• Article |

    Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

    • Stanley W. K. Ng
    • , Foad J. Rouhani
    •  & Peter J. Campbell
  • Article |

    Laser-capture microdissection and mini-bulk exome sequencing are combined to analyse somatic mutations in morphologically normal tissues from nine organs from five donors, revealing variation in mutation burdens, mutational signatures and clonal expansions.

    • Ruoyan Li
    • , Lin Di
    •  & Chen Wu
  • Article |

    The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

    • Luiza Moore
    • , Alex Cagan
    •  & Raheleh Rahbari
  • Article |

    NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.

    • Federico Abascal
    • , Luke M. R. Harvey
    •  & Iñigo Martincorena
  • Article |

    Analysis of blood-derived DNA from participants in the UK Biobank demonstrates that clonal expansions of acquired copy-neutral loss of heterozygosity mutations act on inherited alleles along a chromosome arm by modifying their allelic dosages.

    • Po-Ru Loh
    • , Giulio Genovese
    •  & Steven A. McCarroll
  • Article
    | Open Access

    A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

    • Ryan L. Collins
    • , Harrison Brand
    •  & Michael E. Talkowski
  • Article |

    Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.

    • Luiza Moore
    • , Daniel Leongamornlert
    •  & Michael R. Stratton
  • Article
    | Open Access

    The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

    • Ludmil B. Alexandrov
    • , Jaegil Kim
    •  & Michael R. Stratton
  • Article |

    Whole-genome sequencing of normal bronchial epithelium from 16 individuals shows that tobacco smoking increases genomic heterogeneity, mutational burden and driver mutations, whereas stopping smoking promotes replenishment of the epithelium with near-normal cells.

    • Kenichi Yoshida
    • , Kate H. C. Gowers
    •  & Peter J. Campbell
  • Article |

    Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions.

    • Kosaku Nanki
    • , Masayuki Fujii
    •  & Toshiro Sato
  • Article |

    Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.

    • Simon F. Brunner
    • , Nicola D. Roberts
    •  & Peter J. Campbell
  • Letter |

    DNA repair by break-induced replication begins with the Rad51-mediated invasion of single-stranded DNA into a double-stranded donor template; this study shows that successful recombination between highly mismatched substrates can occur when only five consecutive bases can be paired and that mismatch correction is most efficient near the invading end of the recipient strand.

    • Ranjith Anand
    • , Annette Beach
    •  & James Haber
  • Letter |

    Whole-genome sequencing of normal blood cells sampled from 241 adults is used to infer mosaic point mutations that are likely to have arisen during early embryogenesis, providing insight into how early cellular dynamics may affect adult tissues.

    • Young Seok Ju
    • , Inigo Martincorena
    •  & Michael R. Stratton
  • Article |

    Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

    • Jeremy F. McRae
    • , Stephen Clayton
    •  & Matthew E. Hurles
  • Letter |

    Genomic duplications in the SOX9 region are associated with human disease phenotypes; a study using human cells and mouse models reveals that the duplications can cause the formation of new higher-order chromatin structures called topologically associated domains (TADs) thereby resulting in changes in gene expression.

    • Martin Franke
    • , Daniel M. Ibrahim
    •  & Stefan Mundlos
  • Letter |

    The zebrafish cloche gene is required for the formation of most endothelial and haematopoietic cells, however, it has been difficult to isolate; this study reveals that cloche encodes a PAS-domain-containing bHLH transcription factor, and a mammalian orthologue can partially rescue cloche mutants, indicating a possible conserved role in mammals.

    • Sven Reischauer
    • , Oliver A. Stone
    •  & Didier Y. R. Stainier
  • Letter |

    When transcription and replication machineries collide on DNA, they can cause mutations to occur in the area near the collision; these mutations are now shown to include two types—duplications/deletions within the transcription unit and base substitutions in the cis-regulatory element of gene expression.

    • T. Sabari Sankar
    • , Brigitta D. Wastuwidyaningtyas
    •  & Jue D. Wang
  • Letter |

    Maximum-depth sequencing (MDS), a new method of detecting extremely rare variants within a bacterial population, is used to show that mutation rates in Escherichia coli vary across the genome by at least an order of magnitude, and also to uncover mechanisms of antibiotic-induced mutagenesis.

    • Justin Jee
    • , Aviram Rasouly
    •  & Evgeny Nudler
  • Letter |

    An analysis of cancer genomic data reveals an increased rate of somatic mutations at active transcription factor binding sites located both within promoter regions and distal from genes; the increased mutation rate at these genomic regions can be explained by reduced accessibility of the protein-bound DNA to nucleotide excision repair machinery.

    • Radhakrishnan Sabarinathan
    • , Loris Mularoni
    •  & Núria López-Bigas
  • Letter |

    Mutation rates vary within genomes; here, by calling mutation events directly using a parent–offspring sequencing strategy in Arabidopsis, replicated in the rice and honey bee genomes, mutation rates are found to be higher in heterozygotes and in proximity to crossover events.

