Mutation

  • Article
    | Open Access

    Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

    • Shengjiang Tan
    • , Laëtitia Kermasson
    •  & Patrick Revy
  • Article
    | Open Access

    How natural selection shapes the rate and molecular spectrum of mutations is debated. Yeast mutation accumulation experiments identify a gene promoting mutagenesis and show stabilizing selection maintaining the mutation rate above the drift barrier. Selection also preserves the mutation spectrum.

    • Haoxuan Liu
    •  & Jianzhi Zhang
  • Article
    | Open Access

    BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.

    • Jekaterina Vohhodina
    • , Liana J. Goehring
    •  & David M. Livingston
  • Article
    | Open Access

    In chronic myeloid leukaemia (CML), the drivers of blast crisis and resistance to tyrosine kinase inhibitors are not fully characterised. Here, the authors analyse a cohort of CML samples with genomic technologies and find that at least one driver alteration is associated with progression and worse prognosis.

    • Yotaro Ochi
    • , Kenichi Yoshida
    •  & Lee-Yung Shih
  • Article
    | Open Access

    Accurate prediction of variant pathogenicity is essential to understanding genetic risks in disease. Here, the authors present a deep neural network method for prediction of missense variant pathogenicity, MVP, and demonstrate its utility in prioritizing de novo variants contributing to developmental disorders.

    • Hongjian Qi
    • , Haicang Zhang
    •  & Yufeng Shen
  • Article
    | Open Access

    In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.

    • Xianghua Li
    •  & Ben Lehner
  • Article
    | Open Access

    For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

    • Tianyun Wang
    • , Kendra Hoekzema
    •  & Evan E. Eichler
  • Article
    | Open Access

    The clinical benefit from immunotherapy response in patients with mutations of genes forming the chromatin remodelling complex PBAF remains controversial. Here the authors show that PBAF complex mutations are not associated with favourable response in pan-cancer cohorts of patients treated with immune-checkpoint blockade.

    • A. Ari Hakimi
    • , Kyrollis Attalla
    •  & Robert J. Motzer
  • Article
    | Open Access

    Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.

    • Karin Voordeckers
    • , Camilla Colding
    •  & Kevin J. Verstrepen
  • Article
    | Open Access

    Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.

    • Chunyu Li
    • , Ni Wang
    •  & Bo Gao
  • Article
    | Open Access

    Somatic and germline mutations are found at different densities across the genome. Here, the authors compare human somatic tumour mutations with the germline of humans, chimpanzees, and gorillas, and find that the mutation density of tumours correlates better with non-human great apes than with the human germline.

    • José María Heredia-Genestar
    • , Tomàs Marquès-Bonet
    •  & Arcadi Navarro
  • Article
    | Open Access

    Genetic changes acquired during in vitro culture pose a challenge to application of stem cells. Here the authors use whole genome sequencing to show that cultured human adult and pluripotent stem cells have a high mutational load caused by oxidative stress and reduced oxygen tension in culture lowers mutation rates.

    • Ewart Kuijk
    • , Myrthe Jager
    •  & Edwin Cuppen
  • Article
    | Open Access

    The genetic basis of prolactinomas remains poorly understood. Here, the authors find a recurrent hotspot somatic mutation in the splicing factor 3 subunit B1 (SF3B1R625H) in prolactinomas, and show that this mutation causes aberrant splicing of ESRRG mRNA leading to up-regulation of prolactin.

    • Chuzhong Li
    • , Weiyan Xie
    •  & Yazhuo Zhang
  • Article
    | Open Access

    Nitrogen-starved fission yeast cells survive for weeks without dividing. Here, the authors show that some of these surviving cells accumulate mutations in the stress- and mitogen-activated protein kinase pathways and outcompete their parental cells, which provide nutrients for the mutant cells.

    • Rostyslav Makarenko
    • , Claire Denis
    •  & Benoît Arcangioli
  • Article
    | Open Access

    While biallelic mutations of the SLC26A4 gene cause non-syndromic hearing loss with enlarged vestibular aqueducts or Pendred syndrome, a considerable number of patients carry mono-allelic mutations. Here the authors identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4.

    • Mengnan Li
    • , Shin-ya Nishio
    •  & Masanori Nakayama
  • Article
    | Open Access

    Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

    • Eugene J. Gardner
    • , Elena Prigmore
    •  & Matthew E. Hurles
  • Article
    | Open Access

    Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.

    • Robert Fragoza
    • , Jishnu Das
    •  & Haiyuan Yu
  • Article
    | Open Access

    Estimates of mutation rates differ between species. Here, Lindsay et al. perform side-by-side analyses of germline mutation rates using multi-sibling mouse and human pedigrees and find different mutation rates between species, also stratified by sex and temporal stage of mutation acquisition.

    • Sarah J. Lindsay
    • , Raheleh Rahbari
    •  & Matthew E. Hurles
  • Article
    | Open Access

    The role of mitochondrial DNA mutations in organismal fitness and lifespan have been studied in mitochondrial mutator models with varying results. Here, the authors generate a new APOBEC1 expression-based Drosophila mutator model and show that it has limited mitochondrial function and reduced lifespan.

