers are predicted, but their validation remains challenging. Here, the authors report genome-wide enhancer function quantification and high-resolution dissection for millions of accessible DNA fragments, revealing driver nucleotides and helping interpret non-coding disease variants.
- Xinchen Wang
- , Liang He
- & Manolis Kellis
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Article
| Open AccessTranscriptomic meta-signatures identified in Anopheles gambiae populations reveal previously undetected insecticide resistance mechanisms
Increasing insecticide resistance of mosquitoes represents a public health threat, and underlying mechanisms are poorly understood. Here, Ingham et al. identify putative insecticide resistance genes in Anopheles gambiae populations across Africa and develop a web-based application that maps their expression.
- V. A. Ingham
- , S. Wagstaff
- & H. Ranson
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Article
| Open AccessPredicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features
CTCF mediates long-range chromatin interactions which are important for genome organization and function. Here, the authors demonstrate that CTCF-mediated interactome exhibits extensive plasticity and present Lollipop, a machine-learning framework which predicts CTCF-mediated long-range interactions using genomic and epigenomic features.
- Yan Kai
- , Jaclyn Andricovich
- & Weiqun Peng
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Article
| Open AccessPooled CRISPR interference screening enables genome-scale functional genomics study in bacteria with superior performance
Systemic investigation of the bacterial genome is essential for both basic microbiology and bioengineering. Here the authors demonstrate CRISPRi pooled screening as a high-throughput tool for identifying gene and phenotype associations in bacteria.
- Tianmin Wang
- , Changge Guan
- & Xin-Hui Xing
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Article
| Open AccessThe evolution of the temporal program of genome replication
Temporal programs of genome replication show different levels of conservation between closely or distantly related species. Here, the authors generate genome-wide replication timing profiles for ten yeast species, and analyze their evolutionary dynamics.
- Nicolas Agier
- , Stéphane Delmas
- & Gilles Fischer
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Article
| Open AccessGenome-scale identification of transcription factors that mediate an inflammatory network during breast cellular transformation
Systematic analysis of the control of dynamic cellular processes remains a challenge. Here the authors introduce a pipeline enabling them to identify TFs involved in Src-induced cellular transformation, and find that a large number of TFs with diverse DNA binding specificities orchestrate the process.
- Zhe Ji
- , Lizhi He
- & Kevin Struhl
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Article
| Open AccessPrecise control of SCRaMbLE in synthetic haploid and diploid yeast
The SCRaMbLE system integrated into Sc2.0’s synthetic yeast chromosome project allows rapid strain evolution. Here the authors use a genetic logic gate to control induction of recombination in a haploid and diploid yeast carrying synthetic chromosomes.
- Bin Jia
- , Yi Wu
- & Ying-Jin Yuan
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Article
| Open AccessBayesian nonparametric discovery of isoforms and individual specific quantification
Alternative splicing leads to transcript isoform diversity. Here, Aguiar et al. develop biisq, a Bayesian nonparametric approach to discover and quantify isoforms from RNA-seq data.
- Derek Aguiar
- , Li-Fang Cheng
- & Barbara E. Engelhardt
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Article
| Open AccessIntegration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS
GWAS have identified numerous genetic loci for BMI and related traits. Here, Pan et al. generate Promoter Capture Hi-C data for human white adipocytes and integrate these with data of transcription factor motifs, RNA-seq and GWAS to identify eQTL-eGene relationships mediated by chromosomal interactions.
- David Z. Pan
- , Kristina M. Garske
- & Arthur Ko
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Article
| Open AccessATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration
Age-related macular degeneration (AMD) leads to dysfunctional retinal pigment epithelium (RPE) and vision loss. Here, the authors perform ATAC-seq to study chromatin accessibility and find that differentially accessible regions are enriched for photoreceptor and RPE-specific transcription factors in AMD
- Jie Wang
- , Cristina Zibetti
- & Jiang Qian
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Article
| Open AccessThe genomic and functional landscapes of developmental plasticity in the American cockroach
The American cockroach (Periplaneta americana) is an hemimetabolous insect with rapid growth, high fecundity, and remarkable tissue-regeneration capability. Here Li et al sequence its 3.38-Gb genome and perform the functional studies, yielding insights into its environmental adaptation and developmental plasticity.
- Sheng Li
- , Shiming Zhu
- & Shuai Zhan
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Article
| Open AccessCtIP fusion to Cas9 enhances transgene integration by homology-dependent repair
The integration of exogenous DNA into the genome using CRISPR–Cas9 often presents a challenge to researchers. Here the authors fuse CtIP to Cas9 to stimulate recombination at target loci.
