Mutation articles within Nature Communications

Featured

  • Article
    | Open Access

    Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.

    • Lene Clausen
    • , Vasileios Voutsinos
    •  & Rasmus Hartmann-Petersen

  • Article
    | Open Access

    Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.

    • Elizabeth J. Radford
    • , Hong-Kee Tan
    •  & Matthew E. Hurles

  • Article
    | Open Access

    Mutagens and DNA repair defects generate context-specific mutational signatures in cancer cells. Here, Ruis et al. provide evidence of similar processes in bacteria, showing that mutational spectra may be associated with sites of bacterial replication when mutagen exposures differ, and can be used in these cases to infer transmission routes.

    • Christopher Ruis
    • , Aaron Weimann
    •  & Julian Parkhill

  • Article
    | Open Access

    In individuals with rare, monogenic disorders it often remains challenging to identify the disease-causing genetic variants among numerous potential candidates. Here, the authors develop a neural network ensemble for variant pathogenicity prediction, specifically for this type of disorder.

    • Matt C. Danzi
    • , Maike F. Dohrn
    •  & Stephan Züchner

  • Article
    | Open Access

    An important step in understanding and using proteins is to identify the residues that are important for function. The authors present a machine-learning based method to predict functional sites that leverages and combines the information available in protein sequences and structures.

    • Matteo Cagiada
    • , Sandro Bottaro
    •  & Kresten Lindorff-Larsen

  • Article
    | Open Access

    Gastric cancers (GC) are driven by genomic alterations, but the underlying molecular mechanisms remain unclear. Here, the authors analyse the structural rearrangement landscape of 170 GCs using whole-genome sequencing, identify recurrent structural variant hotspots and find oncogene amplicons driven by extrachromosomal DNA.

    • Mihoko Saito-Adachi
    • , Natsuko Hama
    •  & Tatsuhiro Shibata

  • Article
    | Open Access

    Most of the mutations accumulated in cancer cells are deleterious, and it is unclear how such alterations are tolerated. Here, the authors propose that copy number amplifications could increase the tolerance to deleterious mutations, and analyse the features that could determine the underlying selection process.

    • Fabio Alfieri
    • , Giulio Caravagna
    •  & Martin H. Schaefer

  • Article
    | Open Access

    Rapid and facile detection of specific nucleic acid modifications could have numerous applications. Here the authors present Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) as a generic and accessible approach, and demonstrate proof-of-principle cancer biomarker detection.

    • Gaolian Xu
    • , Hao Yang
    •  & Hongchen Gu

  • Article
    | Open Access

    Long-read sequencing is promising for the detection of structural variants (SVs), which requires algorithms with high sensitivity and precision. Here, the authors develop DeBreak, an algorithm for comprehensive and accurate SV detection in long-read sequencing data across different platforms, which outperforms other SV callers.

    • Yu Chen
    • , Amy Y. Wang
    •  & Zechen Chong

  • Article
    | Open Access

    The mutation rate at any specific position in the human genome depends on sequence context. Here, the authors develop a method for predicting mutation rates of point mutations and indels based on sequence context; the results can be used to find genes where de novo mutations cause disease and genes under strong selective constraint.

    • Jörn Bethune
    • , April Kleppe
    •  & Søren Besenbacher

  • Article
    | Open Access

    Evolutionary principles could help distinguish driver from passenger mutations in cancer. Here, the authors develop SEISMIC, a method to identify cancer driver genes based on their deviation from expected mutation status patterns across a cohort under neutral evolution, and find potential drivers in melanoma and other cancer types.

    • Martin Boström
    •  & Erik Larsson

  • Article
    | Open Access

    Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.

    • Derek W. Brown
    • , Weiyin Zhou
    •  & Mitchell J. Machiela

  • Article
    | Open Access

    Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Here the authors analyse the locations of thousands of human disease mutations and their predicted effects on protein structure and show that,while loss-of-function mutations tend to be highly disruptive, non-loss-of-function mutations are in general much milder at a protein structural level.

    • Lukas Gerasimavicius
    • , Benjamin J. Livesey
    •  & Joseph A. Marsh

  • Article
    | Open Access

    Base editing to treat diseases is progressing but tissue delivery and progenitor cells correction are challenging. Here, the authors show sustained effects and propagation of mutation-corrected progenitors by transient adenine base editor expression, improving the skin phenotype of HGPS mice.

    • Daniel Whisenant
    • , Kayeong Lim
    •  & Maria Eriksson

  • 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

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