Genetics articles within Nature Communications

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  • Article
    | Open Access

    Interpreting genetic variation in the noncoding genome remains challenging, with functional effects difficult to predict. Here, the authors perform saturation mutagenesis combined with massively parallel reporter assays for 20 disease-associated regulatory elements, quantifying the effects of over 30,000 variants.

    • Martin Kircher
    • , Chenling Xiong
    •  & Nadav Ahituv

  • Article
    | Open Access

    Severe cutaneous adverse reactions (SCAR) is a T cell-mediated, potentially lethal drug hypersensitivity (DH). Here, the authors identify a carbamazepine-specific TCR common among patients with carbamazepine-induced SCAR that confers SCAR-like pathology in mice upon carbamazepine exposure, thereby implicating specific TCRs in DH etiology.

    • Ren-You Pan
    • , Mu-Tzu Chu
    •  & Shuen-Iu Hung

  • Article
    | Open Access

    The genome of influenza is often incomplete in infected cells, but the implications for infection remain unclear. Here, Jacobs et al. show that an average of 3.6 particles is necessary for productive infection and that coinfection supports efficient complementation within a host but not upon transmission to a new host.

    • Nathan T. Jacobs
    • , Nina O. Onuoha
    •  & Anice C. Lowen

  • Article
    | Open Access

    Lateral roots emerge from the primary root at right angles but briefly grow asymmetrically to set a distinct growth angle. Here Waidmann et al. show that cytokinin acts as an anti-gravitropic signal that impairs growth on the upper side of emerged lateral roots to promote radial expansion of the root system.

    • Sascha Waidmann
    • , Michel Ruiz Rosquete
    •  & Jürgen Kleine-Vehn

  • Article
    | Open Access

    Understanding of the genetic factors and molecular mechanisms underlying neurodevelopmental disorders remains incomplete. In this study, authors show that microdeletions in the gene ANKS1B lead to loss of the neuronal synapse-enriched protein AIDA-1 and to a novel neurodevelopmental syndrome

    • Abigail U. Carbonell
    • , Chang Hoon Cho
    •  & Bryen A. Jordan

  • Article
    | Open Access

    Functional variants have been proposed to alter transcription factor binding. Here, the authors provide direct evidence that functional variants within the TBC1D4 gene, encoding an NFκB binding site, can alter transcription factor binding, and use CRISPR-Cas9 to reveal localization of the transcription factor to be the regulator of chromatin accessibility and p65 binding and ultimately TBC1D4 expression.

    • Andrew D. Johnston
    • , Claudia A. Simões-Pires
    •  & John M. Greally

  • Article
    | Open Access

    Identification of disease modules in the human interactome can guide more efficacious therapeutic selections. Here, the authors introduce a network-based methodology to identify individualized disease modules by mapping patients’ DNA and RNA sequencing profiles to the interactome, enabling prediction of cancer type-specific drug responses.

    • Feixiong Cheng
    • , Weiqiang Lu
    •  & Joseph Loscalzo

  • Article
    | Open Access

    Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the circulation is essential for maintaining homeostasis. Here, the authors show that Phc2 in bone marrow stromal cells represses the cell adhesion molecule Vcam1 and facilitates mobilization of HSPCs through regulation of epigenetic marks.

    • Joonbeom Bae
    • , Sang-Pil Choi
    •  & Taehoon Chun

  • Article
    | Open Access

    People with a genetic deletion of the 15q11.2 locus are at increased risk for psychiatric disorders and white matter disturbances, but the gene(s) responsible are unclear. Here, the authors show that low dosage of CYFIP1, present in the human 15q11.2 region, alters white matter structure and cognition in rats.

    • Ana I. Silva
    • , Josephine E. Haddon
    •  & Lawrence S. Wilkinson

  • Article
    | Open Access

    The contribution of transposable elements (TEs) to the creation of heritable mutations is unknown. Here the authors show in Arabidopsis that TEs accumulate exponentially once mobilized and that COPIA retrotransposons preferentially integrate in environmental response genes in a H2A.Z-dependent manner.

    • Leandro Quadrana
    • , Mathilde Etcheverry
    •  & Vincent Colot

  • Article
    | Open Access

    The position, shape and number of transcription start sites (TSS) regulate gene expression. Here authors present MAPCap, a method for high-resolution detection and differential expression analysis of TSS, and apply MAPCap to early fly development, detecting stage and sex-specific promoter and enhancer activity.

