Sequencing articles within Nature Genetics

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  • Article |

    Ryan Emerson and colleagues report immunosequencing of the variable region of the TCRβ chain in 666 individuals with known cytomegalovirus (CMV) status. They show that CMV status and HLA genotype shape the T cell repertoire and demonstrate proof of principle that TCRβ sequencing can be used as a specific diagnostic of pathogen exposure.

    • Ryan O Emerson
    • , William S DeWitt
    •  & Harlan S Robins

  • News & Views |

    An international collaboration has assembled DNA samples and detailed phenotypic information from >13,000 individuals with a clinical diagnosis of either autism spectrum disorder (ASD) or intellectual disability/developmental delay (ID/DD). The application of molecular inversion probe technologies to sequence 208 candidate genes at scale in this impressive resource has identified a large set of plausibly causative mutations for these disorders.

    • David R FitzPatrick

  • Letter |

    Christian Schaaf, Yaping Yang and colleagues report that germline mutations in ABL1, which is best known as part of the fusion gene BCR-ABL1 on the Philadelphia chromosome, cause an autosomal dominant disorder characterized by heart disease, skeletal abnormalities and failure to thrive. They find that these mutations increase the kinase activity of ABL1, establishing another example of mutations in a proto-oncogene leading to developmental defects.

    • Xia Wang
    • , Wu-Lin Charng
    •  & Yaping Yang

  • Technical Report
    | Open Access

    Adam Phillippy, Curtis Van Tassell, Timothy Smith and colleagues present a new reference genome assembly for the domestic goat using a pipeline that improves contiguity of the assembly by more than 250-fold. The pipeline uses a combination of short- and long-read sequencing, optical mapping, and chromatin interaction mapping.

    • Derek M Bickhart
    • , Benjamin D Rosen
    •  & Timothy P L Smith

  • Article |

    Evan Eichler and colleagues use single-molecule molecular-inversion probes to sequence the coding and splicing regions of 208 candidate genes in more than 11,730 individuals with neurodevelopmental disorders. They report 91 genes with an excess of de novo or private disruptive mutations, identify 25 genes showing a bias for autism versus intellectual disability, and highlight a network associated with high-functioning autism.

    • Holly A F Stessman
    • , Bo Xiong
    •  & Evan E Eichler

  • Article |

    David Page and colleagues report the sequence of the chicken W sex chromosome and compare ancestral W-linked genes across bird species. They find that the W chromosome did not acquire genes expressed exclusively in reproductive tissue, but retained genes through selection to maintain appropriate dosage levels of broadly expressed genes.

    • Daniel W Bellott
    • , Helen Skaletsky
    •  & David C Page

  • Article |

    Carl Anderson, Jeffrey Barrett and colleagues use whole-genome sequencing and imputation to explore the genetic architecture of inflammatory bowel disease. They identify a low-frequency missense variant in ADCY7 that doubles risk of ulcerative colitis and detect a burden of very rare, damaging missense variants in known Crohn's disease risk genes.

    • Yang Luo
    • , Katrina M de Lange
    •  & Carl A Anderson

  • Article |

    Jaroslaw Maciejewski, Seishi Ogawa and colleagues examine the clonal dynamics of myelodysplastic syndromes (MDS) by analyzing whole-exome and targeted sequencing data from a large patient collection. They find that progression steps previously defined by pathologic criteria are accompanied by distinct molecular changes, and they show that driver genes can be classified into molecular subtypes differentially associated with low-risk MDS, high-risk MDS or secondary acute myeloid leukemia.

    • Hideki Makishima
    • , Tetsuichi Yoshizato
    •  & Jaroslaw P Maciejewski

  • Analysis |

    Andrew Lane and colleagues analyze somatic alterations across 21 tumor types for evidence of sex bias. They find that an excess of genes on the non-pseudoautosomal region of the X chromosome harbor loss-of-function mutations more frequently in males, suggesting that biallelic expression of these genes in females contributes to reduced cancer incidence in females across a variety of tumor types.