    • Sihai Yang
    • , Long Wang
    •  & Dacheng Tian
  • Article |

    The mechanism for chromothripsis, “shattered” chromosomes that can be observed in cancer cells, is unknown; here, using live-cell imaging and single-cell sequencing, chromothripsis is shown to occur after a chromosome is isolated into a micronucleus, an abnormal nuclear structure.

    • Cheng-Zhong Zhang
    • , Alexander Spektor
    •  & David Pellman
  • Letter |

    An analysis of how regional mutation rates vary across 652 tumours identifies variable DNA mismatch repair as the basis of the characteristic regional variation in mutation rates seen across the human genome; the results show that differential DNA repair, rather than differential mutation supply, is likely to be the primary cause of this variation.

    • Fran Supek
    •  & Ben Lehner
  • Article |

    The emRiboSeq sequencing method is used to track polymerase activity genome-wide in vivo; despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo and comprises 1.5% of the genome, establishing Pol-α as an important source of genomic variability and providing a mechanism for site-specific variation in nucleotide substitution rates.

    • Martin A. M. Reijns
    • , Harriet Kemp
    •  & Martin S. Taylor
  • Letter |

    This paper demonstrates that the mechanism of break-induced replication (BIR) is significantly different from S-phase replication, as it proceeds via a migrating bubble driven by Pif1 helicase, results in conservative inheritance of newly synthesized DNA, and is inherently mutagenic.

    • Natalie Saini
    • , Sreejith Ramakrishnan
    •  & Anna Malkova
  • Letter |

    Mutations in mitochondrial DNA (mtDNA) accumulate at a higher rate than mutations in nuclear DNA, and although somatic mtDNA mutations are known to be involved in mammalian ageing, the role of germline mutations in this process is unclear: here germline-transmitted mtDNA mutations are shown to be associated with ageing and brain malformations, and maternally transmitted mtDNA mutations may thus influence both development and ageing.

    • Jaime M. Ross
    • , James B. Stewart
    •  & Nils-Göran Larsson
  • Letter |

    Investigation of neural cells from post-mortem human brains and differentiated from patient-derived induced pluripotent stem cells shows that the LRRK2 mutation (G2019S) associated with familial and sporadic Parkinson's disease correlates with abnormalities at the nuclear envelope.

    • Guang-Hui Liu
    • , Jing Qu
    •  & Juan Carlos Izpisua Belmonte
  • Letter |

    EZH2 is a methyltransferase that is mutated in lymphoma; here a potent small molecule inhibitor of EZH2 is described, which inhibits the proliferation of EZH2 mutant cell lines and growth of EZH2 mutant xenografts in mice, thus providing a potential treatment for EZH2 mutant lymphoma.

    • Michael T. McCabe
    • , Heidi M. Ott
    •  & Caretha L. Creasy
  • Article |

    Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.

    • Augustine Kong
    • , Michael L. Frigge
    •  & Kari Stefansson
  • Letter |

    Mutations in the profilin 1 (PFN1) gene, which is crucial for the conversion of monomeric to filamentous actin, can cause familial amyotrophic lateral sclerosis, suggesting that alterations in cytoskeletal pathways contribute to disease pathogenesis.

    • Chi-Hong Wu
    • , Claudia Fallini
    •  & John E. Landers
  • Article
    | Open Access

    Whole-genome analysis of oestrogen-receptor-positive tumours in patients treated with aromatase inhibitors show that distinct phenotypes are associated with specific patterns of somatic mutations; however, most recurrent mutations are relatively infrequent so prospective clinical trials will require comprehensive sequencing and large study populations.

    • Matthew J. Ellis
    • , Li Ding
    •  & Elaine R. Mardis
  • Letter |

    Exome sequencing is used to investigate the role of mutations and copy number aberrations in metastatic castration-resistant prostate cancer, revealing recurrent mutations in multiple chromatin/histone modifying genes, as well as genes involved in androgen signalling.

    • Catherine S. Grasso
    • , Yi-Mi Wu
    •  & Scott A. Tomlins
  • Letter
    | Open Access

    Whole-genome sequencing of 25 metastatic melanomas and matched germline DNA in humans reveals that the highest mutation load is associated with chronic sun exposure, and that the PREX2 gene is mutated in approximately 14 per cent of cases

    • Michael F. Berger
    • , Eran Hodis
    •  & Levi A. Garraway
  • Letter |

    Exome sequencing on a large cohort of parent–child trios with sporadic autism spectrum disorders shows that de novo point mutations are mainly paternal in origin and positively correlate with paternal age, and identifies a highly interconnected network formed from the products of the most severe mutations.

    • Brian J. O’Roak
    • , Laura Vives
    •  & Evan E. Eichler
  • Letter |

    Exome sequencing of 175 autism spectrum disorder parent–child trios reveals that few de novo point mutations have a role in autism spectrum disorder and those that do are distributed across many genes and are incompletely penetrant, further supporting extreme genetic heterogeneity of this spectrum disorder.

    • Benjamin M. Neale
    • , Yan Kou
    •  & Mark J. Daly