    • Vivek Bhardwaj
    • , Giuseppe Semplicio
    •  & Asifa Akhtar

  • Article
    | Open Access

    Ime4p is a yeast N6-methyladenosine (m6A) methyltransferase with an unknown role in meiosis. Rme1p is a repressor of meiosis. Here the authors show that Ime4p methylates RME1 3′ UTR to reduce its expression and enable meiosis, thus providing an example of an m6A site with a physiological role.

    • G. Guy Bushkin
    • , David Pincus
    •  & Gerald R. Fink

  • Article
    | Open Access

    Finding driver genes sheds lights on the biological mechanisms propelling the development of a tumour, and can suggest therapeutic strategies. Here, the authors develop driverMAPS, a model-based approach to identify driver genes, and apply it to TCGA datasets.

    • Siming Zhao
    • , Jun Liu
    •  & Xin He

  • Article
    | Open Access

    PIWI-interacting RNAs (piRNAs) are ~25–33 nt small RNAs expressed in animal germ cells. Here, the authors develop a single-cell small RNA sequencing method and report that a class of ~20-nt piRNAs lacking 3′ end 2′-O-methylation are associated with PIWIL3 protein and predominantly expressed in human and monkey oocytes.

    • Qiyuan Yang
    • , Ronghong Li
    •  & Ligang Wu

  • Article
    | Open Access

    Genetic adaptation and physiological acclimation can potentially buffer species against climate change. Here, the authors perform a long-term warming experiment of Antarctic encrusting communities and show that focal animal species failed to acclimate and lacked genetic variation in tolerance to warming.

    • Melody S. Clark
    • , Leyre Villota Nieva
    •  & Lloyd S. Peck

  • Article
    | Open Access

    Most databases of genotype-phenotype associations are manually curated. Here, Kuleshov et al. describe a machine curation system that extracts such relationships from the GWAS literature and synthesizes them into a structured knowledge base called GWASkb that can complement manually curated databases.

    • Volodymyr Kuleshov
    • , Jialin Ding
    •  & Michael Snyder

  • Article
    | Open Access

    The SWI2/SNF2-Related 1 chromatin remodeling complex (SWR1-C) is important for gene regulation, but its composition remains largely uncharacterized in plants. Here, the authors report that methyl-CpG-binding domain 9 (MBD9) is a SWR1-C interacting protein required for histone H2A.Z deposition in Arabidopsis.

    • Magdalena E. Potok
    • , Yafei Wang
    •  & Steven E. Jacobsen

  • Article
    | Open Access

    The repertoire of adaptive immune receptor is generated by V(D)J recombination, somatic rearrangements of V, D and J gene segments, in the respective loci. Here the authors show that the deficiency of Setd2, a histone methyl transfer, impairs V(D)J recombination and induces severe developmental blocks in both T and B lineages.

    • Zhongzhong Ji
    • , Yaru Sheng
    •  & Helen He Zhu

  • Article
    | Open Access

    Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

    • Xiaopu Zhou
    • , Yu Chen
    •  & Nancy Y. Ip

  • Article
    | Open Access

    Many genetic variants identified in genome-wide association studies are associated with gene expression. Here, Porcu et al. propose a transcriptome-wide summary statistics-based Mendelian randomization approach (TWMR) that, applied to 43 human traits, uncovers hundreds of previously unreported gene–trait associations.

    • Eleonora Porcu
    • , Sina Rüeger
    •  & Zoltán Kutalik

  • Article
    | Open Access

    The role of mitochondrial DNA mutations in organismal fitness and lifespan have been studied in mitochondrial mutator models with varying results. Here, the authors generate a new APOBEC1 expression-based Drosophila mutator model and show that it has limited mitochondrial function and reduced lifespan.

    • Simonetta Andreazza
    • , Colby L. Samstag
    •  & Alexander J. Whitworth

  • Article
    | Open Access

    Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.

    • W. K. Jacky Lam
    • , Peiyong Jiang
    •  & Y. M. Dennis Lo

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic search method which they apply to six immune-mediated diseases.

    • Jennifer L. Asimit
    • , Daniel B. Rainbow
    •  & Chris Wallace

  • Article
    | Open Access

    Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.

    • Adebowale A. Adeyemo
    • , Norann A. Zaghloul
    •  & Charles N. Rotimi

  • Article
    | Open Access

    Tissue- and cell type-specific information helps to interpret findings from genome-wide association studies. Here, the authors leverage multiple single cell expression datasets to infer cell type specificity of traits.