    • Andrew Dunford
    • , David M Weinstock
    •  & Andrew A Lane

  • Letter |

    Lars Bullinger, Jinghui Zhang, Jeffery Klco, James Downing and colleagues report a detailed genomic analysis of pediatric and adult core-binding factor acute myeloid leukemias (CBF-AMLs). They identify recurrent mutations in CCND2, MGA, DHX15 and ZBTB7A and highlight dramatic differences in the landscape of cooperating mutations between different CBF-AML subtypes.

    • Zachary J Faber
    • , Xiang Chen
    •  & James R Downing

  • Article |

    Mark Rubin, Francesca Demichelis and colleagues study the evolution of urothelial carcinomas by performing whole-exome sequencing of tumors collected from patients before and after chemotherapy. They find marked within-patient tumor heterogeneity and increased mutations involved in integrin signaling pathways and APOBEC-induced mutation signatures after treatment.

    • Bishoy M Faltas
    • , Davide Prandi
    •  & Mark A Rubin

  • Article |

    Gelareh Zadeh, Kenneth Aldape and colleagues present an integrative genomic analysis of schwannomas. In addition to finding recurrent mutations in ARID1A, ARID1B and DDR1, they identify a recurrent SH3PXD2A-HTRA1 fusion that confers increased proliferation, invasion and in vivo transformation, and is associated with sensitivity to MEK inhibition.

    • Sameer Agnihotri
    • , Shahrzad Jalali
    •  & Gelareh Zadeh

  • News & Views |

    A new study based on single-nucleus sequencing reports that triple-negative breast cancers acquire copy number aberrations in short punctuated bursts in the earliest stages of tumor evolution, rather than continuously and gradually, challenging prevailing models of tumor evolution.

    • Florian Markowetz

  • Analysis |

    Nicole Soranzo, Alexander Reiner, Paul Auer and colleagues use whole-genome sequencing data to impute the genotypes of over 35,000 individuals and perform a genome-wide association study for 20 quantitative cardiometabolic and hematological traits. They find 17 new associations and apply fine-mapping analysis to resolve causal variants for a number of the loci.

    • Valentina Iotchkova
    • , Jie Huang
    •  & Nicole Soranzo

  • Letter |

    Rickard Sandberg and colleagues use allele-sensitive single-cell RNA–seq on primary mouse fibroblasts and human T cells to study clonal and dynamic monoallelic expression patterns. They find that the majority of random monoallelic expression of autosomal genes occurs transiently within individual cells rather than being stably inherited within clonally related cells.

    • Björn Reinius
    • , Jeff E Mold
    •  & Rickard Sandberg

  • Article |

    Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment.

    • Maria Secrier
    • , Xiaodun Li
    •  & Sean M Grimmond

  • Letter |

    Michael Speicher and colleagues analyze plasma DNA whole-genome sequencing data from healthy donors and patients with cancer to infer nucleosome positioning on the basis of read depth coverage patterns. They use this approach to accurately predict expression of cancer driver genes from circulating tumor DNA in regions with somatic copy number gains.

    • Peter Ulz
    • , Gerhard G Thallinger
    •  & Michael R Speicher

  • Letter |

    Christian Fuchsberger, Gonçalo Abecasis and colleagues describe a new web-based imputation service that enables rapid imputation of large numbers of samples and allows convenient access to large reference panels of sequenced individuals. Their state space reduction provides a computationally efficient solution for genotype imputation with no loss in imputation accuracy.

    • Sayantan Das
    • , Lukas Forer
    •  & Christian Fuchsberger

  • Article
    | Open Access

    Kjetill S. Jakobsen, Sissel Jentoft and colleagues assemble partial draft genomes and analyze sequences from 66 teleost fish species to determine major histocompatibility complex (MHC) class I and class II gene status. They find that MHC II is absent from the Gadiformes lineage, while MHC I gene expansions have occurred multiple times.

