Featured
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| Open AccessTemporal dynamic reorganization of 3D chromatin architecture in hormone-induced breast cancer and endocrine resistance
In breast cancer, the 3D architecture of the genome can impact gene regulation. Here, the authors use tethered chromatin conformation profiling to investigate 3D chromatin structure in models of hormone-induced breast cancer and endocrine resistance, finding dynamic temporal reorganisation.
- Yufan Zhou
- , Diana L. Gerrard
- & Victor X. Jin
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Article
| Open AccessWhole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology
Being man’s best friend, dogs have been bred and selected for certain morphologic traits and breed-associated behaviours. Here, Plassais et al. analyse 722 canine whole genome sequences including modern breeds, wild canids and village dogs by GWAS and search for signatures of selection.
- Jocelyn Plassais
- , Jaemin Kim
- & Elaine A. Ostrander
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Article
| Open AccessA high-quality apple genome assembly reveals the association of a retrotransposon and red fruit colour
Existing apple genome assemblies all derive from Golden Delicious. Here, the authors combine different sequencing technologies to assemble a high quality genome of an anther-derived homozygous genotype HFTH1 and find the association of a retrotransposon and red fruit colour.
- Liyi Zhang
- , Jiang Hu
- & Peihua Cong
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Article
| Open AccessGenome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
- Henry R. Kranzler
- , Hang Zhou
- & Joel Gelernter
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Article
| Open AccessIdentification of human D lactate dehydrogenase deficiency
D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.
- Glen R. Monroe
- , Albertien M. van Eerde
- & Judith J. Jans
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Article
| Open AccessA study of the extraordinarily strong and tough silk produced by bagworms
Spider silk is widely studied for its structural properties; however, other creatures produce silk that could be of interest. Here, the authors study the properties and structure of Bagworm silk and report it as being extraordinarily strong and tough compared to other known silks.
- Taiyo Yoshioka
- , Takuya Tsubota
- & Tsunenori Kameda
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Article
| Open AccessRad52 prevents excessive replication fork reversal and protects from nascent strand degradation
Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism.
- Eva Malacaria
- , Giusj Monia Pugliese
- & Pietro Pichierri
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Article
| Open AccessThe anti-cancer drugs curaxins target spatial genome organization
Curaxins are a recently discovered class of anti-cancer agents that disturbs DNA/histone interactions within. Here the authors provide evidence that curaxins affect the spatial genome organization and compromise enhancer-promoter communication necessary for expression of several oncogenes, including MYC.
- Omar L. Kantidze
- , Artem V. Luzhin
- & Sergey V. Razin
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Article
| Open AccessPiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice
Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.
- Julia Weber
- , Jorge de la Rosa
- & Roland Rad
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Article
| Open AccessTargeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
- Evelyne Lima-Fernandes
- , Alex Murison
- & Catherine A. O’Brien
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Article
| Open AccessParent of origin genetic effects on methylation in humans are common and influence complex trait variation
Parent-of-origin effects (POE) are observed when there are different effects from alleles inherited from the two parents on phenotypic measures. Here, Zeng et al. study POE on DNA methylation in 5,101 individuals and identify genetic variants that associate with methylation variation via POE and their potential phenotypic consequences.
- Yanni Zeng
- , Carmen Amador
- & Chris S. Haley
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Article
| Open AccessMyoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions
Myoglobin is a hemeprotein that reversibly binds oxygen and gives muscle its red color. Here, the authors report a genetic variant in the MB gene that associates with myoglobinopathy, an autosomal dominant progressive myopathy, and altered oxygen binding properties of the mutant protein.
- Montse Olivé
- , Martin Engvall
- & Nigel G. Laing
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Article
| Open AccessAllele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA
Differential binding of RNA-binding proteins mediated by genetic variants (GVs) can influence posttranscriptional regulation. Here, the authors develop BEAPR, a computational approach to identify allele-specific binding events in eCLIP-Seq data.
