scholarly journals APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

2016 ◽  
Author(s):  
Vladimir B. Seplyarskiy ◽  
Maria A. Andrianova ◽  
Georgii A. Bazykin
Keyword(s):  
Human Population ◽  
De Novo ◽  
Cytidine Deaminase ◽  
Large Fraction ◽  
Induced Mutations ◽  
De Novo Mutations ◽  
Translesion Bypass ◽  
Induced Mutagenesis ◽  
Cancerous Cells ◽  
Lagging Strand

AbstractAPOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most of APOBEC3A/B-induced mutations occur on the lagging strand during replication. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis, and analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strand-coordinated clusters, which are also biased towards the lagging strand. Finally, we show that the mutation rate is increased 3’ of C→G mutations to a greater extent than 3’ of C→T mutations, suggesting pervasive translesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C→T and C→G mutations segregating as polymorphisms in human population are attributable to APOBEC3A/B activity.

Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes

CNS Spectrums ◽  
2002 ◽  
Vol 7 (1) ◽  
pp. 26-29 ◽  
Author(s):  
Dolores Malaspina ◽  
Alan Brown ◽  
Deborah Goetz ◽  
Nelly Alia-Klein ◽  
Jill Harkavy-Friedman ◽  
...  
Keyword(s):  
Human Population ◽  
Potential Role ◽  
De Novo ◽  
Paternal Age ◽  
Current Evidence ◽  
Parental Age ◽  
De Novo Mutations ◽  
New Mutations

ABSTRACTHow schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

scholarly journals Estimating error models for whole genome sequencing using mixtures of Dirichlet-multinomial distributions

2015 ◽  
Author(s):  
Steven H Wu ◽  
Rachel S Schwartz ◽  
David J Winter ◽  
Don Conrad ◽  
Reed A Cartwright
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Large Fraction ◽  
Minor Component ◽  
Read Depth ◽  
Sequencing Error ◽  
De Novo Mutations ◽  
Accurate Identification ◽  
Component Distribution ◽  
Reference Bias

Motivation: Accurate identification of genotypes is critical in identifying de novo mutations, linking mutations with disease, and determining mutation rates. Because de novo mutations are rare, even low levels of genotyping error can cause a large fraction of false positive de novo mutations. Biological and technical processes that adversely affect genotyping include copy-number-variation, paralogous sequences, library preparation, sequencing error, and reference-mapping biases, among others. Results: We modeled the read depth for all data as a mixture of Dirichlet-multinomial distributions, resulting in significant improvements over previously used models. In most cases the best model was comprised of two distributions. The major-component distribution is similar to a binomial distribution with low error and low reference bias. The minor-component distribution is overdispersed with higher error and reference bias. We also found that sites fitting the minor component are enriched for copy number variants and low complexity region. We expect that this approach to modeling the distribution of NGS data, will lead to improved genotyping. For example, this approach provides an expected distribution of reads that can be incorporated into a model to estimate de novo mutations using reads across a pedigree.

scholarly journals Moderate nucleotide diversity in the Atlantic herring is associated with a low mutation rate

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Chungang Feng ◽  
Mats Pettersson ◽  
Sangeet Lamichhaney ◽  
Carl-Johan Rubin ◽  
Nima Rafati ◽  
...  
Keyword(s):  
Population Size ◽  
Mutation Rate ◽  
Nucleotide Diversity ◽  
De Novo ◽  
Large Fraction ◽  
Atlantic Herring ◽  
De Novo Mutations ◽  
High Nucleotide Diversity ◽  
Census Population Size ◽  
High Degree

The Atlantic herring is one of the most abundant vertebrates on earth but its nucleotide diversity is moderate (π = 0.3%), only three-fold higher than in human. Here, we present a pedigree-based estimation of the mutation rate in this species. Based on whole-genome sequencing of four parents and 12 offspring, the estimated mutation rate is 2.0 × 10-9 per base per generation. We observed a high degree of parental mosaicism indicating that a large fraction of these de novo mutations occurred during early germ cell development. The estimated mutation rate – the lowest among vertebrates analyzed to date – partially explains the discrepancy between the rather low nucleotide diversity in herring and its huge census population size. But a species like the herring will never reach its expected nucleotide diversity because of fluctuations in population size over the millions of years it takes to build up high nucleotide diversity.

scholarly journals Recurrence of de novo mutations in families

2017 ◽  
Author(s):  
Hákon Jónsson ◽  
Patrick Sulem ◽  
Gudny A. Arnadottir ◽  
Gunnar Pálsson ◽  
Hannes P. Eggertsson ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Large Fraction ◽  
Genetic Diseases ◽  
De Novo Mutations ◽  
Sibling Pairs ◽  
Rare Genetic Diseases ◽  
Early Embryos ◽  
Parent Of Origin ◽  
Serious Disease

ABSTRACTDe novo mutations (DNMs) cause a large fraction of severe rare diseases of childhood. DNMs that occur in early embryos may result in mosaicism of both somatic and germ cells. Such early mutations may be transmitted to more than one offspring and cause recurrence of serious disease. We scanned 1,007 sibling pairs from 251 families and identified 885 DNMs shared by siblings (ssDNMs) at 451 genomic sites. We estimated the probability of DNM recurrence based on presence in the blood of the parent, sharing by other siblings, parent-of-origin, mutation type, and genomic position. We detected 52.1% of ssDNMs in the parental blood. The probability of a DNM being shared goes down by 2.28% per year for paternal DNMs and 1.82% for maternal DNMs. Shared paternal DNMs are more likely to be T>C mutations than maternal ones, but less likely to be C>T mutations. Depending on DNM properties, the probability of recurrence in a younger sibling ranges from 0.013% to 29.6%. We have launched an online DNM recurrence probability calculator, to use in genetic counselling in cases of rare genetic diseases.

scholarly journals Elevated temperature increases genome-wide selection on de novo mutations

2021 ◽  
Vol 288 (1944) ◽  
pp. 20203094
Author(s):  
David Berger ◽  
Josefine Stångberg ◽  
Julian Baur ◽  
Richard J. Walters
Keyword(s):  
Genetic Variation ◽  
Natural Selection ◽  
Elevated Temperature ◽  
De Novo ◽  
Ecological Factors ◽  
De Novo Mutation ◽  
Induced Mutations ◽  
De Novo Mutations ◽  
Genome Wide ◽  
The Cost

Adaptation in new environments depends on the amount of genetic variation available for evolution, and the efficacy by which natural selection discriminates among this variation. However, whether some ecological factors reveal more genetic variation, or impose stronger selection pressures than others, is typically not known. Here, we apply the enzyme kinetic theory to show that rising global temperatures are predicted to intensify natural selection throughout the genome by increasing the effects of DNA sequence variation on protein stability. We test this prediction by (i) estimating temperature-dependent fitness effects of induced mutations in seed beetles adapted to ancestral or elevated temperature, and (ii) calculate 100 paired selection estimates on mutations in benign versus stressful environments from unicellular and multicellular organisms. Environmental stress per se did not increase mean selection on de novo mutation, suggesting that the cost of adaptation does not generally increase in new ecological settings to which the organism is maladapted. However, elevated temperature increased the mean strength of selection on genome-wide polymorphism, signified by increases in both mutation load and mutational variance in fitness. These results have important implications for genetic diversity gradients and the rate and repeatability of evolution under climate change.

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