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Matters Arising
| Open AccessRe-evaluating evidence for adaptive mutation rate variation
- Long Wang
- , Alexander T. Ho
- & Sihai Yang
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Article
| Open AccessWidespread somatic L1 retrotransposition in normal colorectal epithelium
This study illustrates long interspersed nuclear element-1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.
- Chang Hyun Nam
- , Jeonghwan Youk
- & Young Seok Ju
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Article
| Open AccessIncreased mutation and gene conversion within human segmental duplications
A study comparing the pattern of single-nucleotide variation between unique and duplicated regions of the human genome shows that mutation rate and interlocus gene conversion are elevated in duplicated regions.
- Mitchell R. Vollger
- , Philip C. Dishuck
- & Evan E. Eichler
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Article
| Open AccessPan-cancer whole-genome comparison of primary and metastatic solid tumours
The genomic differences between primary and metastatic tumours are assessed across 23 cancer types using pan-cancer whole-genome analysis.
- Francisco Martínez-Jiménez
- , Ali Movasati
- & Arne Van Hoeck
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Article |
Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis
Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.
- Joshua S. Weinstock
- , Jayakrishnan Gopakumar
- & Siddhartha Jaiswal
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Article
| Open AccessEvolution of the germline mutation rate across vertebrates
Using sequencing and comparing high-coverage genomes, the germline mutation rates across vertebrates are quantified.
- Lucie A. Bergeron
- , Søren Besenbacher
- & Guojie Zhang
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Article
| Open AccessA NPAS4–NuA4 complex couples synaptic activity to DNA repair
A neuron-specific activity-dependent DNA repair mechanism is identified, the impairment of which may lead to neurodevelopmental disorders, neurodegeneration and ageing.
- Elizabeth A. Pollina
- , Daniel T. Gilliam
- & Michael E. Greenberg
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Article
| Open AccessAfrican-specific molecular taxonomy of prostate cancer
A molecular taxonomy for prostate cancer reveals a subtype associated with copy-number loss found in African and European populations that predicts poor outcomes and two subtypes—one associated with high mutational noise and one with copy-number gain—specific to African populations.
- Weerachai Jaratlerdsiri
- , Jue Jiang
- & Vanessa M. Hayes
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Article |
Synonymous mutations in representative yeast genes are mostly strongly non-neutral
A survey of 8,341 mutations in 21 yeast genes shows that synonymous mutations are nearly as harmful as nonsynonymous mutations, in part because they both affect the mRNA level of the gene mutated.
- Xukang Shen
- , Siliang Song
- & Jianzhi Zhang
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Article
| Open AccessClonal dynamics of haematopoiesis across the human lifespan
Haematopoiesis has high clonal diversity up to about 65 years of age, after which diversity drops precipitously owing to positive selection acting on a handful of clones that expand exponentially throughout adulthood.
- Emily Mitchell
- , Michael Spencer Chapman
- & Peter J. Campbell
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Article
| Open AccessThe longitudinal dynamics and natural history of clonal haematopoiesis
A long-term study of 385 human donors reports that driver gene mutations and age determine the lifelong dynamics of clonal haematopoiesis
- Margarete A. Fabre
- , José Guilherme de Almeida
- & George S. Vassiliou
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Article |
A natural mutator allele shapes mutation spectrum variation in mice
Natural variation in the mouse gene Mutyh influences the rate of C>A germline mutations.
- Thomas A. Sasani
- , David G. Ashbrook
- & Kelley Harris
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Article
| Open AccessGenetic and chemotherapeutic influences on germline hypermutation
A study of 21,879 families with rare genetic diseases identifies 12 with 2- to 7-fold excess of germline mutations, most of which are due to DNA repair defects or exposure to mutagenic chemotherapy, although most individuals with a hypermutated genome will not have a genetic disease.
- Joanna Kaplanis
- , Benjamin Ide
- & Matthew Hurles
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Article
| Open AccessSignatures of TOP1 transcription-associated mutagenesis in cancer and germline
Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.
- Martin A. M. Reijns
- , David A. Parry
- & Andrew P. Jackson
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Article
| Open AccessMutation bias reflects natural selection in Arabidopsis thaliana
Data on de novo mutations in Arabidopsis thaliana reveal that mutations do not occur randomly; instead, epigenome-associated mutation bias reduces the occurrence of deleterious mutations.
- J. Grey Monroe
- , Thanvi Srikant
- & Detlef Weigel
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Article |
Convergent somatic mutations in metabolism genes in chronic liver disease
Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.