    • Simonetta Andreazza
    • , Colby L. Samstag
    •  & Alexander J. Whitworth
  • Article
    | Open Access

    Mutators are expected to re-evolve low mutation rates to reduce deleterious load, but empirical evidence is mixed. Here, the authors show that load can vary across mutators and genetic backgrounds, which their simulations suggest can substantially alter antimutator dynamics.

    • Alejandro Couce
    •  & Olivier Tenaillon
  • Article
    | Open Access

    The role of brain somatic mutations in neurodegenerative diseases such as Alzheimer’s disease (AD) is not well understood. Here the authors carry out high-depth exome sequencing ~500× on brain tissue from patients with AD and controls, and identify mutations in a number of genes that are known to contribute to phosphorylation and aggregation of tau, including PIN1.

    • Jun Sung Park
    • , Junehawk Lee
    •  & Jeong Ho Lee
  • Article
    | Open Access

    Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.

    • Xuanxuan Xing
    • , Daniel P. Kane
    •  & Polina V. Shcherbakova
  • Article
    | Open Access

    A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.

    • Mafalda Barbosa
    • , Ricky S. Joshi
    •  & Andrew J. Sharp
  • Article
    | Open Access

    As cells evolve towards malignancy, somatic mutations arise from defects in DNA damage and repair processes which are each associated with individual mutation signatures. Here the authors show it is possible to recreate cancer mutational signatures in vitro using gene editing experiments in an isogenic human-cell system.

    • Xueqing Zou
    • , Michel Owusu
    •  & Serena Nik-Zainal
  • Article
    | Open Access

    Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.

    • Johanna Tommiska
    • , Johanna Känsäkoski
    •  & Taneli Raivio
  • Article
    | Open Access

    Germline mutation rates are known to vary between species but somatic mutation rates are less well understood. Here the authors compare mice and humans, observing that somatic mutation rates were nearly two orders of magnitude higher in both species, with both mutation rates significantly higher in mice.

    • Brandon Milholland
    • , Xiao Dong
    •  & Jan Vijg
  • Article
    | Open Access

    Genes in the cytochrome P450 family have evolved a wide range of functions. Here, Liu et al. reconstruct the evolution of the P450 genes CYP98A8 and CYP98A9in the Brassicales, revealing a complex history of retrotransposition, tandem duplication and neofunctionalization, followed by subfunctionalization or gene loss in specific lineages.

    • Zhenhua Liu
    • , Raquel Tavares
    •  & Hugues Renault
  • Article
    | Open Access

    Recent studies using in depth DNA sequencing techniques led to the identification of cancer driver genes but mainly focused on the effect on their expression. Here, the authors analyse 266 cases of breast cancer and report gene expression signatures associated with the number and character of signature mutations.

    • Marcel Smid
    • , F. Germán Rodríguez-González
    •  & John W. M. Martens
  • Article
    | Open Access

    Deleterious germline variants in the MC1Rgene are associated with red hair and freckles, and with an increased risk of developing melanoma. Here, the authors investigate melanoma samples from patients with and without these variants and find that their presence is predictive of a higher overall mutation prevalence.

    • Carla Daniela Robles-Espinoza
    • , Nicola D. Roberts
    •  & David J. Adams
  • Article
    | Open Access

    Osteogenesis imperfecta (OI) is genetically linked to autosomal dominant or autosomal recessive mutations. Here, Marini et al. describe two families with X-chromosome-linked OI with mutations in MBTPS2 that alter regulated intramembrane proteolysis and subsequent defects in collagen crosslinking and osteoblast function.

    • Uschi Lindert
    • , Wayne A. Cabral
    •  & Vorasuk Shotelersuk
  • Article
    | Open Access

    Some individuals present with multiple synchronous colorectal tumours, but the genetic understanding of this is unclear. Here, the authors use a sequencing strategy to show that the synchronous tumours are genetically independent and the patients harbour rare germline damaging mutations in genes associated with the immune system.

    • Matteo Cereda
    • , Gennaro Gambardella
    •  & Francesca D. Ciccarelli
  • Article
    | Open Access

    The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.

    • Daniel Chubb
    • , Peter Broderick
    •  & Richard S. Houlston
  • Article
    | Open Access

    APC is a well-known tumour suppressor that is frequently inactivated in colorectal cancer. Here, the authors sequence more than 1000 cancer genes in 468 colorectal cancers and show that mutation signatures can be used to classify the tumours and that multiple mutations in APCare associated with a poor prognosis.

    • Michael J. Schell
    • , Mingli Yang
    •  & Timothy J. Yeatman
  • Article
    | Open Access

    The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.

    • Luise Hartmann
    • , Sayantanee Dutta
    •  & Philipp A. Greif
  • Article
    | Open Access

    Women with germline variants in BRCA genes are predisposed to ovarian cancer. In this study, the authors demonstrate that fimbrial tissue from the ovary, the site of ovarian cancer, in BRCAmutant carriers contains marked DNA methylation changes compared with the proximal region of the ovary.

    • Thomas E. Bartlett
    • , Kantaraja Chindera
    •  & Martin Widschwendter
  • Article
    | Open Access

    Antimalarial chemotherapy relies on combination therapies (ACTs) consisting of an artemisinin derivative and a partner drug. Here, the authors study the effects of globally prevalent mutations in a multidrug resistance transporter (PfMDR1) on the parasite’s susceptibility to ACT drugs.

    • M. Isabel Veiga
    • , Satish K. Dhingra
    •  & David A. Fidock