scholarly journals Identification and characterization of base-substitution mutations in the macronuclear genome of the ciliate Tetrahymena thermophila

2020 ◽  
Author(s):  
Guangying Wang ◽  
Lu Fu ◽  
Jie Xiong ◽  
Kazufumi Mochizuki ◽  
Yunxin Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Tetrahymena Thermophila ◽  
Repetitive Sequences ◽  
Primary Source ◽  
Base Substitution ◽  
De Novo Mutations ◽  
Molecular Features ◽  
Substitution Mutations ◽  
Evolving Populations

Abstract Polyploidy can provide adaptive advantages and drive evolution. Amitotic division of the polyploid macronucleus (MAC) in ciliates acts as a non-sexual genetic mechanism to enhance adaptation to stress conditions and thus provides a unique model to investigate the evolutionary role of polyploidy. Mutation is the primary source of the variation responsible for evolution and adaptation; however, to date, de novo mutations that occur in ciliate MAC genomes during these processes have not been characterized and their biological impacts are undefined. Here, we carried out long-term evolution experiments to directly explore de novo MAC mutations and their molecular features in the model ciliate, Tetrahymena thermophila. A simple but effective method was established to detect base-substitution mutations in evolving populations while filtering out most of the false positive base-substitutions caused by repetitive sequences and the programmed genome rearrangements. The detected mutations were rigorously validated using the MassARRAY system. Validated mutations showed a strong G/C→A/T bias, consistent with observations in other species. Moreover, a progressive increase in growth rate of the evolving populations suggested that some of these mutations might be responsible for cell fitness. The established mutation identification and validation methods will be an invaluable resource to make ciliates an important model system to study the role of polyploidy in evolution.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
MS Oud ◽  
RM Smits ◽  
HE Smith ◽  
FK Mastrorosa ◽  
GS Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

scholarly journals Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse

2007 ◽  
Vol 16 (19) ◽  
pp. 2272-2280 ◽  
Author(s):  
Yuzuru Kato ◽  
Masahiro Kaneda ◽  
Kenichiro Hata ◽  
Kenji Kumaki ◽  
Mizue Hisano ◽  
...  
Keyword(s):  
Germ Cell ◽  
De Novo ◽  
Repetitive Sequences ◽  
Cell Development ◽  
Male Germ Cell ◽  
Germ Cell Development ◽  
De Novo Methylation

scholarly journals New insights into the generation and role of de novo mutations in health and disease

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Rocio Acuna-Hidalgo ◽  
Joris A. Veltman ◽  
Alexander Hoischen
Keyword(s):  
De Novo ◽  
De Novo Mutations ◽  
Health And Disease

scholarly journals Role of the dinB Gene Product in Spontaneous Mutation in Escherichia coli with an Impaired Replicative Polymerase

2000 ◽  
Vol 182 (23) ◽  
pp. 6742-6750 ◽  
Author(s):  
B. S. Strauss ◽  
R. Roberts ◽  
L. Francis ◽  
P. Pouryazdanparast
Keyword(s):  
Escherichia Coli ◽  
Mismatch Repair ◽  
Spontaneous Mutation ◽  
Luria Bertani ◽  
Base Substitution ◽  
Temperature Sensitive ◽  
Selection Scheme ◽  
Mutator Effect ◽  
Substitution Mutations

ABSTRACT We isolated several new mutator mutations of the Escherichia coli replicative polymerase dnaE subunit alpha and used them and a previously reported dnaE mutation to study spontaneous frameshift and base substitution mutations. Two of thesednaE strains produce many more mutants when grown on rich (Luria-Bertani) than on minimal medium. A differential effect of the medium was not observed when these dnaE mutations were combined with a mismatch repair mutation. The selection scheme for thednaE mutations required that they be able to complement a temperature-sensitive strain. However, the ability to complement is not related to the mutator effect for at least one of the mutants. Comparison of the mutation rates for frameshift and base substitution mutations in mutS and dnaE mutS strains suggests that the mismatch repair proteins respond differently to the two types of change. Deletion of dinB from both chromosome and plasmid resulted in a four- to fivefold decrease in the rate of frameshift and base substitution mutations in a dnaE mutSdouble mutant background. This reduction indicates that most mistakes in replication occur as a result of the action of the auxiliary rather than the replicative polymerase in this dnaE mutant. Deletion of dinB from strains carrying a wild-typednaE had a measurable effect, suggesting that a fraction of spontaneous mutations occur as a result of dinB polymerase action even in cells with a normal replicative polymerase.

scholarly journals Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders

2021 ◽  
pp. jmedgenet-2020-107459
Author(s):  
Eduardo Calpena ◽  
Maud Wurmser ◽  
Simon J McGowan ◽  
Rodrigo Atique ◽  
Débora R Bertola ◽  
...  
Keyword(s):  
De Novo ◽  
Population Data ◽  
Cranial Sutures ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Data Enrichment ◽  
Whole Exome ◽  
Lambdoid Synostosis ◽  
Suture Fusion

BackgroundPathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported.MethodsWe investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse.ResultsFrom 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme.ConclusionCraniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.

scholarly journals A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA

2021 ◽  
Author(s):  
Monica Sanchez-Contreras ◽  
Mariya T Sweetwyne ◽  
Brendan F Kohrn ◽  
Kristine A Tsantilas ◽  
Michael J Hipp ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Mutations ◽  
De Novo ◽  
Primary Source ◽  
Regulatory Elements ◽  
Genome Replication ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Genome Composition ◽  
Mtdna Mutations

Abstract Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational ‘hot-spots’ or ‘cold-spots’. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.

scholarly journals Rare Variants in Complex Traits: Novel Identification Strategies and the Role of de novo Mutations

2012 ◽  
Vol 74 (3-4) ◽  
pp. 215-225 ◽  
Author(s):  
Loubna Jouan ◽  
Julie Gauthier ◽  
Patrick A. Dion ◽  
Guy A. Rouleau
Keyword(s):  
Complex Traits ◽  
Rare Variants ◽  
De Novo ◽  
De Novo Mutations

The Autism Spectrum

2018 ◽  
pp. 243-260
Author(s):  
Marco Del Giudice
Keyword(s):  
Risk Factors ◽  
De Novo ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Evolutionary Models ◽  
De Novo Mutations ◽  
Life History Variation ◽  
New Directions ◽  
Developmental Features

The chapter discusses autism spectrum disorder (ASD). Autism is defined by a triad of symptoms: impairments in social interaction, impairments in communication, and restricted/repetitive behaviors and interests. After an overview of this disorder, its developmental features, and the main risk factors identified in the epidemiological literature, the chapter critically reviews existing evolutionary models and suggests new directions for research. The final section applies the criteria developed earlier in the book to classify the disorder within the fast-slow-defense (FSD) model and identify functionally distinct subtypes. The author proposes to distinguish between a slow spectrum subtype with normal or high IQ and a major role of common alleles (S-ASD) and a subtype unrelated to life history variation, with high rates of intellectual disability and a major role of rare and de novo mutations (O-ASD).

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