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| Open AccessA mutational atlas for Parkin proteostasis
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
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Article
| Open AccessNAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD+ depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.
- Liang Yang
- , Zifeng Ruan
- & Xingguo Liu
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Article
| Open AccessPIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome
PIEZO1 is a mechanosensitive ion channel. Here, authors identify PIEZO1 human mutations in Prune Belly Syndrome. At a single molecule level these mutations exhibit loss-of-function characteristics.
- Nathalia G. Amado
- , Elena D. Nosyreva
- & Ruhma Syeda
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| Open AccessiMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis
DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
- Aldo S. Bader
- & Martin Bushell
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Article
| Open AccessSaturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation
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
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Article
| Open AccessMutational spectra are associated with bacterial niche
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
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Article
| Open AccessGenome-wide probing of eukaryotic nascent RNA structure elucidates cotranscriptional folding and its antimutagenic effect
Here, the authors present eSPET-seq a method to measure cotranscriptional RNA folding in eukaryotes. Further analysis reveals an antimutagenic effect of nascent RNA folding and contribution to the variability of local mutation rates across the yeast genome.
- Gongwang Yu
- , Yao Liu
- & Jian-Rong Yang
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Article
| Open AccessDeep structured learning for variant prioritization in Mendelian diseases
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
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Article
| Open AccessDiscovering functionally important sites in proteins
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
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Article
| Open AccessSequence variants affecting the genome-wide rate of germline microsatellite mutations
Microsatellites are tandem repeats of short DNA motifs and represent some of the most polymorphic sites in the genome. Here, the authors report that the human germline microsatellite mutation rate is, in part, under genetic control.
- Snaedis Kristmundsdottir
- , Hakon Jonsson
- & Kari Stefansson
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Article
| Open AccessOncogenic structural aberration landscape in gastric cancer genomes
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
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Article
| Open AccessCancer genomes tolerate deleterious coding mutations through somatic copy number amplifications of wild-type regions
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
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Article
| Open AccessContributions of replicative and translesion DNA polymerases to mutagenic bypass of canonical and atypical UV photoproducts
Vandenberg et al. identify differing roles of yeast DNA polymerases during accurate and mutagenic synthesis past common and rare ultraviolet light photoproducts. Similar mechanisms may contribute to driver mutations causing skin cancer in humans.
- Brittany N. Vandenberg
- , Marian F. Laughery
- & Steven A. Roberts
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Article
| Open AccessSequence terminus dependent PCR for site-specific mutation and modification detection
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
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| Open AccessDeciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak
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
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| Open AccessA method to build extended sequence context models of point mutations and indels
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
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Article
| Open AccessSomatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer
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
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| Open AccessSystematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data
This paper proposed a novel in-silico framework for automatically screening disease-related variants and applied it to over 200,000 transcriptomes, providing an example to acquire medically relevant knowledge from publicly available sequence data.
- Yuichi Shiraishi
- , Ai Okada
- & Akihide Yoshimi
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Article
| Open AccessGermline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
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
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| Open AccessRapid evolution of mutation rate and spectrum in response to environmental and population-genetic challenges
How rapidly the mutation rate responds evolutionarily to ecological and population-genetic factors over time is unclear. Here, the authors show that the evolution of mutation rates in E. coli proceeds rapidly in response to these factors with substantial bidirectional shifts.
- Wen Wei
- , Wei-Chin Ho
- & Michael Lynch
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| Open AccessLoss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure
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
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| Open AccessTransient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice
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
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| Open AccessA rare variant analysis framework using public genotype summary counts to prioritize disease-predisposition genes
Sequencing studies in clinical and cancer genomics often utilize public data sets to identify genes enriched with pathogenic variants. Here, the authors propose a framework which controls for confounding factors that can bias the results in these studies.
- Wenan Chen
- , Shuoguo Wang
- & Gang Wu
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Article
| Open AccessSomatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy
Here the authors show that elimination of germ cells carrying damaged genomes is regulated by intestinal stress signalling in nematodes. Failure of the intestinal signalling results in stress-induced aneuploidy indicating that environmental stress impacts inheritance.
