News & Views

  • News & Views |

    Half of all colorectal cancers bear KRAS-activating mutations that affect the metabolic dependencies of cancer cells and drive resistance to commonly used drugs. A new study provides insights into KRAS-driven metabolic rewiring and identifies a new therapeutic target for KRAS-mutant cancers.

    • Sanne Bootsma
    • , Sanne M. van Neerven
    •  & Louis Vermeulen
  • News & Views |

    Maintaining ignorance to self-nucleic acids can prevent inflammatory diseases such as Aicardi–Goutières syndrome (AGS). A new study finds that mutations in LSM11 and RNU7-1, which encode components of the histone messenger RNA–preprocessing complex, cause AGS by loosening the binding of cyclic GMP–AMP synthase (cGAS) to nucleosomes, thus enabling cGAS activation and induction of type I interferons.

    • Fiachra Humphries
    •  & Katherine A. Fitzgerald
  • News & Views |

    Patterns of co-occurring and mutually exclusive mutations reveal synergistic interactions among cancer driver genes. A new study functionally confirms these interactions and builds the pairwise relationships into networks of pathway disruption that have better predictive power than specific mutations alone.

    • Martin S. Taylor
  • News & Views |

    In a classical view of carcinogenesis, carcinogens directly cause mutations. In this issue, Riva et al. explore the effects of 20 known or suspected human carcinogens and find discernible mutational signatures for only three of them.

    • Nuria Lopez-Bigas
    •  & Abel Gonzalez-Perez
  • News & Views |

    FOXA1 is a key pioneer factor in androgen-receptor activity but has been an elusive drug target. A new study shows that inhibition of the associated cofactor LSD1 modifies the methylation state of FOXA1, thus resulting in chromatin dissociation and tumor inhibition, even in models of treatment-resistant prostate cancer.

    • Soleilmane Omarjee
    •  & Jason S. Carroll
  • News & Views |

    How do boundary elements divide chromosomes into domains? A new study uses random genomic insertions to show how small genomic fragments can shape chromatin folding through the interplay of loop extrusion and compartmentalization. Spoiler: context matters.

    • Erika C. Anderson
    •  & Elphège P. Nora
  • News & Views |

    The role of N6-methyladenosine (m6A) is still not fully understood. Two new studies advance understanding of this RNA modification. One shows that m6A modification of nascent messenger RNA promotes transcription by recruiting the histone H3 K9 demethylase KDM3B. Another study identifies genetic variants that affect m6A deposition and human disease.

    • Dalen Chan
    •  & Pedro J. Batista
  • News & Views |

    Binding of RNA to the gene expression regulator Polycomb repressive complex 2 (PRC2) has been proposed to antagonize PRC2’s chromatin recruitment. A new study now shows that RNA is in fact critical for correct recruitment of PRC2 at its target genes in human pluripotent stem cells and suggests that interplay of PRC2 and RNA can fine-tune PRC2’s regulatory role.

    • Ivano Mocavini
    •  & Luciano Di Croce
  • News & Views |

    Genomes are highly organized in space and time. Compartments, topologically associating domains (TADs) and loops are three dimensional (3D) genome features that have been extensively studied. Among these three levels of organization, TADs have sparked the most debate. New microscopy data shed light on how TADs and their leaky borders contribute to gene regulation.

    • Irene Farabella
    •  & Marc A. Marti-Renom
  • News & Views |

    How ‘difficult’ is it for somatic evolution to produce a cell that is capable of leaving the primary tumor and growing in a distant organ? In this issue, Reiter et al. assess genetic diversity across metastatic lesions and identify a tight selective bottleneck preceding distant metastasis.

    • Trevor A. Graham
    •  & Darryl Shibata
  • News & Views |

    Pachytene Piwi-interacting RNAs (piRNAs) are abundant small non-coding RNAs expressed in mammalian germ lines. A new study indicates that, among the diverse pool of piRNA sequences, a small number act as highly selective guides that induce cleavage of coding and non-coding transcripts, thus promoting piRNA generation and regulating gene expression.