    • Martin Malmstrøm
    • , Michael Matschiner
    •  & Sissel Jentoft

  • Analysis |

    Douglas Ruderfer, Shaun Purcell and colleagues characterized the rates and properties of rare genic copy number variants in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium. These data are available through an integrated database that spans the spectrum of human genetic variation, aiding in the interpretation of personal genomes and population-based disease studies.

    • Douglas M Ruderfer
    • , Tymor Hamamsy
    •  & Shaun M Purcell

  • News & Views |

    Analysis of a large whole-genome sequencing data set of 36,441 high-quality de novo mutations (DNMs) that arose in 816 family trios provides an unprecedented view into the landscape of DNMs in the germ line. This work both refines and challenges some of the views previously held on the nature and origin of DNMs.

    • Anne Goriely

  • Article |

    Abraham Palmer and colleagues use genotyping by sequencing to perform genome-wide association studies on CFW mice for behavioral, physiological and gene expression traits. They find many QTLs and incorporate expression QTL analysis to prioritize specific genes at loci of interest that underlie different complex traits.

    • Clarissa C Parker
    • , Shyam Gopalakrishnan
    •  & Abraham A Palmer

  • Technical Report |

    Richard Mott, Simon Myers and colleagues present a new imputation method, STITCH, which does not require genotyping arrays or high-quality reference panels. They use STITCH to accurately impute genotypes in both outbred laboratory mice and a sample human population directly from low-coverage (<2×) sequencing data.

    • Robert W Davies
    • , Jonathan Flint
    •  & Richard Mott

  • News & Views |

    The genome sequence of carrot (Daucus carota L.) is the first completed for an Apiaceae species, furthering knowledge of the evolution of the important euasterid II clade. Analyzing the whole-genome sequence allowed for the identification of a gene that may regulate the accumulation of carotenoids in the root.

    • Jordi Garcia-Mas
    •  & Manuel Rodriguez-Concepcion

  • Article |

    Matthew Meyerson, Ramaswamy Govindan and colleagues examine the exome sequences and copy number profiles of 660 lung adenocarcinoma and 484 lung squamous cell carcinoma tumors. They identify novel significantly mutated genes and amplification peaks and find that around half of the tumors have at least five predicted neoepitopes.

    • Joshua D Campbell
    • , Anton Alexandrov
    •  & Matthew Meyerson

  • Letter |

    James Collins and colleagues explore the role of the bacterial epigenome in antibiotic stress survival. They find that Escherichia coli survival under antibiotic pressure is strongly compromised in the absence of adenine methylation at GATC sites, suggesting that targeting adenine methylation might be a viable approach to enhance antibiotic activity.

    • Nadia R Cohen
    • , Christian A Ross
    •  & James J Collins

  • Article
    | Open Access

    Ingo Braasch, John Postlethwait and colleagues report the genome of the spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before genome duplication. Their data provide insights into the evolution of genes involved in immunity, mineralization and development and facilitate the comparison of cis-regulatory elements between teleosts and humans.

    • Ingo Braasch
    • , Andrew R Gehrke
    •  & John H Postlethwait

  • Letter |

    Daniel Gudbjartsson, Kari Stefansson and colleagues propose a new weighted Bonferroni approach for determining significance thresholds for human genome-wide association studies (GWAS). They demonstrate that the weighted approach, which is based on sequence annotation enrichments, improves power over standard GWAS methods.

    • Gardar Sveinbjornsson
    • , Anders Albrechtsen
    •  & Kari Stefansson

  • Article
    | Open Access

    Taisei Kikuchi, Mark Viney, Matthew Berriman and colleagues report the genome sequences of six species of nematodes from the Strongyloides clade of nematodes, including human and animal pathogens, facultative parasites and a free-living species. They find that expansions of the astacin and SCP/TAPS gene families are associated with parasitism in these species.

    • Vicky L Hunt
    • , Isheng J Tsai
    •  & Matthew Berriman

  • Article |

    Matthew Hurles and colleagues sequence the genomes of three multi-sibling families and investigate the rates and spectra of germline mutation. Their analyses suggest that the mutation rate per cell division is higher during early embryogenesis than in post-pubertal spermatogenesis.