- Najmeh Soltanmohammadi
- , Siyao Wang
- & Björn Schumacher
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Article
| Open AccessHelicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications
Microhomology-mediated end-joining (MMEJ) is a poorly defined mutagenic DNA break repair pathway. Here the authors show that the helicase HELQ is essential for polymerase theta-independent MMEJ, single-strand annealing and homologous recombination through synthesis dependent strand annealing in C. elegans.
- J. A. Kamp
- , B. B. L. G. Lemmens
- & M. Tijsterman
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Article
| Open AccessSomatic genetic rescue of a germline ribosome assembly defect
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
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| Open AccessDNA transposons mediate duplications via transposition-independent and -dependent mechanisms in metazoans
Transposons are accepted as evolutionary catalysts but how they do so remains less clear. Analyzing 100 animal genomes finds that terminal inverted repeat-type transposable elements catalyze new gene structures and new genes in animals via both transposition-independent and -dependent mechanisms.
- Shengjun Tan
- , Huijing Ma
- & Yong E. Zhang
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| Open AccessThe rate and molecular spectrum of mutation are selectively maintained in yeast
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
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Article
| Open AccessBRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
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
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| Open AccessClonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
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
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| Open AccessMVP predicts the pathogenicity of missense variants by deep learning
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
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Article
| Open AccessPrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts
Bulky DNA adducts are important replication-blocking lesions. Here the authors reveal that homologous recombination at bulky adducts in mammalian cells involves post-replicative gap repair in a PrimPol dependent manner.
- Ann Liza Piberger
- , Akhil Bowry
- & Eva Petermann
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Article
| Open AccessBiophysical ambiguities prevent accurate genetic prediction
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
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Article
| Open AccessLarge-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
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
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| Open AccessA pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response
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
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Article
| Open AccessEthanol exposure increases mutation rate through error-prone polymerases
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
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| Open AccessMutations in COMP cause familial carpal tunnel syndrome
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
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Article
| Open AccessBRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining
Cancer mutational signatures have been associated with defects in genome maintenance pathways. Here the authors, by using a worm germline mutagenesis model defective of human orthologue BRCA-1, identify polymerase theta-mediated end-joining (TMEJ) as causing the BRCAness mutational signature.
- J. A. Kamp
- , R. van Schendel
- & M. Tijsterman
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Article
| Open AccessExtreme differences between human germline and tumor mutation densities are driven by ancestral human-specific deviations
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
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| Open AccessThe mutational impact of culturing human pluripotent and adult stem cells
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
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Article
| Open AccessSomatic SF3B1 hotspot mutation in prolactinomas
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
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Article
| Open AccessNitrogen starvation reveals the mitotic potential of mutants in the S/MAPK pathways
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
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Article
| Open AccessNucleosome positioning stability is a modulator of germline mutation rate variation across the human genome
Nucleosome organization has been suggested to affect local mutation rates in the genome. Here, the authors analyse data on >300,000 human de novo mutations and high-resolution nucleosome maps and provide evidence that nucleosome positioning stability modulates germline mutation rate variation across the human genome.
- Cai Li
- & Nicholas M. Luscombe
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Article
| Open AccessDigenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome
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
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Article
| Open AccessTissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant
TP53 mutations can cause increased risk for cancers. Here, the authors show a noncoding polymorphism in TP53 increases risk of some cancers but delays onset of others, and in a mouse model show this is via alteration of microRNA targeting sites that differ in impact depending on the tissue.
- Qipan Deng
- , Hui Hu
- & Yong Li
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Article
| Open AccessIntronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
- Mark A. Corbett
- , Thessa Kroes
- & Jozef Gecz
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Article
| Open AccessContribution of retrotransposition to developmental disorders
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
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Article
| Open AccessExtensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations
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
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Article
| Open AccessSimilarities and differences in patterns of germline mutation between mice and humans
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