Featured
-
-
Article |
Muscle stem cells contribute to myofibres in sedentary adult mice
Skeletal muscle satellite cells are muscle stem cells believed to contribute only to regenerating myofibres. Here Keefe et al. show that in adult sedentary mice satellite cells continue to fuse with uninjured myofibres, but they are not globally required for the maintenance of aging muscles.
- Alexandra C. Keefe
- , Jennifer A. Lawson
- & Gabrielle Kardon
-
Article
| Open AccessGenome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese
Raised serum urate levels are a risk factor for gout, a common form of inflammatory arthritis. Here Li et al.conduct a multistage genome-wide association study in a Han Chinese population and identify three novel loci likely associated with the progression from hyperuricemia to gout.
- Changgui Li
- , Zhiqiang Li
- & Yongyong Shi
-
Article |
Two susceptibility loci identified for prostate cancer aggressiveness
Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.
- Sonja I. Berndt
- , Zhaoming Wang
- & Stephen J. Chanock
-
Article |
Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes
Historically, Mendelian disorders were used to provide the first insight into cancer-associated genes. Here Melamed et al.use the unprecedented scope of electronic health records to explore genetic relationships and uncover potentially new drivers of cancer.
- Rachel D. Melamed
- , Kevin J. Emmett
- & Raul Rabadan
-
Article
| Open AccessCorrection of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy
Phospholamban (PLN) is a regulator of heart contractility. Here the authors show that cardiomyocytes derived from induced pluripotent stem cells of a cardiomyopathy patient with mutant PLN exhibit functional defects consistent with the disease, and that this mutation can be functionally corrected by genome editing and gene therapy.
- Ioannis Karakikes
- , Francesca Stillitano
- & Roger J. Hajjar
-
Article
| Open AccessA dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells
How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.
- Peter C. Cook
- , Heather Owen
- & Andrew S. MacDonald
-
Article
| Open AccessLong-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome
Enhancers regulate the transcription of genes over long genomic distances. Here, the authors show that enhancer function is correlated with maintenance of linkage between non-coding elements and neighbouring genes in the human X chromosome and that enhancers in zebrafish drive expression in a pattern consistent with the expression of a linked gene.
- Magali Naville
- , Minaka Ishibashi
- & Hugues Roest Crollius
-
Article
| Open AccessGenome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility
Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here Yin et al. conduct a large trans-ethnic genome-wide meta-analysis and identify novel loci that contribute to population-specific susceptibility.
- Xianyong Yin
- , Hui Qi Low
- & Jianjun Liu
-
Article
| Open AccessC-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle
SHGC syndrome affects cattle and has clinical features similar to human Seckel syndrome. Here Floriot et al. identify the causative mutation in the centrosomal protein C-Nap1 that affects centriole cohesion and cell migration, extending the range of loci involved in human Seckel-like syndromes.
- Sandrine Floriot
- , Christine Vesque
- & Laurent Schibler
-
Article |
APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma
Rearrangements of the Ig loci are essential for generating antibody diversity but abnormal translocations can be a driving event for myeloma. Here Walker et al. perform whole exome sequencing on myeloma patients to capture the diversity of mutational changes.
- Brian A. Walker
- , Christopher P. Wardell
- & Gareth J. Morgan
-
Article
| Open AccessEpigenomic evolution in diffuse large B-cell lymphomas
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here the authors characterize epigenetic evolution in aggressive B-cell lymphoma and find that epigenomic heterogeneity may not only support and drive the relapse phenotype but also be used to predict lymphoma relapse.
- Heng Pan
- , Yanwen Jiang
- & Olivier Elemento
-
Article |
Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells
Common variable immunodeficiency disorder (CVID) is a primary immunodeficiency with autoimmune comorbidity. Here, Li et al. show shared genetic susceptibility with autoimmune diseases, identifying the first non HLA risk locus at CLEC16Ain the largest CVID genetic study to date.
