• Article |

    An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

    • Matthew J. Yousefzadeh
    • , Rafael R. Flores
    •  & Laura J. Niedernhofer
  • Article |

    Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.

    • Tim H. H. Coorens
    • , Thomas R. W. Oliver
    •  & Sam Behjati
  • Article |

    Transcriptional adaptation, a genetic compensation process by which organisms respond to mutations by upregulating related genes, is triggered by mRNA decay and involves a sequence-dependent mechanism.

    • Mohamed A. El-Brolosy
    • , Zacharias Kontarakis
    •  & Didier Y. R. Stainier
  • Article |

    Analysis of embryonic lethal and sub-viable mouse knockout lines reveals that ablation of many genes affects placental development, and that the occurrence of placental defects is co-associated with abnormal brain, heart and vascular system development.

    • Vicente Perez-Garcia
    • , Elena Fineberg
    •  & Myriam Hemberger
  • 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 |

    Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

    • Eirini Marouli
    • , Mariaelisa Graff
    •  & Guillaume Lettre
  • Article |

    Alx3-induced modulation of Mitf expression alters melanocyte differentiation and gives rise to the hair colour differences underlying the repeated evolution of dorsal stripes in rodents.

    • Ricardo Mallarino
    • , Corneliu Henegar
    •  & Hopi E. Hoekstra
  • 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 |

    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 |

    Preclinical evaluation and optimization of mitochondrial replacement therapy reveals that a modified form of pronuclear transfer is likely to give rise to normal pregnancies with a reduced risk of mitochondrial DNA disease, but may need further modification to eradicate the disease in all cases.

    • Louise A. Hyslop
    • , Paul Blakeley
    •  & Mary Herbert
  • Letter |

    Increased maternal age is known to increase the risk of congenital heart disease in offspring; here, this link is investigated by transplanting ovaries between young and old mice, revealing that the maternal-age-associated risk is independent of the age of the ovaries but depends on the age of the mother, and that this risk can be mitigated by maternal genetic background or exercise.

    • Claire E. Schulkey
    • , Suk D. Regmi
    •  & Patrick Y. Jay
  • Letter |

    Systematically assaying the activity of 7,705 candidate enhancers during Drosophila embryogenesis shows that nearly half are active in the embryo and display dynamic spatial patterns during development; enhancer activity is matched to expression patterns of putative target genes and predictive cis-regulatory motifs are identified.

    • Evgeny Z. Kvon
    • , Tomas Kazmar
    •  & Alexander Stark
  • Article
    | Open Access

    Whole-genome analysis of the elephant shark, a cartilaginous fish, shows that it is the slowest evolving of all known vertebrates, lacks critical bone formation genes and has an unusual adaptive immune system.

    • Byrappa Venkatesh
    • , Alison P. Lee
    •  & Wesley C. Warren
  • Letter |

    In Caenorhabditis elegans, genome instability in the form of exogenous and endogenous DNA damage in germ cells evokes elevated heat- and oxidative-stress resistance in somatic tissues; this is mediated by MPK-1, which triggers the induction of putative secreted peptides associated with innate immunity, leading to activation of the ubiquitin–proteasome system.

    • Maria A. Ermolaeva
    • , Alexandra Segref
    •  & Björn Schumacher
  • Article |

    This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB.

    • Elena Rivkin
    • , Stephanie M. Almeida
    •  & Sabine P. Cordes
  • Letter |

    Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases.

    • Samir Zaidi
    • , Murim Choi
    •  & Richard P. Lifton
  • Letter |

    A project to identify the phenotypes of disruptive mutations in every zebrafish protein-coding gene has so far revealed potentially disruptive mutations in more than 38% of the protein-coding genes, and the phenotypic consequences of each allele can be assessed using a novel multi-allelic phenotyping scheme.

    • Ross N. W. Kettleborough
    • , Elisabeth M. Busch-Nentwich
    •  & Derek L. Stemple
  • Letter |

    In the fission yeast Schizosaccharomyces pombe RNA interference (RNAi) machinery promotes heterochromatin assembly and silencing of centromeric repeats; here it is shown that RNAi participates in silencing other genomic regions, such as sexual differentiation genes and retrotransposons, and this process is regulated by developmental and environmental signals.

    • Soichiro Yamanaka
    • , Sameet Mehta
    •  & Shiv I. S. Grewal
  • Letter |

    A common stem cell is known to produce both neural plate and mesoderm, but the factors regulating this choice are unknown. This study determines that Tbx6-dependent modulation of the developmental transcription factor Sox2 drives the fate of axial stem cells. In the absence of Tbx6, cells aberrantly upregulated Sox2 activity, with the result that cells originally destined to be mesoderm turned into ectopic neural tubes. In the absence of the N1 enhancer, this aberrant regulation is corrected and cells follow the appropriate fate, even in the absence of Tbx6. Therefore, active repression of the neural fate program is essential for mesoderm tissue to develop from axial stem cells.

    • Tatsuya Takemoto
    • , Masanori Uchikawa
    •  & Hisato Kondoh
  • Article |

    This study focuses on developing mouse skin where mitotic basal progenitor cells switch from symmetric divisions to asymmetric division concomitant with stratification. Using a novel technical approach, the genetic pathway regulating spindle orientation is dissected, providing the first direct evidence that the proteins governing spindle orientation (LGN, NuMA and Dctn1) promote asymmetric cell divisions regulated by Notch signalling in mammalian cells in vivo.

    • Scott E. Williams
    • , Slobodan Beronja
    •  & Elaine Fuchs
  • Article |

    Even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may generate phenotypic diversity. Intestinal specification in the nematode Caenorhabditis elegans, in which wild-type cell fate is invariant and controlled by a small transcriptional network, is now studied. The results demonstrate that mutations in developmental networks can expose stochastic variability in gene expression, leading to phenotypic variation.

    • Arjun Raj
    • , Scott A. Rifkin
    •  & Alexander van Oudenaarden
  • Letter |

    Although cyclin D1 is frequently overexpressed in human cancers, the full range of its functions in normal development and oncogenesis is unclear. Here, tagged cyclin D1 knock-in mouse strains are developed to allow a search for cyclin D1-binding proteins in different mouse organs using high-throughput mass spectrometry. The results show that, in addition to its established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development.

    • Frédéric Bienvenu
    • , Siwanon Jirawatnotai
    •  & Piotr Sicinski
  • Letter |

    Much of the mammalian genome is derived from retroelements, a significant proportion of which are endogenous retroviruses (ERVs). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation, but the initiators of this process are largely unknown. Here, deletion of KAP1 is shown to lead to a marked upregulation of a range of ERVs in mouse embryonic stem cells and in early embryos.

    • Helen M. Rowe
    • , Johan Jakobsson
    •  & Didier Trono
  • Letter |

    After fertilization in mammals, the maternal and paternal genomes undergo epigenetic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs. One of the events that takes place is the demethylation of the paternal genome. To identify the factors involved in this process, a live cell imaging system is now used to monitor the paternal DNA methylation state in zygotes; Elp3, a component of the elongator complex, is found to have an important role.

    • Yuki Okada
    • , Kazuo Yamagata
    •  & Yi Zhang