- Ei-Wen Yang
- , Jae Hoon Bahn
- & Xinshu Xiao
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Article
| Open AccessChiral DNA sequences as commutable controls for clinical genomics
Any DNA sequence can be represented by a chiral partner sequence – an exact copy arranged in reverse nucleotide order. Here, the authors show that chiral DNA sequence pairs share important properties and show the utility of synthetic chiral sequences (sequins) as controls for clinical genomics.
- Ira W. Deveson
- , Bindu Swapna Madala
- & Tim R. Mercer
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Article
| Open AccessBromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
Liposarcoma (LPS) is a rare cancer that can acquire resistance to chemotherapy. Here, the authors map super-enhancers in LPS, finding BET-protein dependent mechanisms that can be targeted by a BET protein degrader, which also can overcome acquired resistance to chemotherapy in LPS.
- Ye Chen
- , Liang Xu
- & H. Phillip Koeffler
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Article
| Open AccessAutophagy within the mushroom body protects from synapse aging in a non-cell autonomous manner
The role of macroautophagy in neuronal processes mediating brain maintenance remains enigmatic. Authors show here that impairing autophagy within the major learning related brain center of Drosophila, and not other regions, triggered a form of presynaptic metaplasticity that was invariably connected to the absence of the specific component of aversive olfactory memory, which normally only declines in the course of aging process
- Anuradha Bhukel
- , Christine Brigitte Beuschel
- & Stephan J. Sigrist
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Article
| Open AccessThe Arabidopsis H3K27me3 demethylase JUMONJI 13 is a temperature and photoperiod dependent flowering repressor
Jumonji domain-containing histone demethylases regulate flowering in plants. Here Zheng et al. show that Arabidopsis JMJ13 is an H3K27me3 demethylase that recognizes H3K27me3 via hydrogen bonding and hydrophobic interactions and affects both photoperiod and temperature-dependent flowering responses.
- Shuzhi Zheng
- , Hongmiao Hu
- & Jiamu Du
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Article
| Open AccessSequence variation at ANAPC1 accounts for 24% of the variability in corneal endothelial cell density
The corneal endothelium is crucial for proper vision. Here, Ivarsdottir et al. perform genome-wide association studies for various corneal endothelial cell measurements and find that an intergenic variant near ANAPC1 explains 24% of the variance of endothelial cell density and associates with corneal hysteresis.
- Erna V. Ivarsdottir
- , Stefania Benonisdottir
- & Kari Stefansson
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Article
| Open AccessReversible histone glycation is associated with disease-related changes in chromatin architecture
Proteins continuously undergo non-enzymatic modifications such as glycation, which accumulate under physiological conditions but can be enhanced in disease. Here the authors characterise histone glycation, provide evidence that it affects chromatin, particularly in breast cancer, and identify DJ-1 as a deglycase.
- Qingfei Zheng
- , Nathaniel D. Omans
- & Yael David
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Article
| Open AccessSperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans
The mechanisms of paternal epigenetic inheritance and its influence on offspring are still poorly understood. Here the authors provide evidence that in C. elegans, sperm-inherited chromatin states influence transcription and cell identity in the germ cells of offspring.
- Kiyomi Raye Kaneshiro
- , Andreas Rechtsteiner
- & Susan Strome
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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 AccessH3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
Lysine27-to-methionine mutations in histone H3 genes (H3K27M) occur in a subgroup of gliomas and decrease genome-wide H3K27 trimethylation. Here the authors utilise primary H3K27M tumour lines and isogenic CRISPR-edited controls and show that H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3.
- Ashot S. Harutyunyan
- , Brian Krug
- & Jacek Majewski
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Article
| Open AccessLate Pleistocene human genome suggests a local origin for the first farmers of central Anatolia
Central Anatolia harbored some of the earliest farming societies outside the Fertile Crescent of the Near East. Here, the authors report and analyze genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers, and suggest high genetic continuity between the hunter-gatherers and early farmers of Anatolia.