- M. Charpentier
- , A. H. Y. Khedher
- & J. P. Concordet
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Article
| Open AccessA transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis
Progressive remodeling and calcification of the aortic valve leads to calcific aortic valve stenosis (CAVS) and, ultimately, heart failure. In a combined GWAS and TWAS approach, Thériault et al. identify PALMD as a candidate causal gene for CAVS, which is further supported by Mendelian randomization.
- Sébastien Thériault
- , Nathalie Gaudreault
- & Yohan Bossé
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Article
| Open AccessSingle-cell full-length total RNA sequencing uncovers dynamics of recursive splicing and enhancer RNAs
Total RNA sequencing has been used to profile poly(A) and non-poly(A) RNA expression, processing and the activity of enhancers. Here the authors develop RamDA-seq, a method for full-length total RNA sequencing in single cells.
- Tetsutaro Hayashi
- , Haruka Ozaki
- & Itoshi Nikaido
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Article
| Open AccessIdentification and characterization of two functional variants in the human longevity gene FOXO3
FOXO3 is one of the few established longevity genes. Here, the authors fine-map the FOXO3-longevity association to two intronic SNPs and, using luciferase assays and EMSAs, show that these SNPs affect binding of transcription factors CTCF and SRF and associate with FOXO3 expression.
- Friederike Flachsbart
- , Janina Dose
- & Almut Nebel
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Article
| Open AccessMultiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity
Genome editing technologies enable the rapid interrogation of genetic alterations. Here, the authors present a CRISPR/Cas9-based platform to simultaneously investigate multiple activating point mutations in de novo cancers in mice; and generate panels of Kras-variants in different tissues to induce cancer.
- Ian P. Winters
- , Shin-Heng Chiou
- & Monte M. Winslow
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Article
| Open AccessGenome-wide identification and differential analysis of translational initiation
Translation initiation sequencing (TI-seq) has revealed unexpected diversity in protein isoforms. Here, Zhang et al. present Ribo-TISH, a computational toolkit that can detect and compare TIs across conditions and improve open reading frame prediction from different types of ribosome profiling data.
- Peng Zhang
- , Dandan He
- & Yiwen Chen
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Article
| Open AccessCarrageenan catabolism is encoded by a complex regulon in marine heterotrophic bacteria
Carrageenans, major cell wall polysaccharides of red macroalgae, are metabolised by marine heterotrophic bacteria through unclear mechanisms. Here, the authors identify an unusual polysaccharide-utilization locus encoding carrageenan catabolism in a marine bacterium, and characterise the complete pathway.
- Elizabeth Ficko-Blean
- , Aurélie Préchoux
- & Gurvan Michel
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Article
| Open AccessA large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction
The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.
- Michael R. Bowl
- , Michelle M. Simon
- & Steve D. M. Brown
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Article
| Open AccessHigh-throughput screens using photo-highlighting discover BMP signaling in mitochondrial lipid oxidation
High-throughput genetic screens in animals could benefit from an easy way to mark positive hits. Here the authors introduce photo-highlighting using a photoconvertible fluorescent protein, and in combination with stimulated Raman scattering (SRS) microscopy, define a role for BMP signaling in lipid metabolism in C. elegans.
- Yong Yu
- , Ayse Sena Mutlu
- & Meng C. Wang
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Article
| Open AccessTia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells
Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner.
- Manuel D. Díaz-Muñoz
- , Vladimir Yu. Kiselev
- & Martin Turner
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Article
| Open AccessBlood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis
The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte’s transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.
- Yongmei Liu
- , Lindsay M. Reynolds
- & James H. Stein
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Article
| Open AccessGenetic regulatory effects modified by immune activation contribute to autoimmune disease associations
Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.
- Sarah Kim-Hellmuth
- , Matthias Bechheim
- & Veit Hornung
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Article
| Open AccessPlatelet function is modified by common sequence variation in megakaryocyte super enhancers
Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.
- Romina Petersen
- , John J. Lambourne
- & Mattia Frontini
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Article
| Open AccessEnrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations
Isolated populations often have special genetic compositions that can be leveraged for genetic association studies. Here, Xue and colleagues generate and analyse 3,059 low-depth whole-genome sequences from eight European isolated populations and two matched general populations.
- Yali Xue
- , Massimo Mezzavilla
- & Eleftheria Zeggini
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Article
| Open AccessA scalable double-barcode sequencing platform for characterization of dynamic protein-protein interactions
Protein-protein interactions (PPIs) play a major role in defining biological functions. Here, the authors present PPiSeq, a method to quantitatively score dynamic PPIs in yeast combining fragment complementation assays, genomic double-barcoding, and an analytical framework to precisely call fitness from barcode lineage trajectories.
