Functional genomics

  • Article |

    In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation.

    • Direna Alonso-Curbelo
    • , Yu-Jui Ho
    •  & Scott W. Lowe
  • Article |

    An ultra-high-throughput multiplex protein–DNA binding assay is used to assess binding of 270 human transcription factors to 95,886 noncoding variants in the human genome, providing data to improve prediction of the effects of noncoding variants on transcription factor binding and thereby increase understanding of molecular pathways involved in diverse human traits and genetic diseases.

    • Jian Yan
    • , Yunjiang Qiu
    •  & Bing Ren
  • Article |

    Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

    • Alexander G. Bick
    • , Joshua S. Weinstock
    •  & Pradeep Natarajan
  • Article |

    Haploid genetic screening of cells under different types of mitochondrial perturbation shows that a pathway involving OMA1, DELE1 and the eIF2α kinase HRI communicates mitochondrial stress to the cytosol to trigger the integrated stress response.

    • Evelyn Fessler
    • , Eva-Maria Eckl
    •  & Lucas T. Jae
  • Review Article |

    This Review examines inflammatory bowel disease in the context of human genetics studies that help to identify pathways that regulate homeostasis of the mucosal immune system and discusses future prospects for disease-subtype classification and therapeutic intervention.

    • Daniel B. Graham
    •  & Ramnik J. Xavier
  • Review Article |

    This Review describes progress in the study of human genetics, in which rapid advances in technology, foundational genomic resources and analytical tools have contributed to the understanding of the mechanisms responsible for many rare and common diseases and to preventative and therapeutic strategies for many of these conditions.

    • Melina Claussnitzer
    • , Judy H. Cho
    •  & Mark I. McCarthy
  • Article |

    The transcriptomes of seven major organs across developmental stages from several mammalian species are used for comparative analyses of gene expression and evolution across organ development.

    • Margarida Cardoso-Moreira
    • , Jean Halbert
    •  & Henrik Kaessmann
  • Letter |

    A screen of 23 transcriptional cofactors for their ability to activate 72,000 candidate core promoters in Drosophila melanogaster identified distinct compatibility groups, providing insight into mechanisms that underlie the selective activation of transcriptional programs.

    • Vanja Haberle
    • , Cosmas D. Arnold
    •  & Alexander Stark
  • Article |

    In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.

    • Fiona M. Behan
    • , Francesco Iorio
    •  & Mathew J. Garnett
  • Article |

    Germline BRCA1 loss-of-function variants are associated with predisposition to early-onset breast and ovarian cancer; here the authors use CRISPR/Cas9 genome editing to functionally assess thousands of BRCA1 variants in order to facilitate the clinical interpretation of these variants.

    • Gregory M. Findlay
    • , Riza M. Daza
    •  & Jay Shendure
  • Letter
    | Open Access

    The authors show that rare genetic variants contribute to large gene expression changes across diverse human tissues and provide an integrative method for interpretation of rare variants in individual genomes.

    • Xin Li
    • , Yungil Kim
    •  & Stephen B. Montgomery
  • Article |

    The authors describe a two-cell-type CRISPR screen to identify tumour-intrinsic genes that regulate the sensitivity of cancer cells to effector T cell function.

    • Shashank J. Patel
    • , Neville E. Sanjana
    •  & Nicholas P. Restifo
  • Article |

    In vivo CRISPR screening reveals that loss of Ptpn2 increases the response of tumour cells to immunotherapy and increases IFNγ signalling, suggesting that PTPN2 inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response.

    • Robert T. Manguso
    • , Hans W. Pope
    •  & W. Nicholas Haining
  • Article |

    Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.

    • Mary E. Dickinson
    • , Ann M. Flenniken
    •  & Stephen A. Murray
  • Letter |

    A CRISPR screening approach shows that endoplasmic reticulum (ER)-associated protein complexes, including the oligosaccharyltransferase (OST) protein complex, are important for infection by dengue virus and other related mosquito-borne flaviviruses, whereas hepatitis C virus is dependent on distinct entry factors, RNA binding proteins and FAD biosynthesis.

    • Caleb D. Marceau
    • , Andreas S. Puschnik
    •  & Jan E. Carette
  • Article |

    PRDM9 is a DNA-binding protein that controls the position of double-strand breaks in meiosis, and the gene that encodes it is responsible for hybrid infertility between closely related mouse species; this hybrid infertility is eliminated by introducing the zinc-finger domain sequence from the human version of the PRDM9 gene, a change which alters both the position of double-strand breaks and the symmetry of PRDM9 binding and suggests that PRDM9 may have a more general but transient role in the early stages of speciation.

    • Benjamin Davies
    • , Edouard Hatton
    •  & Peter Donnelly
  • Letter |

    Splicing factors such as BUD31 are identified in a synthetic-lethal screen with cells overexpressing the transcription factor MYC; oncogenic MYC leads to an increase in pre-mRNA synthesis, and spliceosome inhibition impairs the growth and tumorigenicity of MYC-dependent breast cancers, suggesting that spliceosome components may be potential therapeutic targets for MYC-driven cancers.