    • Alexei A. Aravin
  • News & Views |

    TET2 and DNMT3A mutations lead to similar long-term outcomes in blood cancers despite the antagonistic biochemical functions of their encoded proteins. A new study highlights the opposing effects of TET2 and DNMT3A mutations in shaping the early erythroid or myeloid bias of hematopoietic progenitors.

    • Isaac F. López-Moyado
    •  & Anjana Rao
  • News & Views |

    Many normal tissues are populated by clonal expansions that compete for space. Colom et al. now show that mutant clones keep other mutant clones in check by effectively annulling one another’s advantages.

    • Kamila Naxerova
  • News & Views |

    A new study addresses whether transcription of enhancers and the resulting enhancer RNAs (eRNAs) play a role in mediating long-range interactions between enhancers and promoters. Studying the immunoglobulin heavy chain (Igh) locus, the authors find that transcription of the enhancers per se is required to establish but not maintain these interactions, and this mechanism may apply to a subset of other enhancer–promoter interactions.

    • Douglas R. Higgs
  • News & Views |

    A new study identifies sorbitol dehydrogenase (SORD) deficiency as a slowly progressive hereditary motor axonopathy caused by a genetic defect in the second step of the polyol pathway, thus leading to elevated tissue and blood sorbitol. SORD deficiency is the most common recessive cause of neuropathy, for which therapeutic intervention with aldose reductase inhibitors may have potential.

    • Eva Morava
  • News & Views |

    Cancer cells have the extraordinary evolutionary potential to adapt and acquire resistance to most conventional and targeted therapies. In a new study, Lin et al., develop a systematic approach to identify combination therapies that produce cancer traps, in which evading the first drug makes the cancer vulnerable to the second.

    • Charles Y. Lin
  • News & Views |

    Efforts to systematically characterize silencers in animal genomes have been limited. Two studies in this issue of Nature Genetics bring silencers into the spotlight, identifying these elements genome wide in human and mouse cells, and providing insights into their function.

    • Monica Della Rosa
    •  & Mikhail Spivakov
  • News & Views |

    Huntington’s disease is a severe progressive neurological disorder caused by a CAG-repeat expansion in the HTT gene. A small molecule shows therapeutic potential by inducing contraction of these expanded CAG repeats in cell and mouse models of the disease.

    • Michael D. Flower
    •  & Sarah J. Tabrizi
  • News & Views |

    RNA:DNA hybrids that form across genomes control a wide range of biological processes. A new study shows that N6-methyladenosine (m6A) modification on the RNA moieties regulates the formation and genome integrity of these hybrids. This finding opens a new avenue of research on how RNA modifications (the ‘epitranscriptome’) can help control genome maintenance.

    • Aline Marnef
    •  & Gaëlle Legube
  • News & Views |

    A new study presents a powerful experimental approach, CRISPRi-FlowFISH, for mapping regulatory interactions, and uses it to characterize thousands of putative enhancer–gene pairs. The results suggest that most current approaches for predicting enhancer–gene interactions perform poorly, but a simple mathematical model combining distance with enhancer activity shows promise.

    • Daniel J. Gaffney
  • News & Views |

    Two genetic studies uncover how domestication changed fruit quality traits in melon and watermelon. The studies combine population genomic and quantitative genetic tools to study crop evolution and provide breeders with comprehensive variation maps.

    • Murukarthick Jayakodi
    • , Mona Schreiber
    •  & Martin Mascher
  • News & Views |

    A new study identifies germline NPM1 mutations in people with dyskeratosis congenita. These NPM1 mutations inhibit ribosomal RNA 2´-O-methylation by decreasing the binding of the rRNA methyltransferase FBL to small nucleolar RNAs. Thus, NPM1 influences ribosomal functions via epitranscriptomic regulation.

    • Fengbiao Zhou
    •  & Carsten Müller-Tidow
  • News & Views |

    Common genetic variants increase the risk of schizophrenia, but the downstream biological mechanisms are largely unknown. A new study demonstrates that schizophrenia risk genes cause neuronal dysfunction and have synergistic effects on gene expression.