- Michal Feldman
- , Eva Fernández-Domínguez
- & Johannes Krause
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Article
| Open AccessImpact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis
- Eevi Kaasinen
- , Outi Kuismin
- & Lauri A. Aaltonen
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Article
| Open AccessLow genetic variation is associated with low mutation rate in the giant duckweed
While the role of effective population size (Ne) in explaining variation in genetic diversity has received much attention, the role of spontaneous mutation rate is largely ignored. Here, Xu et al. show that giant duckweed has a high Ne yet low genetic diversity, likely due to its low mutation rate.
- Shuqing Xu
- , Jessica Stapley
- & Meret Huber
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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 AccessDissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements
Obesity and related metabolic complications represent an important health burden. Here the authors carry out a methylC-capture sequencing-based epigenome-wide association study to link circulating plasma lipid levels, CpG methylation and cardiometabolic risk across adipose and blood tissues.
- Fiona Allum
- , Åsa K. Hedman
- & Elin Grundberg
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Article
| Open AccessMemory and relatedness of transcriptional activity in mammalian cell lineages
Phenotypically identical mammalian cells often display considerable variability in transcript levels of individual genes. Here the authors document how different genes propagate their expression levels in cell lineages and suggest a potential role of transcriptional memory for generating spatial patterns of gene expression.
- Nicholas E. Phillips
- , Aleksandra Mandic
- & David M. Suter
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Article
| Open AccessA reference-grade wild soybean genome
Wild relatives of crop plants are invaluable germplasm for genetic improvement. Here, Xie et al. report a reference-grade wild soybean genome and show that it can be used to identify structural variation and refine quantitative trait loci.
- Min Xie
- , Claire Yik-Lok Chung
- & Hon-Ming Lam
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Article
| Open AccessWhole-genome resequencing of 472 Vitis accessions for grapevine diversity and demographic history analyses
Despite the importance of grapevine cultivation in human history and the economic values of cultivar improvement, large-scale genomic variation data are lacking. Here the authors resequence 472 Vitis accessions and use the identified genetic variations for domestication history, demography, and GWAS analyses.
- Zhenchang Liang
- , Shengchang Duan
- & Yang Dong
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Article
| Open AccessHomozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.
- Najim Lahrouchi
- , Aman George
- & Abdelaziz Sefiani
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Article
| Open AccessLive imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour
The process of alveologenesis is incompletely understood, partly due to the lack of applicable real-time imaging methods. Here the authors describe the process of alveologenesis and the behaviour of epithelial cells in real-time, using widefield microscopy and image deconvolution in precision-cut lung slices, revealing the dominant role of epithelial cell migration.
- Khondoker M. Akram
- , Laura L. Yates
- & Charlotte H. Dean
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Article
| Open AccessWhole-genome resequencing reveals Brassica napus origin and genetic loci involved in its improvement
Brassica napus is a globally important oil crop, but the origin of the allotetraploid genome and its improvement process are largely unknown. Here, the authors take a population genetic approach to resolve its origin and evolutionary history, and identify candidate genes related to important agricultural traits.
- Kun Lu
- , Lijuan Wei
- & Jiana Li
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Article
| Open AccessCRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
CRISPR-Cas9 has been rapidly adopted to generate cell line models of disease. Here the authors show, while attempting to establish a congenital erythropoietic porphyria model, unexpected chromosome truncations generated by a p53-dependent mechanism.
- Grégoire Cullot
- , Julian Boutin
- & Aurélie Bedel
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Article
| Open AccessGenome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.
- Christos Tziotzios
- , Christos Petridis
- & John A. McGrath
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Article
| Open AccessDiversifying the structure of zinc finger nucleases for high-precision genome editing
Genome editing often requires cleavage within a narrow sequence window. Here the authors develop an expanded set of zinc finger nuclease architectures that increase the available configurations by a factor of 64 and can target almost every base at loci of therapeutic significance.
- David E. Paschon
- , Stephanie Lussier
- & Edward J. Rebar
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Article
| Open AccessThe molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells
Transcription factor (TF) networks are essential for the molecular identity of each cell type. Here, the authors show that TF Nanog utilises multiple molecular strategies to enhance embryonic stem cell self-renewal, which include regulation of chromatin accessibility in the presence of LIF or maintenance of H3K27me3 at developmental regulators in its absence.
