Featured
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Article
| Open AccessUnraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine
Congenital vertebral malformation has a complex genetic architecture that isn’t fully understood. Here, the authors explore the genetic architecture of congenital vertebral malformation through case-control rare variant genetic analyses and embryonic transcriptome analyses of the developing spine.
- Sen Zhao
- , Hengqiang Zhao
- & Nan Wu
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Article
| Open AccessAncestry-specific polygenic risk scores are risk enhancers for clinical cardiovascular disease assessments
Polygenic risk scores have been proposed as useful to refine cardiovascular risk assessments. Here, the authors validate polygenic risk scores in multiple ancestries and demonstrate their utility to more accurately assess 10 year risk.
- George B. Busby
- , Scott Kulm
- & Giordano Bottà
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Article
| Open AccessSystematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation
Chameleolyser enables the accurate identification of genetic variants hidden within complex regions of the genome. Its application uncovers the disease-explanatory variant in 25 previously undiagnosed patients.
- Wouter Steyaert
- , Lonneke Haer-Wigman
- & Christian Gilissen
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Article
| Open AccessTargetable NOTCH1 rearrangements in reninoma
Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.
- Taryn D. Treger
- , John E. G. Lawrence
- & Tanzina Chowdhury
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Article
| Open AccessA landscape of complex tandem repeats within individual human genomes
Haplotype-resolved long, complex tandem repeats remain largely hidden despite their potential relevance to disease. Here, the authors reveal and analyze the genome-wide landscape of these repeats using a high-precision algorithm.
- Kazuki Ichikawa
- , Riki Kawahara
- & Shinichi Morishita
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Article
| Open AccessA genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.
- Parsa Akbari
- , Dragana Vuckovic
- & William J. Astle
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Article
| Open AccessIdentifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.
- Yiming Wu
- , Kyle Gettler
- & Yuval Itan
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Article
| Open AccessDiverse monogenic subforms of human spermatogenic failure
The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.
- Liina Nagirnaja
- , Alexandra M. Lopes
- & Donald F. Conrad
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Article
| Open AccessGenetic architecture of heart failure with preserved versus reduced ejection fraction
While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.
- Jacob Joseph
- , Chang Liu
- & Yan V. Sun
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Article
| Open AccessPrioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection
Immune genes under selection can shed light on phenotypes contributing to survival and modern inflammatory conditions. Here, the authors prioritize adaptive disease variants in 535 risk loci for 21 inflammatory conditions and report promising SNPs for functional studies with predictions of cell context and function.
- Vasili Pankratov
- , Milyausha Yunusbaeva
- & Bayazit Yunusbayev
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Article
| Open AccessAn atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation
By comprehensively mapping the impact that different classes of mutations (substitutions, insertions, deletions) have on the ability of the amyloid beta peptide to nucleate amyloids, the authors identify a large set of likely pathogenic variants of amyloid beta that are specifically enriched at its polar N-terminal region.
- Mireia Seuma
- , Ben Lehner
- & Benedetta Bolognesi
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Article
| Open AccessDevelopment of a novel core genome MLST scheme for tracing multidrug resistant Staphylococcus capitis
Staphylococcus capitis is a common causative agent of bloodstream infections in neonatal intensive care units, with multidrug resistant isolates complicating treatment. Authors aimed to establish a core genome multilocus sequence typing (cgMLST) scheme to document the transmission and dissemination of multidrug-resistant S. capitis isolates.
- Zhengan Wang
- , Chao Gu
- & Yunsong Yu
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Article
| Open AccessPhasing analysis of lung cancer genomes using a long read sequencer
Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.
- Yoshitaka Sakamoto
- , Shuhei Miyake
- & Ayako Suzuki
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Article
| Open AccessElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.
- David Stacey
- , Lingyan Chen
- & Dirk S. Paul
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Article
| Open AccessCRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations
CRISPR-Cas9 can introduce unintended off-target effects. Here authors show that unintended mutations produced by in vivo of zebrafish can be inherited by their off-spring.
- Ida Höijer
- , Anastasia Emmanouilidou
- & Adam Ameur
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Article
| Open AccessAccurate and scalable variant calling from single cell DNA sequencing data with ProSolo
Obtaining accurate variant calls from multiple displacement amplified single cell DNA sequencing data needs dedicated models that account for amplification bias and copy errors. Here, the authors describe ProSolo, a model for calling single nucleotide variants with control over the false discovery rate.
- David Lähnemann
- , Johannes Köster
- & Alexander Schönhuth
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Comment
| Open AccessThe growing need for controlled data access models in clinical proteomics and metabolomics
More and more clinical studies include potentially sensitive human proteomics or metabolomics datasets, but bioinformatics resources for managing the access to these data are not yet available. This commentary discusses current best practices and future perspectives for the responsible handling of clinical proteomics and metabolomics data.
- Thomas M. Keane
- , Claire O’Donovan
- & Juan Antonio Vizcaíno
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Article
| Open AccessHaploinsufficiency of SF3B2 causes craniofacial microsomia
Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.
- Andrew T. Timberlake
- , Casey Griffin
- & Daniela V. Luquetti
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Article
| Open AccessDeterminants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
- Julia K. Goodrich
- , Moriel Singer-Berk
- & Miriam S. Udler
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Article
| Open AccessDistinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome
Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.
- Alyssa L. Kennedy
- , Kasiani C. Myers
- & R. Coleman Lindsley
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Article
| Open AccessDeep transfer learning for reducing health care disparities arising from biomedical data inequality
Developing machine learning models that work equally well for all ethnic groups is of crucial importance to health disparity prevention and reduction. Here, using an extensive set of machine learning experiments on cancer omics data, the authors find that transfer learning can improve model performance for data-disadvantaged ethnic groups.
