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  • Review Article |

    This Review discusses strategies for the genetic engineering of adoptive T cell immunotherapies with a focus on approaches harnessing transgenic T cell receptors or chimeric antigen receptors to treat cancer. The authors also discuss the more complex levels of genetic regulation that will be needed to ensure both safety and efficacy.

    • Gavin I. Ellis
    • , Neil C. Sheppard
    •  & James L. Riley

  • Review Article |

    Interactions between microorganisms and their hosts are highly context dependent and contribute to both normal tissue function and infectious disease pathology. In this Review, Westermann and Vogel describe how advances in RNA sequencing techniques are providing molecular insights into host–microbe interactions, including advances in cross-species and single-cell transcriptomics.

    • Alexander J. Westermann
    •  & Jörg Vogel

  • Review Article |

    There is a rapidly growing appreciation of the complexities of 3D genome organization, as well as associations with gene expression and wider cellular and organismal phenotypes, including diseases. In this Review, the authors describe diverse experimental methods for manipulating 3D genome organization — from fine-scale control of DNA contacts to large-scale nuclear repositioning — which are facilitating detailed testing of the biological functions of 3D genome organization.

    • Haifeng Wang
    • , Mengting Han
    •  & Lei S. Qi

  • Review Article |

    Maintenance of cell-type identity requires the faithful inheritance of chromatin states through cell division, despite the challenges posed by the disruptive passage of the DNA replication fork and the dilution of nucleosome components in complex with the daughter DNA strands. In this Review, Escobar, Loyola and Reinberg discuss how methodological advances are providing unprecedented mechanistic insights into the segregation of parental nucleosomes, how these mechanisms maintain gene expression programmes and how non-faithful nucleosome segregation is linked to differentiation and disease.

    • Thelma M. Escobar
    • , Alejandra Loyola
    •  & Danny Reinberg

  • Review Article |

    MicroRNAs (miRNA) exert essential functions in mammalian development and physiology. The authors review recent insights from the phenotypic analysis of miRNA knockouts in mice that emphasize roles for these non-coding RNAs at different developmental stages and in adults, and illustrate the importance of functional miRNA targets, miRNA dosage, miRNA interactions and cellular context.

    • Brian DeVeale
    • , Jennifer Swindlehurst-Chan
    •  & Robert Blelloch

  • Review Article |

    Shadow enhancers regulate a common target gene and drive expression patterns that overlap spatiotemporally. The authors review recent insights into the prevalence and role of shadow enhancers in metazoans, as well as their mechanisms of action to fine-tune gene expression. They also discuss the evolution of shadow enhancers and their implication in disease.

    • Evgeny Z. Kvon
    • , Rachel Waymack
    •  & Zeba Wunderlich

  • Review Article |

    Africa is a continent with deep evolutionary history, which has implications for the genetic underpinnings of disease. In this Review, the authors discuss how genetic features of African populations provide both challenges and opportunities for understanding disease genetics in Africa. They describe how this genetic knowledge — combined with initiatives including capacity-building, data sharing and increased representation of African genomes in genetic variation databases — can be leveraged towards achieving precision medicine approaches in African healthcare.

    • Luisa Pereira
    • , Leon Mutesa
    •  & Michèle Ramsay

  • Review Article |

    Our evolutionary history has resulted in highly complex and sophisticated human physiology. Yet evolutionary footprints have also left us prone to diseases. In this Review, the authors discuss how events from the earliest history of life on Earth through to modern human evolution influence many disease traits and outcomes. They describe how an understanding and application of evolutionary frameworks can inform precision medicine initiatives.

    • Mary Lauren Benton
    • , Abin Abraham
    •  & John A. Capra

  • Review Article |

    The ability to reprogramme cellular translation and genomes to produce non-canonical biopolymers has wide-ranging applications, including in therapeutics, but has yet to be fully realized. In this Review, de la Torre and Chin discuss recent advances towards achieving this goal.

    • Daniel de la Torre
    •  & Jason W. Chin

  • Review Article |

    Haematopoietic stem and progenitor cell (HSPC) gene therapy using lentiviral or gammaretroviral vectors has now been approved for clinical use. In this Review, Ferrari, Thrasher and Aiuti discuss the history of HSPC gene therapy, the clinical promise of gene-editing HPSCs and the use of HSPC gene therapy to treat specific diseases.

    • Giuliana Ferrari
    • , Adrian J. Thrasher
    •  & Alessandro Aiuti

  • Review Article |

    Infectious diseases are an ever-present global threat. In this Review, Kwok, Mentzer and Knight discuss our latest understanding of how human genetics influence susceptibility to disease. Furthermore, they discuss emerging progress in the interplay between host and pathogen genetics, molecular responses to infection and vaccination, and opportunities to bring these aspects together for rapid responses to emerging diseases such as COVID-19.

    • Andrew J. Kwok
    • , Alex Mentzer
    •  & Julian C. Knight

  • Perspective |

    Although cancer genetics analyses have often focused on individual mutations of classic cancer genes, a wealth of cancer sequencing data are allowing a more comprehensive understanding of the cumulative effects of mutations genome-wide. In this Perspective article, the authors propose how the burden of different types of mutation — from point mutations to large-scale chromosomal aberrations — has distinct and compensatory effects on tumour fitness and selection during different stages of cancer evolution.

    • Erez Persi
    • , Yuri I. Wolf
    •  & Eugene V. Koonin

  • Review Article |

    In this Review, Carter and Zhao discuss how single-cell sequencing technologies are being applied to investigate epigenetic heterogeneity among seemingly homogeneous populations of cells and how this epigenetic variability relates to cell–cell differences in gene expression.

    • Benjamin Carter
    •  & Keji Zhao

  • Review Article |

    RNA-binding proteins (RBPs) are critical effectors of gene expression, and their malfunction underlies many diseases. The authors review the role of RBPs in human genetic disorders, both Mendelian and somatic, discuss the molecular mechanisms of disease and highlight emerging therapeutic interventions that target RBPs.

    • Fátima Gebauer
    • , Thomas Schwarzl
    •  & Matthias W. Hentze

  • Review Article |

    In this Review, Oudelaar and Higgs discuss the relationship between genome structure and gene regulation, with a focus on whether genome organization has an instructive role or largely reflects the activity of regulatory elements.

    • A. Marieke Oudelaar
    •  & Douglas R. Higgs

  • Perspective |

    This Perspective reviews efforts to map six different RNA modifications — pseudouridine (Ψ), 5-methylcytidine (m5C), N 1-methyladenosine (m1A), N 4-acetylcytidine (ac4C), ribose methylations (Nm) and N 7-methylguanosine (m7G) — and how they differ from N 6-methyladenosine (m6A). The authors discuss the technical and analytical challenges of characterizing the epitranscriptome and provide their own conclusions on the abundance and distribution of these modifications.

    • David Wiener
    •  & Schraga Schwartz

  • Review Article |

    Cell–cell interactions and communication can be inferred from RNA sequencing data of, for example, ligand–receptor pairs. The authors review insights gained and the methods and tools used in studies of cell–cell interactions based on transcriptomic data.

    • Erick Armingol
    • , Adam Officer
    •  & Nathan E. Lewis

  • Review Article |

    The effects of genetic variation on the adaptive potential of species depend on the frequencies of alleles at other loci in the individual or in the population, and the patterns of spatio-temporal co-occurrence between alleles in interacting species. This Review explores these population and community genomic contexts and their direct and indirect effects on biodiversity, ecosystems and people.

    • Madlen Stange
    • , Rowan D. H. Barrett
    •  & Andrew P. Hendry