    • Kyoko Watanabe
    • , Maša Umićević Mirkov
    •  & Danielle Posthuma

  • Article
    | Open Access

    Leucine-rich repeat (LRR) domains are commonly present in immune regulatory proteins. Here the authors show that LRR exonic modularity and alternative splicing of an LRR-containing protein, NLRP3, modulate the ratio of functional/afunctional NLRP3 isoforms to instill a stochastic regulation of NLRP3-mediated inflammation and innate immunity.

    • Florian Hoss
    • , James L. Mueller
    •  & Eicke Latz

  • Article
    | Open Access

    Quantifying the effects of noise in gene expression is difficult since noise and mean expression are coupled. Here the authors determine fitness landscapes in mean-noise expression space to uncouple these two parameters and show that changes in noise and mean expression are similarly detrimental to fitness.

    • Jörn M. Schmiedel
    • , Lucas B. Carey
    •  & Ben Lehner

  • Article
    | Open Access

    Prior evidence suggested mesenchymal stromal cells (MSCs) required for skeletal formation, maintenance, and repair arise postnatally. Here, the authors show that Hoxa11 lineage-marked cells give rise to all skeletal lineages from embryogenesis through adulthood and are upstream progenitors of LepR- and Osx-lineage MSCs

    • Kyriel M. Pineault
    • , Jane Y. Song
    •  & Deneen M. Wellik

  • Article
    | Open Access

    Germline cells transfer genetic information to offspring, and in zebrafish, drive sex determination. Here the authors report that, unlike mammals, the germline of zebrafish does not undergo genome-wide DNA methylation erasure, while amplifying and demethylating sex-linked rDNA during feminisation.

    • Oscar Ortega-Recalde
    • , Robert C. Day
    •  & Timothy A. Hore

  • Article
    | Open Access

    Mutators are expected to re-evolve low mutation rates to reduce deleterious load, but empirical evidence is mixed. Here, the authors show that load can vary across mutators and genetic backgrounds, which their simulations suggest can substantially alter antimutator dynamics.

    • Alejandro Couce
    •  & Olivier Tenaillon

  • Article
    | Open Access

    CTLA-4 is critical for balancing protective immunity with self-tolerance. Here the authors identify homozygous DEF6 mutations in patients with severe autoimmunity, one of which received and responds to CTLA-4-Ig, and show that DEF6 is crucial for CTLA-4 cell surface trafficking and immune regulatory function.

    • Nina K. Serwas
    • , Birgit Hoeger
    •  & Kaan Boztug

  • Article
    | Open Access

    In prostate cancer, investigating aberrant gene expression may shed light on disease etiology. Here, the authors imputed expression transcriptome-wide for 233,955 European ancestry men, discovering and replicating the associations between prostatic expression for select genes and prostate cancer risk, including the highly prevalent gene fusion partner TMPRSS2. The authors furthermore integrate diverse functional genomic datasets to interpret the epigenetic mechanisms by which the implicated risk variants and genes modulate disease risk.

    • Nima C. Emami
    • , Linda Kachuri
    •  & John S. Witte

  • Article
    | Open Access

    Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

    • Vincenzo Salpietro
    • , Christine L. Dixon
    •  & Henry Houlden

  • Article
    | Open Access

    The role of brain somatic mutations in neurodegenerative diseases such as Alzheimer’s disease (AD) is not well understood. Here the authors carry out high-depth exome sequencing ~500× on brain tissue from patients with AD and controls, and identify mutations in a number of genes that are known to contribute to phosphorylation and aggregation of tau, including PIN1.

    • Jun Sung Park
    • , Junehawk Lee
    •  & Jeong Ho Lee

  • Article
    | Open Access

    Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in TH2 response.

    • Andres Cardenas
    • , Joanne E. Sordillo
    •  & Diane R. Gold

  • Article
    | Open Access

    The transcription factor p63 is a master regulator of ectoderm development. Here the authors show that zebrafish p63 binds enhancers associated with neural genes to limit Sox3 binding and gene expression while also acting as a pioneer factor by promoting chromatin opening at epidermal gene enhancers.

    • José M. Santos-Pereira
    • , Lourdes Gallardo-Fuentes
    •  & Juan J. Tena

  • Article
    | Open Access

    Germ cells are the means of transferring genetic information to the next generation. Here the authors characterise the DNA methylomes of zebrafish primordial germ cells and find that, unlike mammals, the zebrafish germ cells do not undergo genome-wide DNA demethylation but rather retain paternal DNA methylation patterns

    • Ksenia Skvortsova
    • , Katsiaryna Tarbashevich
    •  & Ozren Bogdanovic

  • Article
    | Open Access

    Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.

    • Jacob L. Taylor
    • , Jean-Christophe P. G. Debost
    •  & Elise B. Robinson

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