    • Jane H. Christensen
    •  & Anders D. Børglum
  • News & Views |

    Inferring adaptation, migration and population history would be profoundly easier if we could use the genomes that we sequence to infer the true genealogical history of each locus. Two new papers bring us close to achieving this goal.

    • Kelley Harris
  • News & Views |

    Far from being junk DNA, the pervasive retrotransposons that populate the genome have a powerful capacity to influence genes and chromatin. A new study demonstrates how the transcription of one such element, HERV-H, can modify the higher-order 3D structure of chromatin during early primate development.

    • Michael I. Robson
    •  & Stefan Mundlos
  • News & Views |

    Chromatin loops and domains are major organizational hallmarks of chromosomes. New work suggests, however, that these topological features of the genome are poor global predictors of gene activity, raising questions about their function.

    • Elizabeth H. Finn
    •  & Tom Misteli
  • News & Views |

    Although human genetics can help identify new drug targets, the best way to prioritize genes as therapeutic targets is uncertain. A new study describes a framework to prioritize potential targets by integrating genome-wide association data with genomic features, disease ontologies and network connectivity.

    • Robert M. Plenge
  • News & Views |

    Fhb1 is the most effective and most widely deployed source of durable resistance against Fusarium graminearum, a devastating toxin-producing fungal pathogen affecting wheat. Two new studies identify Fhb1 as an atypical disease resistance gene; this discovery is expected to fuel discussion on the molecular nature of this important disease-resistance locus.

    • Evans S. Lagudah
    •  & Simon G. Krattinger
  • News & Views |

    Genetics has played a key role in understanding the relationship between the DNA sequence encoding a protein and the protein’s three-dimensional structure. Two new studies present similar analytical approaches to predict three-dimensional structure on the basis of genetic interaction data.

    • Melissa Chiasson
    •  & Douglas M. Fowler
  • News & Views |

    Epigenetic heterogeneity underlies the diversity of cell states found in health and disease. A new study presents a method for profiling of histone modifications in single cells and applies it to identify rare chromatin states, possibly predisposed to drug resistance, within patient-derived tumor xenografts.

    • Anna Minkina
    •  & Jay Shendure
  • News & Views |

    The conserved ligand–receptor pair CLAVATA1–CLAVATA3, which maintains homeostasis in shoot apical meristems, responds differently to perturbation in tomato, Arabidopsis and maize. Active compensation occurs in CLE signaling peptides in tomato, but compensation is passive in Arabidopsis.

    • Elizabeth A. Kellogg
  • News & Views |

    More than one dozen hereditary ataxias are caused by repeat expansions. A newly discovered expansion may be the first known common genetic cause of late-onset ataxia.

    • Vikram Shakkottai
    •  & Henry Paulson
  • News & Views |

    Resolving variant-to-function relationships is a key challenge faced by human geneticists. A new study combining statistical fine-mapping with cell-type-specific functional annotations advances the understanding of the regulatory consequences of genetic variants associated with variations in blood-cell traits.

    • Manuel Tardaguila
    •  & Nicole Soranzo
  • News & Views |

    The origin of strawberry is truly global, involving both natural processes and human intervention. The strawberry genome sequence provides support for an influential hypothesis of genome dominance.

    • David J. Bertioli
  • News & Views |

    Contemporary genomics and informatics technologies were used to provide a meaningful and insightful overview of more than 20,000 wild and domesticated barley genotypes from one of the largest crop germplasm collections. The data provide a framework for the rational exploitation of genetic resources in crop improvement, which will be central to addressing global food security.

    • Peter Langridge
    •  & Robbie Waugh
  • News & Views |

    The genomes for essentially all worm parasites of humans are in hand thanks to a new study. Now we have to use them.

    • Paul W. Sternberg
  • News & Views |

    A new study identifies loss-of-function mutations in HAVCR2, which encodes TIM-3, in patients with a rare cutaneous T cell lymphoma associated with aberrant immunological activation. These mutations lead to loss of the TIM-3 immunological checkpoint, thus promoting inflammation and malignancy.