- Stanley W. K. Ng
- , Foad J. Rouhani
- & Peter J. Campbell
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Article |
A body map of somatic mutagenesis in morphologically normal human tissues
Laser-capture microdissection and mini-bulk exome sequencing are combined to analyse somatic mutations in morphologically normal tissues from nine organs from five donors, revealing variation in mutation burdens, mutational signatures and clonal expansions.
- Ruoyan Li
- , Lin Di
- & Chen Wu
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Article |
The mutational landscape of human somatic and germline cells
The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.
- Luiza Moore
- , Alex Cagan
- & Raheleh Rahbari
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Article |
Somatic mutation landscapes at single-molecule resolution
NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.
- Federico Abascal
- , Luke M. R. Harvey
- & Iñigo Martincorena
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Article |
Tracking break-induced replication shows that it stalls at roadblocks
A method of tracking break-induced replication reveals the details of this repair process and shows that it can be impaired by certain genomic elements and by transcription.
- Liping Liu
- , Zhenxin Yan
- & Anna Malkova
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Article |
Patterns of de novo tandem repeat mutations and their role in autism
A bioinformatics pipeline to identify tandem repeat mutations is developed and used to characterize precise changes in repeat copy number associated with autism spectrum disorder.
- Ileena Mitra
- , Bonnie Huang
- & Melissa Gymrek
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Article |
Monogenic and polygenic inheritance become instruments for clonal selection
Analysis of blood-derived DNA from participants in the UK Biobank demonstrates that clonal expansions of acquired copy-neutral loss of heterozygosity mutations act on inherited alleles along a chromosome arm by modifying their allelic dosages.
- Po-Ru Loh
- , Giulio Genovese
- & Steven A. McCarroll
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Article
| Open AccessA structural variation reference for medical and population genetics
A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.
- Ryan L. Collins
- , Harrison Brand
- & Michael E. Talkowski
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Article |
The mutational landscape of normal human endometrial epithelium
Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.
- Luiza Moore
- , Daniel Leongamornlert
- & Michael R. Stratton
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Article
| Open AccessThe repertoire of mutational signatures in human cancer
The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.
- Ludmil B. Alexandrov
- , Jaegil Kim
- & Christian von Mering
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Article |
Tobacco smoking and somatic mutations in human bronchial epithelium
Whole-genome sequencing of normal bronchial epithelium from 16 individuals shows that tobacco smoking increases genomic heterogeneity, mutational burden and driver mutations, whereas stopping smoking promotes replenishment of the epithelium with near-normal cells.
- Kenichi Yoshida
- , Kate H. C. Gowers
- & Peter J. Campbell
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Article |
Somatic inflammatory gene mutations in human ulcerative colitis epithelium
Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions.
- Kosaku Nanki
- , Masayuki Fujii
- & Toshiro Sato
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Article |
Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.
- Najoua Lalaoui
- , Steven E. Boyden
- & John Silke
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Article |
Somatic mutations and clonal dynamics in healthy and cirrhotic human liver
Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.
- Simon F. Brunner
- , Nicola D. Roberts
- & Peter J. Campbell
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Letter |
A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene
When Lama1 was upregulated using CRISPR and a catalytically inactive Cas9 in a mouse model of congenital muscular dystrophy type 1A, apparent hindlimb paralysis, muscle fibrosis and nerve myelination defects were ameliorated in symptomatic mice.
- Dwi U. Kemaladewi
- , Prabhpreet S. Bassi
- & Ronald D. Cohn
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Article |
Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations
Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.
- Po-Ru Loh
- , Giulio Genovese
- & Alkes L. Price
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Letter |
Rad51-mediated double-strand break repair and mismatch correction of divergent substrates
DNA repair by break-induced replication begins with the Rad51-mediated invasion of single-stranded DNA into a double-stranded donor template; this study shows that successful recombination between highly mismatched substrates can occur when only five consecutive bases can be paired and that mismatch correction is most efficient near the invading end of the recipient strand.
- Ranjith Anand
- , Annette Beach
- & James Haber
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Letter |
Somatic mutations reveal asymmetric cellular dynamics in the early human embryo
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
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Article |
Prevalence and architecture of de novo mutations in developmental disorders
Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.
- Jeremy F. McRae
- , Stephen Clayton
- & Matthew E. Hurles
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Letter |
Formation of new chromatin domains determines pathogenicity of genomic duplications
Genomic duplications in the SOX9 region are associated with human disease phenotypes; a study using human cells and mouse models reveals that the duplications can cause the formation of new higher-order chromatin structures called topologically associated domains (TADs) thereby resulting in changes in gene expression.
- Martin Franke
- , Daniel M. Ibrahim
- & Stefan Mundlos
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Letter |
Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification
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
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Letter |
The nature of mutations induced by replication–transcription collisions
When transcription and replication machineries collide on DNA, they can cause mutations to occur in the area near the collision; these mutations are now shown to include two types—duplications/deletions within the transcription unit and base substitutions in the cis-regulatory element of gene expression.