    • Tiffany Y.-T. Hsu
    • , Lukas M. Simon
    •  & Thomas F. Westbrook
  • Letter |

    This study demonstrates a role for the Integrator complex in the stimulus-dependent induction of eRNAs and their 3′ processing; together with previously known roles of Integrator in transcription elongation and RNA processing, these results indicate that Integrator has broad functions in the regulation of eukaryotic gene expression.

    • Fan Lai
    • , Alessandro Gardini
    •  & Ramin Shiekhattar
  • Letter |

    Patterns of amino acid conservation have been used to guide the interpretation of the disease-causing potential of genetic variants in patients; now, an appreciable fraction of pathogenic alleles are shown to be fixed in the genomes of other species, suggesting that the genomic context has an important role in allele pathogenicity.

    • Daniel M. Jordan
    • , Stephan G. Frangakis
    •  & Nicholas Katsanis
  • Article
    | Open Access

    As part of the mouse ENCODE project, genome-wide transcription factor (TF) occupancy repertoires and co-association patterns in mice and humans are studied; many aspects are conserved but the extent to which orthologous DNA segments are bound by TFs in mice and humans varies both among TFs and genomic location, and TF-occupied sequences whose occupancy is conserved tend to be pleiotropic and enriched for single nucleotide variants with known regulatory potential.

    • Yong Cheng
    • , Zhihai Ma
    •  & Michael P. Snyder
  • Article |

    DNA double-stranded breaks (DSBs) are shown to form in greater numbers in yeast cells lacking ZMM proteins, which are traditionally regarded as acting strictly downstream of DSB formation; these findings shed light on how cells balance the beneficial and deleterious outcomes of DSB formation.

    • Drew Thacker
    • , Neeman Mohibullah
    •  & Scott Keeney
  • Article
    | Open Access

    A large-scale transcriptome analysis in Drosophila melanogaster, across tissues, cell types and conditions, provides insights into global patterns and diversity of transcription initiation, splicing, polyadenylation and non-coding RNA expression.

    • James B. Brown
    • , Nathan Boley
    •  & Susan E. Celniker
  • Article |

    Evolutionary study of long noncoding RNA (lncRNA) repertoires and expression patterns in 11 tetrapod species identifies approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have ancient origins; many lncRNAs, particularly ancient ones, are actively regulated and may function mainly in embryonic development.

    • Anamaria Necsulea
    • , Magali Soumillon
    •  & Henrik Kaessmann
  • Letter |

    A risk haplotype for type 2 diabetes is identified with four amino acid substitutions in SLC16A11, which is present at 50% frequency in Native American samples and 10% in east Asian samples, but is rare in European and African samples; SLC16A11 may alter hepatic lipid metabolism, causing an increase in triacylglycerol levels.

    • Amy L. Williams
    • , Suzanne B. R. Jacobs
    •  & Teresa Tusié-Luna
  • Analysis |

    This Analysis compares two large-scale pharmacogenomic data sets that catalogued the sensitivity of a large number of cancer cell lines to approved and potential drugs, and finds that whereas the gene expression data are largely concordant between the two studies, the reported drug sensitivity measures and subsequently their association with genomic features are highly discordant.

    • Benjamin Haibe-Kains
    • , Nehme El-Hachem
    •  & John Quackenbush
  • Article |

    Sequencing and deep analysis of mRNA and miRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project reveal widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent, and the analyses point to putative causal variants for dozens of disease-associated loci.

    • Tuuli Lappalainen
    • , Michael Sammeth
    •  & Emmanouil T. Dermitzakis
  • Article |

    Here, the first genome-wide in vivo RNA interference screens in a mammalian animal model are reported: genes involved in normal and abnormal epithelial cell growth are studied in developing skin tissue in mouse embryos, and among the findings, β-catenin is shown to act as an antagonist to normal epithelial cell growth as well as promoting oncogene-driven growth.

    • Slobodan Beronja
    • , Peter Janki
    •  & Elaine Fuchs
  • Article
    | Open Access

    An integrated high-resolution genetic, physical and shotgun sequence assembly of the barley genome, one of the earliest domesticated and most important crops, is described; it will provide a platform for genome-assisted research and future crop improvement.

    • Klaus F. X. Mayer
    • , Robbie Waugh
    •  & Nils Stein
  • Letter |

    A comparison of more than 1,000 orthologues of diverse proteins shows that the rate of amino-acid substitution in recent evolution is an order of magnitude lower than that expected in the absence of epistasis, indicating that epistasis is pervasive throughout protein evolution.

    • Michael S. Breen
    • , Carsten Kemena
    •  & Fyodor A. Kondrashov
  • Letter |

    Although zebrafish is an important animal model for basic vertebrate biology and human disease modelling, rapid targeted genome modification has not been possible in this species; here a technique based on improved artificial transcription activator-like effector nucleases (TALENs) allows precise sequence modifications at pre-determined genomic locations.

    • Victoria M. Bedell
    • , Ying Wang
    •  & Stephen C. Ekker
  • Letter |

    Genetic analysis of breakthrough infections in people vaccinated against HIV-1 show that vaccine efficacy increased by up to 80% against viruses carrying two mutations in Env V2, but also raises the possibility of population-level adaptation to the vaccine.

    • Morgane Rolland
    • , Paul T. Edlefsen
    •  & Jerome H. Kim