    • Raheleh Rahbari
    • , Arthur Wuster
    •  & Matthew E Hurles

  • Letter |

    Murat Günel and colleagues use an integrated genomic approach to analyze the malignant progression of IDH1-mutant gliomas. They observe nonlinear clonal expansion of the original tumors and identify oncogenic pathways driving progression, including activation of MYC and RTK-RAS-PI3K pathways and epigenetic silencing of developmental transcription factors.

    • Hanwen Bai
    • , Akdes Serin Harmancı
    •  & Murat Günel

  • Letter
    | Open Access

    Terry Burke, Mark Blaxter, David Lank and colleagues report a reference genome sequence of the ruff and analysis of the three distinct male morphs of this bird species. They identify a ‘supergene’ consisting of a fixed inversion in two of the morphs and identify candidate reproductive trait genes in this region.

    • Clemens Küpper
    • , Michael Stocks
    •  & Terry Burke

  • Article |

    Christopher Haiman, Bogdan Pasaniuc, David Reich and colleagues report a major role for low-frequency variation in the risk for prostate cancer. They show that alleles with >1% minor allele frequency contribute an order of magnitude more to risk for prostate cancer than these alleles do to overall genetic variation.

    • Nicholas Mancuso
    • , Nadin Rohland
    •  & David Reich

  • Brief Communication |

    Rogier Versteeg and colleagues analyze the whole-genome sequences of 108 neuroblastoma samples and detect structural rearrangements of TERT in 23% of high-stage cases. TERT rearrangements are associated with increased TERT expression, increased telomere length and very poor prognosis.

    • Linda J Valentijn
    • , Jan Koster
    •  & Rogier Versteeg

  • Article
    | Open Access

    Ray Ming, Robert Paull, Qingyi Yu and colleagues report the genome sequences of two cultivated pineapple varieties and one wild pineapple relative. Their analysis supports the use of the pineapple as a reference genome for monocot comparative genomics and provides insight into the evolution of crassulacean acid metabolism photosynthesis.

    • Ray Ming
    • , Robert VanBuren
    •  & Qingyi Yu

  • Editorial |

    A large collection of human genomes from Sardinia is reported in three linked papers that implicate new genetic variants in the regulation of height, blood lipids, inflammatory markers and hemoglobin levels. These analyses provide new insight into disease susceptibility and evolution in isolated human populations and illuminate the genetics of complex phenotypes.

  • News & Views |

    Three new studies have identified new genes and sequence variants implicated in blood lipids, inflammatory markers, hemoglobin levels and adult height variation in Sardinia. These reports highlight the usefulness of large-scale genotype imputation based on whole-genome sequencing, particularly in isolated populations, in studying the genetics of complex human phenotypes.

    • Guillaume Lettre
    •  & Joel N Hirschhorn

  • Letter |

    Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies.

    • Francois Le Loarer
    • , Sarah Watson
    •  & Franck Tirode

  • Editorial |

    The reference human genome assembly is remarkable in its completeness and usefulness in research. However, the range of allelic variation in the human population is not well described by a haploid assembly with a profusion of alternative loci. Homozygous regions and the use of multiple sequencing technologies increasingly have roles in strategies for identifying regulatory and trait-associated variation.

  • News & Views |

    A new study has conducted a comprehensive exome and transcriptome analysis of a large number of intrahepatic, perihilar and distal cholangiocarcinomas and gallbladder cancers in Japanese patients. This study identifies many new alterations, confirms genetic differences in these distinct subtypes of biliary tract cancer and demonstrates that approximately 40% of described genetic aberrations are potentially targetable.

    • Nataliya Razumilava
    •  & Gregory J Gores

  • Letter |

    Jessica Zucman-Rossi and colleagues identify clonal integrations of adeno-associated virus type 2 (AAV2) in hepatocellular carcinomas. These AAV2 integrations occurred within known cancer driver genes, suggesting a pathogenic role of AAV2 in these patients.

    • Jean-Charles Nault
    • , Shalini Datta
    •  & Jessica Zucman-Rossi

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