- Jin Li
- , Silje F. Jørgensen
- & Eva Ellinghaus
-
Article
| Open AccessFTO influences adipogenesis by regulating mitotic clonal expansion
Mutations in the FTO gene have been linked to obesity. Here, Merkestein et al. provide in vitro and in vivo evidence that FTOdirectly regulates adipogenesis in mice at the stage of mitotic clonal expansion, likely by modulating the expression of the transcription factor RUNX1T1.
- Myrte Merkestein
- , Samantha Laber
- & Roger D. Cox
-
Article
| Open AccessIncreased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension
Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al.use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.
- John H. Newman
- , Timothy N. Holt
- & Rizwan Hamid
-
Article |
Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
-
Article
| Open AccessWhole-exome SNP array identifies 15 new susceptibility loci for psoriasis
Psoriasis is a chronic inflammatory disease affecting up to 3% of the population. Here, Zuo et al.perform exome array analysis, identify single-nucleotide polymorphisms at 15 new loci, implicating several biological pathways in psoriasis risk and disease heritability.
- Xianbo Zuo
- , Liangdan Sun
- & Xuejun Zhang
-
Article
| Open AccessReduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2requirement for antiviral response in insulin-producing cells.
- Kenichi Izumi
- , Keiichiro Mine
- & Seiho Nagafuchi
-
Article
| Open AccessGenetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
Somatic mutations drive the clonal proliferation of myeloproliferative neoplasms. Here the authors conduct a genome-wide association study and identify germline variation at multiple loci associated with the development and disease phenotype of these cancers.
- William Tapper
- , Amy V. Jones
- & Nicholas C.P. Cross
-
Article
| Open AccessTracking the origins and drivers of subclonal metastatic expansion in prostate cancer
Primary prostate tumours are known to be genetically heterogeneous and clonal selection has the potential to drive metastasis. Here Hong et al. show that the acquisition of TP53 mutations is linked to clonal expansion and metastatic progression to lethality.
- Matthew K.H. Hong
- , Geoff Macintyre
- & Christopher M. Hovens
-
Article |
Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia
Myopia is a significant and increasing public health concern. Here Miyake et al. conduct a genome-wide association study and identify WNT7Bas a susceptibility gene across different ethnic groups, suggesting a possible role in the development of myopia.
- Masahiro Miyake
- , Kenji Yamashiro
- & Nagahisa Yoshimura
-
Article
| Open AccessA PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females
Girls are tenfold more likely than boys to require surgical treatment for idiopathic scoliosis, a common paediatric skeletal disorder. Here, Sharma et al. identify the first sexually dimorphic idiopathic scoliosis risk locus, and demonstrate that it may play a role in the regulation of spinal cells.
- Swarkar Sharma
- , Douglas Londono
- & Carol A. Wise
-
Article
| Open AccessInterferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease
Tissue fibrosis is a major contributor to mortality in the developed world. Here, the authors identify a genetic variant in the intronic region of interferon-λ4 that is a strong predictor of hepatic inflammation and fibrosis, independent of liver disease aetiology
- Mohammed Eslam
- , Ahmed M. Hashem
- & Rosanna Santaro
-
Article
| Open AccessAn analytical framework for optimizing variant discovery from personal genomes
The standardization of clinical sequencing data generation and analysis is of critical importance. Here, the authors develop the Genome Comparison and Analytic Testing platform to facilitate the development of performance metrics and comparisons of analysis tools for clinical sequencing studies.
- Gareth Highnam
- , Jason J. Wang
- & David Mittelman
-
Article
| Open AccessEscape from crossover interference increases with maternal age
Recombination is a meiotic process that ensures accurate chromosome segregation. Here, the authors characterize recombination patterns in over 4,200 families. Their results show that recombination rate increases with maternal age, and highlight sex differences in the distribution of these events.