- Yan Gao
- & Yan Cui
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Article
| Open AccessPolygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.
- Akl C. Fahed
- , Minxian Wang
- & Amit V. Khera
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Article
| Open AccessCharacterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.
- Nicola Whiffin
- , Konrad J. Karczewski
- & James S. Ware
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Article
| Open AccessCombined burden and functional impact tests for cancer driver discovery using DriverPower
Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.
- Shimin Shuai
- , Federico Abascal
- & Christian von Mering
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Article
| Open AccessThe Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
- Mark Pinese
- , Paul Lacaze
- & David M. Thomas
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Article
| Open AccessInsights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.
- Gavin Band
- , Quang Si Le
- & Dominic P. Kwiatkowski
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Article
| Open AccessRanking of non-coding pathogenic variants and putative essential regions of the human genome
Whole genome sequencing (WGS) holds promise to solve a subset of Mendelian disease cases for which exome sequencing did not provide a genetic diagnosis. Here, Wells et al. report a supervised machine learning model trained on functional, mutational and structural features for rank-scoring and interpreting variants in non-coding regions from WGS.
- Alex Wells
- , David Heckerman
- & Julia di Iulio
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Article
| Open AccessContribution of retrotransposition to developmental disorders
Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.
- Eugene J. Gardner
- , Elena Prigmore
- & Matthew E. Hurles
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Article
| Open AccessGenome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth
Changes in body mass index (BMI) during infancy and childhood follow a well-characterized pattern. Here, Helgeland et al. perform genome-wide association studies for BMI at 12 time points between birth and 8 years of age and find transient associations at the LEP and LEPR loci.
- Øyvind Helgeland
- , Marc Vaudel
- & Pål Rasmus Njølstad
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Article
| Open AccessComprehensive evaluation and characterisation of short read general-purpose structural variant calling software
A number of computational methods have been developed for calling structural variants (SVs) using short read sequencing data. Here, the authors perform a comprehensive benchmarking analysis comparing 10 general-purpose callers and provide recommendations for both users and methods developers.
- Daniel L. Cameron
- , Leon Di Stefano
- & Anthony T. Papenfuss
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Article
| Open AccessClinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data
Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.
- C. F. Wright
- , E. Prigmore
- & M. E. Hurles
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Article
| Open AccessA frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.
- Konstantinos Nikopoulos
- , Katarina Cisarova
- & Carlo Rivolta
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Article
| Open AccessSequencing of human genomes with nanopore technology
Nanopore sequencing technology generates longer reads than current technologies, but with more errors. Here, the authors develop new analytical tools to improve accuracy and evaluate the potential of nanopore sequencing for clinical human genomics.
- Rory Bowden
- , Robert W. Davies
- & Peter Donnelly
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Perspective
| Open AccessA framework for enhancing ethical genomic research with Indigenous communities
Indigenous peoples are still underrepresented in genetic research. Here, the authors propose an ethical framework consisting of six major principles that encourages researchers and Indigenous communities to build strong and equal partnerships to increase trust, engagement and diversity in genomic studies.
- Katrina G. Claw
- , Matthew Z. Anderson
- & Joseph M. Yracheta
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Article
| Open AccessPatterns of genomic evolution in advanced melanoma
As melanoma progresses, it evolves. Here, in advanced melanoma the authors study genomic evolution, highlighting trunk mutations dominated by the ultraviolet damage signature, common late truncal whole-genome duplication events, as well as selective copy number gain of mutant BRAF.
- E. Birkeland
- , S. Zhang
- & P. E. Lønning
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Article
| Open AccessPervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster
The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.
- Janani Iyer
- , Mayanglambam Dhruba Singh
- & Santhosh Girirajan
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Article
| Open AccessKMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare and recurrence is difficult to treat. Here, the authors observe in aGCT a novel recurrent somatic truncating mutation of KMT2D, more frequent in recurrent aGCT, and also non-genetic loss of KMT2D expression.
- R. Tyler Hillman
- , Joseph Celestino
- & P. Andrew Futreal
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Article
| Open AccessUrinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract
Urinary tract infections are one of the most common infections in humans. Here, the authors use urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections, and show that it is a versatile analyte for monitoring urinary tract infections.
- Philip Burnham
- , Darshana Dadhania
- & Iwijn De Vlaminck
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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 AccessIdentification of rare de novo epigenetic variations in congenital disorders
A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.
- Mafalda Barbosa
- , Ricky S. Joshi
- & Andrew J. Sharp
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Article
| Open AccessAnalysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
- Connor A. Emdin
- , Amit V. Khera
- & Sekar Kathiresan
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Article
| Open AccessMedical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.
- Christopher DeBoever
- , Yosuke Tanigawa
- & Manuel A. Rivas
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Article
| Open AccessMapping and phasing of structural variation in patient genomes using nanopore sequencing
The detection of structural variants can be difficult with short-read sequencing technology, especially when variants are highly complex. Here, the authors use a MinION nanopore sequencer to analyse two patient genomes and develop NanoSV to map known and novel structural variants in long read data.
- Mircea Cretu Stancu
- , Markus J. van Roosmalen
- & Wigard P. Kloosterman
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Article
| Open AccessHeterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance
Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
- Kashyap A. Patel
- , Jarno Kettunen
- & Michael N. Weedon
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Article
| Open AccessType II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations
Enteropathy associated T-cell lymphoma -EATL- affects the intestine and there are two different subtypes. In this study, the authors carry out exome sequencing of the type II variant and find that it is characterized by recurrent mutations in the histone methyltransferase SETD2 that are accompanied by altered H3K6 methylation.
- Annalisa Roberti
- , Maria Pamela Dobay
- & Laurence de Leval