    • Karen O. Dixon
    • , Madhumita Das
    •  & Vijay K. Kuchroo
  • News & Views |

    The availability of various public resources has hastened the discovery of type 2 diabetes–associated loci in the largest genome-wide association study of the disease reported to date. In addition, these resources have also enabled researchers to get closer to determining the culprit genetic variants and therefore closer to the target effector genes driving these associations.

    • Diana L. Cousminer
    •  & Struan F. A. Grant
  • News & Views |

    Patient-derived cancer cell lines could address two major challenges in oncology: real-time drug response prediction and the creation of massive knowledge banks. A new study showcases the power of this approach for precision oncology.

    • Ultan McDermott
  • News & Views |

    A new study uncovers novel copy number signatures in ovarian cancer genomes. This work sheds light on mutational processes driving ovarian cancer, reveals the distribution of copy number features across the patient population and identifies new genomic properties related to treatment response.

    • Sohrab P. Shah
  • News & Views |

    Two new studies show that a plant-specific complex composed of EBS, or its homolog SHL, and EMF1 acts as a chromatin reader within the Polycomb pathway and effects gene repression. Two domains of EBS and SHL bind distinct chromatin modifications that are associated with active and repressed chromatin.

    • Kristin Krause
    •  & Franziska Turck
  • News & Views |

    Individual genome-wide polygenic risk scores (GPSs) for assessing disease susceptibility have been shown to yield both reliable and clinically meaningful results. However, certain impediments and outdated ways of thinking about health maintenance must be overcome before GPSs are adopted in routine care streams.

    • Andrew J. Schork
    • , M. Anthony Schork
    •  & Nicholas J. Schork
  • News & Views |

    Roses have held an attraction for people all over the world as ornamental plants. Now genome sequencing of the highly heterozygous Rosa chinensis and resequencing of major genotypes open the door to a greater understanding of rose evolutionary history and the regulatory mechanisms determining rose flower color and scent.

    • Qing Xu
    •  & Zhong-Jian Liu
  • News & Views |

    The triplet code underpins analyses of rare and de novo mutations in exome sequencing data, but analysis of the noncoding genome is much more challenging. A new analytical framework for common, complex diseases highlights the need for very large samples to overcome the unavoidable multiple-testing burden and hence provides preemptive warnings against underpowered studies.

    • Naomi R. Wray
    •  & Jacob Gratten
  • News & Views |

    The ability to visualize and study the 3D folding of chromosomes in cells has been propelled forward by several major technological advances in the past two decades. Two new studies now further expand the scientific toolbox for studying chromosome conformation by providing novel methodologies for accurate mapping of genome topology and predicting the topological effects of genomic structural variation.

    • Ralph Stadhouders
  • News & Views |

    In vivo verification of tumor suppressors and their interactions with each other has required complex experiments. A report in this issue uses a novel CRISPR–Cas9 technology with barcodes to test, in parallel, the tumorigenic potential of functional loss of multiple tumor-suppressor genes in the context of a genetically engineered mouse model of lung adenocarcinoma with mutant Kras.

    • James Kim
    •  & John D. Minna
  • News & Views |

    Noncoding expanded repeats have been implicated in a wide range of diseases. A new report uncovers expanded TTTCA and TTTTA repeats in an intronic region of SAMD12, and at least two other genes, in individuals with benign adult familial myoclonic epilepsy.

    • Marka van Blitterswijk
    •  & Rosa Rademakers
  • News & Views |

    The switch from fetal to adult hemoglobin relies on repression or silencing of the upstream γ-globin gene, but identification of the transcriptional repressors that bind to the sites at which a cluster of naturally occurring variants associated with HPFH (hereditary persistence of fetal hemoglobin) are found has been elusive. A new study provides mechanistic evidence for the direct binding of BCL11A and ZBTB7A, two previously identified γ-globin gene repressors.

    • Xunde Wang
    •  & Swee Lay Thein
  • News & Views |

    Alterations in craniofacial size and shape are apparent in many monogenic diseases and syndromes, but remarkably little is known about the genetics of face shape within healthy populations. This may be set to change following publication of a study that combines unsupervised hierarchical spectral clustering and canonical correlation analysis to help identify common genetic variants associated with craniofacial shape.

    • David M. Evans