- Christopher L. Campbell
- , Nicholas A. Furlotte
- & Adam Auton
-
Article
| Open AccessDense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis with a significant genetic component. Here, the authors analyse immune-related genetic markers in 1,962 PsA patients and 8,923 controls to identify novel PsA risk loci and highlight distinct genetic differences between psoriasis and PsA.
- John Bowes
- , Ashley Budu-Aggrey
- & Anne Barton
-
Article |
Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1
Maternal glucose levels during pregnancy can affect the metabolic health of a developing fetus, both early on and later in life. Here, the authors reveal that genetic variants in several regulatory elements alter glucose homeostasis during pregnancy by reducing the expression of a novel hexokinase gene, HKDC1.
- Cong Guo
- , Anton E. Ludvik
- & Timothy E. Reddy
-
Article |
NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes
Tumour cells disseminated from the primary tumour can remain dormant for years before initiating metastases. Here Sosa et al.show that the orphan nuclear receptor NR2F1 can be induced by bone marrow cues and by epigenetic drugs to promote quiescence and tumour cell dormancy in several cancer types.
- Maria Soledad Sosa
- , Falguni Parikh
- & Julio A. Aguirre-Ghiso
-
Article
| Open AccessMulti-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas
Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare neuroendocrine tumours with a significant genetic component. Here, the authors carry out a multi-omic integrative characterization of PCC/PGL and reveal potential genomic alterations and regulatory mechanisms involved in the disease.
- Luis Jaime Castro-Vega
- , Eric Letouzé
- & Anne-Paule Gimenez-Roqueplo
-
Article |
Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci
Alopecia areata (AA) is a common autoimmune disease with a known genetic component. Here, the authors analyse 3,253 AA patients and 7,543 healthy controls, and identify two new risk loci and disrupted immune response pathways associated with the disease.
- Regina C. Betz
- , Lynn Petukhova
- & Angela M. Christiano
-
Article |
Numerical chromosomal instability mediates susceptibility to radiation treatment
Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.
- Samuel F. Bakhoum
- , Lilian Kabeche
- & Duane A. Compton
-
Article
| Open AccessCombining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a heterogeneous group of chronic blood cancers. Here, the authors analyse genomic and gene expression data from MDS patients to investigate how driver mutations alter gene expression, diagnostic clinical variables and survival.
- Moritz Gerstung
- , Andrea Pellagatti
- & Jacqueline Boultwood
-
Article
| Open AccessA genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
- Joseph Vijai
- , Zhaoming Wang
- & Alexandra Nieters
-
Article |
Mutational landscape of intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer with a known genetic component. Here the authors sequence the exomes of matched tumour and normal tissue from 103 ICC patients in China, and identify an ICC mutational profile associated with liver inflammation, fibrosis and cirrhosis.
- Shanshan Zou
- , Jiarui Li
- & Heping Hu
-
Article |
Recurrent de novo mutations implicate novel genes underlying simplex autism risk
Autism spectrum disorder (ASD) is a common disorder with a strong and complex genetic component. Here, the authors resequence 64 candidate neurodevelopmental disorder risk genes in almost 6,000 samples and identify novel genes associated with ASD.
- B. J. O'Roak
- , H. A. Stessman
- & E. E. Eichler
-
Article |
GWAS identifies four novel eosinophilic esophagitis loci
Eosinophilic oesophagitis (EoE) is an allergic, inflammatory disorder of the oesophagus. Here the authors carry out a genome-wide association study in over 5,000 individuals and identify four genetic loci that affect the onset of EoE.
- Patrick M. A. Sleiman
- , Mei-Lun Wang
- & Hakon Hakonarson
-
Article
| Open AccessBiallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity
Primary immunodeficiency disorders can be used to identify key immune functions. Here, the authors identify a biallelic mutation in the gene encoding NF-κB-inducing kinase in a family suffering a range of infections, and show that it causes defects in NK and T-cell function and has broad effects on B-cell function.