- Victor Heurtier
- , Nick Owens
- & Pablo Navarro
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Article
| Open AccessGenome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates
Sleep is essential for homeostasis and insufficient or excessive sleep are associated with adverse outcomes. Here, the authors perform GWAS for self-reported habitual sleep duration in adults, supported by accelerometer-derived measures, and identify genetic correlation with psychiatric and metabolic traits
- Hassan S. Dashti
- , Samuel E. Jones
- & Richa Saxena
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Article
| Open AccessEtv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos
How vegfa expression is transcriptionally regulated in vivo is unclear. Here, the authors demonstrate that the ETS transcription factor Etv6 acts as a repressor and an activator of two direct regulators of vegfa expression (foxo3 and klf4, respectively) to control blood formation in Xenopus.
- Lei Li
- , Rossella Rispoli
- & Catherine Porcher
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Article
| Open AccessZnhit1 controls intestinal stem cell maintenance by regulating H2A.Z incorporation
Lgr5+ stem cells in intestinal crypts are critical for gut epithelium homeostasis. Here, the authors show that Znht1 critically regulates intestinal homeostasis by promoting interaction between histone variant H2A.Z and its chaperone YL1 to incorporate H2A.Z into genes involved in intestinal stem cell fate.
- Bing Zhao
- , Ying Chen
- & Xinhua Lin
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Article
| Open AccessSubtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression
It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.
- William W. Greenwald
- , He Li
- & Kelly A. Frazer
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Article
| Open AccessGenome wide analysis for mouth ulcers identifies associations at immune regulatory loci
Oral ulcerations are sores of the mucous membrane of the mouth and highly prevalent in the population. Here, in a genome-wide association study, the authors identify 97 loci associated with mouth ulcers highlighting genes involved in T cell-mediated immunity and TH1 responses.
- Tom Dudding
- , Simon Haworth
- & Nicholas J. Timpson
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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 AccessThe Wolbachia mobilome in Culex pipiens includes a putative plasmid
Wolbachia bacteria live within the cells of many insects, including the mosquito Culex pipiens. Here, the authors analyse new and existing Wolbachia metagenomes from C. pipiens mosquitoes and find evidence of a plasmid, which may facilitate genetic manipulation of these bacteria for vector control applications.
- Julie Reveillaud
- , Sarah R. Bordenstein
- & A. Murat Eren
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Article
| Open AccessAssessing the causal association of glycine with risk of cardio-metabolic diseases
Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.
- Laura B. L. Wittemans
- , Luca A. Lotta
- & Claudia Langenberg
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Article
| Open AccessGenome maps across 26 human populations reveal population-specific patterns of structural variation
Large structural variants (SV) are understudied in human genetics research because of the difficulty to detect them in the routinely generated short-read sequencing data. Here, the authors generate optical genome maps of 154 individuals from 26 populations that allow comprehensive examination of large SVs.
- Michal Levy-Sakin
- , Steven Pastor
- & Pui-Yan Kwok
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Article
| Open AccessA genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome
Carpal tunnel syndrome (CTS) is caused by entrapment of the median nerve at the wrist. Here, Wiberg et al. perform a GWAS for CTS in the UK Biobank cohort and identify 16 genetic loci, and find a causal relationship between short stature and CTS risk using Mendelian randomisation.
- Akira Wiberg
- , Michael Ng
- & Dominic Furniss
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Article
| Open AccessDeep convolutional neural networks for accurate somatic mutation detection
Somatic mutations are crucial to the understanding of cancer genesis, progression, and treatment, but are still challenging to detect. Here the authors present NeuSomatic, a convolutional neural network approach for accurate somatic mutation detection across various sequencing scenarios.
- Sayed Mohammad Ebrahim Sahraeian
- , Ruolin Liu
- & Hugo Y. K. Lam
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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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