- T. Sabari Sankar
- , Brigitta D. Wastuwidyaningtyas
- & Jue D. Wang
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Letter |
Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing
Maximum-depth sequencing (MDS), a new method of detecting extremely rare variants within a bacterial population, is used to show that mutation rates in Escherichia coli vary across the genome by at least an order of magnitude, and also to uncover mechanisms of antibiotic-induced mutagenesis.
- Justin Jee
- , Aviram Rasouly
- & Evgeny Nudler
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Letter |
Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes
Analysis of 1,161 cancer genomes across 14 cancer types shows that increased mutation density at gene promoters can be linked to transcription initiation activity and impairment of nucleotide excision repair.
- Dilmi Perera
- , Rebecca C. Poulos
- & Jason W. H. Wong
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Letter |
Nucleotide excision repair is impaired by binding of transcription factors to DNA
An analysis of cancer genomic data reveals an increased rate of somatic mutations at active transcription factor binding sites located both within promoter regions and distal from genes; the increased mutation rate at these genomic regions can be explained by reduced accessibility of the protein-bound DNA to nucleotide excision repair machinery.
- Radhakrishnan Sabarinathan
- , Loris Mularoni
- & Núria López-Bigas
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Letter |
Parent–progeny sequencing indicates higher mutation rates in heterozygotes
Mutation rates vary within genomes; here, by calling mutation events directly using a parent–offspring sequencing strategy in Arabidopsis, replicated in the rice and honey bee genomes, mutation rates are found to be higher in heterozygotes and in proximity to crossover events.
- Sihai Yang
- , Long Wang
- & Dacheng Tian
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Article |
Chromothripsis from DNA damage in micronuclei
The mechanism for chromothripsis, “shattered” chromosomes that can be observed in cancer cells, is unknown; here, using live-cell imaging and single-cell sequencing, chromothripsis is shown to occur after a chromosome is isolated into a micronucleus, an abnormal nuclear structure.
- Cheng-Zhong Zhang
- , Alexander Spektor
- & David Pellman
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Article |
Quantitative evolutionary dynamics using high-resolution lineage tracking
Random DNA barcodes were used to simultaneously track hundreds of thousands of lineages in large cell populations, revealing deterministic dynamics early in their evolution.
- Sasha F. Levy
- , Jamie R. Blundell
- & Gavin Sherlock
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Letter |
Differential DNA mismatch repair underlies mutation rate variation across the human genome
An analysis of how regional mutation rates vary across 652 tumours identifies variable DNA mismatch repair as the basis of the characteristic regional variation in mutation rates seen across the human genome; the results show that differential DNA repair, rather than differential mutation supply, is likely to be the primary cause of this variation.
- Fran Supek
- & Ben Lehner
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Article |
Lagging-strand replication shapes the mutational landscape of the genome
The emRiboSeq sequencing method is used to track polymerase activity genome-wide in vivo; despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo and comprises ∼1.5% of the genome, establishing Pol-α as an important source of genomic variability and providing a mechanism for site-specific variation in nucleotide substitution rates.
- Martin A. M. Reijns
- , Harriet Kemp
- & Martin S. Taylor
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Letter |
Migrating bubble during break-induced replication drives conservative DNA synthesis
This paper demonstrates that the mechanism of break-induced replication (BIR) is significantly different from S-phase replication, as it proceeds via a migrating bubble driven by Pif1 helicase, results in conservative inheritance of newly synthesized DNA, and is inherently mutagenic.
- Natalie Saini
- , Sreejith Ramakrishnan
- & Anna Malkova
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Letter |
Germline mitochondrial DNA mutations aggravate ageing and can impair brain development
Mutations in mitochondrial DNA (mtDNA) accumulate at a higher rate than mutations in nuclear DNA, and although somatic mtDNA mutations are known to be involved in mammalian ageing, the role of germline mutations in this process is unclear: here germline-transmitted mtDNA mutations are shown to be associated with ageing and brain malformations, and maternally transmitted mtDNA mutations may thus influence both development and ageing.
- Jaime M. Ross
- , James B. Stewart
- & Nils-Göran Larsson
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Research Highlights |
When neurons mature too early
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Letter |
The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity
Using separation-of-function mutations of TPP1 that inhibit telomerase binding while maintaining telomere capping, a region on the surface of TPP1, the TEL patch, is identified and found to be required for both binding telomerase and enhancing its processivity.
- Jayakrishnan Nandakumar
- , Caitlin F. Bell
- & Thomas R. Cech