- Katharina L. Willmann
- , Stefanie Klaver
- & Kaan Boztuğ
-
Article |
An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth
The Sonic hedgehog (Shh) signalling pathway plays important roles during development and its abnormal activation has been implicated in cancer. Here the authors uncover an epigenetic switch in the Shh pathway that involves the PRC2, Jmjd3/Kdm6b and Set1/MLL complexes in regulating signalling induced gene activation.
- Xuanming Shi
- , Zilai Zhang
- & Jiang Wu
-
Article |
Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in young adults. Here, the authors show that mutations in a sarcomeric protein filamin C contribute to the development of familial HCM and are associated with an increased incidence of sudden cardiac death.
- Rafael Valdés-Mas
- , Ana Gutiérrez-Fernández
- & Carlos López-Otín
-
Article |
Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis
Iron deficiency is the leading cause of anaemia and is known to compromise immune function. Here, the authors identify several new genes associated with iron status in European populations and provide insight into how iron levels may be linked to the risk of metabolic disease.
- Beben Benyamin
- , Tonu Esko
- & John B. Whitfield
-
Article
| Open AccessGermline variants in the SEMA4A gene predispose to familial colorectal cancer type X
It is known that hereditary factors contribute to familial colorectal cancer type X. Here, the authors uncover the SEMA4A p.Val78Met germline mutation and show that the protein product is associated with changes in cell cycle progression in colorectal cancer cells.
- Eduard Schulz
- , Petra Klampfl
- & Heinz Sill
-
Article |
Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity
Critical period plasticity describes a developmental process whereby neural circuits are fine-tuned for specific functions. Here, the authors show that the Rett syndrome protein MeCP2 in GABAergic parvalbumin-expressing neurons is required for critical period plasticity of the visual cortex.
- Ling-jie He
- , Nan Liu
- & Xiao-hui Zhang
-
Article |
Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells
Genetic studies have connected polymorphisms in the IL-2 receptor alpha (IL2RA) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human THcells.
- Felix J. Hartmann
- , Mohsen Khademi
- & Burkhard Becher
-
Article
| Open AccessMeta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process
Glaucoma is the most common cause of irreversible blindness worldwide. Here, the authors carry out a large meta-analysis of genetic data from individuals of European and Asian ancestry and identify 10 new loci associated with vertical cup-disc ratio, a key factor in the clinical assessment of patients with glaucoma.
- Henriët. Springelkamp
- , René Höhn
- & Christopher J. Hammond
-
Article |
De novo TBR1 mutations in sporadic autism disrupt protein functions
Autism spectrum disorders (ASD) are characterized by social impairments, communication deficits and repetitive stereotyped behaviours. Here, the authors show that de novo missense mutations, but not inherited missense mutations, in TBR1disrupt the protein function and contribute to ASD aetiology.
- Pelagia Deriziotis
- , Brian J. O’Roak
- & Simon E. Fisher
-
Article |
A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness
Mutations of the human KALRN gene are implicated in schizophrenia. Here, Russell et al.identify a genetic variant of this gene in a schizophrenia patient and his sibling diagnosed with major depressive disorder and substance abuse, and find that this is associated with reduced cortical volume and thickness.
- Theron A. Russell
- , Katherine D. Blizinsky
- & Peter Penzes
-
Article |
Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells
Trisomy 12 is the most frequent chromosomal abnormality detected in cultures of human pluripotent stem cells. Here the authors show that human pluripotent stem cells carrying this abnormality exhibit gene expression profiles more similar to those of germ cell tumours, and give rise to more aggressive teratomas.
- Uri Ben-David
- , Gal Arad
- & Juan Carlos Biancotti
-
Article |
Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
-
Article
| Open Accessptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease
Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
- Madeline Hayes
- , Xiaochong Gao
- & Brian Ciruna
-
Article |
Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation
The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes.
- Pietro Mesirca
- , Jacqueline Alig
- & Matteo E. Mangoni