- Ulrich Schlecht
- , Zhimin Liu
- & Sasha F. Levy
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Article
| Open AccessComplementary information derived from CRISPR Cas9 mediated gene deletion and suppression
CRISPR-Cas9 has been utilized to screen the genome in loss-of-function studies to identify genetic interactions. Here the authors compare catalytically active and dead Cas9 and observe different off-target effects in a screen for essential genes.
- Joseph Rosenbluh
- , Han Xu
- & William C. Hahn
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Article
| Open AccessQuantification of differential gene expression by multiplexed targeted resequencing of cDNA
Transcriptome sequencing is a powerful tool for functional analysis of different types of RNA molecules in a wide range of applications. Here the authors use targeted resequencing of cDNA with single-molecule molecular inversion probes as a cost-effective, high-throughput tool for mRNA quantification.
- Peer Arts
- , Jori van der Raadt
- & Cornelis A. Albers
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Article
| Open AccessGenome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens
CRISPR-Cas9 screens are powerful high-throughput tools but can be confounded by nuclease toxicity. Here the authors design a library of variable length gRNAs with thousands of negative controls, including the targeting of ‘safe’ loci to account for on-target site DNA damage toxicity.
- David W. Morgens
- , Michael Wainberg
- & Michael C. Bassik
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Article
| Open AccessGenetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10q21.2
Risk for the paediatric cancer high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) has been associated with genetic variants at 10q21.2. Here, the authors characterize this region, establishing a single risk variant and showing its role in dysregulated expression ofARID5B.
- James B. Studd
- , Jayaram Vijayakrishnan
- & Richard S. Houlston
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Article
| Open AccessX-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease resulting in reduced mucus clearance and impaired lung function. Here, the authors show that mutations in PIH1D3 are responsible for an X-linked form of PCD, affecting assembly of a subset of inner arm dyneins.
- Chiara Olcese
- , Mitali P. Patel
- & Hannah M. Mitchison
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Article
| Open AccessInnovation and constraint leading to complex multicellularity in the Ascomycota
The fungal Ascomycota provide a model phylum to investigate the evolution of complex multicellularity. Here, the authors combine genome sequencing with comparative and functional genomics to identify diverse endomembrane related machineries associated with the gain and loss of fungal complexity.
- Tu Anh Nguyen
- , Ousmane H. Cissé
- & Gregory Jedd
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Article
| Open AccessEvidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy
Duchenne muscular dystrophy is a disease caused by a single gene, characterized by progressive muscle weakness, but is variable between patients partly due to interactions of other genes. Here, the authors show that a commonACTN3polymorphism can modify the clinical phenotype.
- Marshall W. Hogarth
- , Peter J. Houweling
- & Kathryn N. North
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Article
| Open Access17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells
Variations in the 17q21 locus are linked to asthma susceptibility and other autoimmune diseases. Here, the authors perform cell type-specific functional genomic analyses of asthma-risk SNPs, and show a genotype specific mechanism of differential gene regulation relevant to immune function.
- Benjamin Joachim Schmiedel
- , Grégory Seumois
- & Pandurangan Vijayanand
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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 AccessNovel gene function revealed by mouse mutagenesis screens for models of age-related disease
Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.
- Paul K. Potter
- , Michael R. Bowl
- & Steve D. M. Brown
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Article
| Open AccessIdentification of Siglec-1 null individuals infected with HIV-1
Binding of virus, HIV-1, to cellular protein Siglec-1 is important for infection of immune cells. Here the authors show that a natural mutation leading to production of truncated Siglec-1 reduces HIV binding and infectivity transfer in vitro, but does not substantially affect infection or AIDS outcome in patients.
- Javier Martinez-Picado
- , Paul J. McLaren
- & Amalio Telenti
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Article
| Open AccessA transgenic approach for controlling Lygus in cotton
Plant-feeding insects of the Lygus genus have emerged as a major pest effecting cotton crops in the USA. Here the authors optimize the insecticidal activity of a Bacillus thuringiensis crystal protein and produce transgenic plants that are resistant to feeding damage by Lygusspecies.
- Anilkumar Gowda
- , Timothy J. Rydel
- & James A. Baum
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Article
| Open AccessIntegrative functional genomics identifies regulatory mechanisms at coronary artery disease loci
Coronary heart disease is the leading cause of death worldwide with multiple environmental and genetic risk factors. Here the authors integrate genomic, epigenomic and transcriptomic mapping to elucidate causal variation and mechanisms of known genetic associations.
- Clint L. Miller
- , Milos Pjanic
- & Thomas Quertermous