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.

Parent-of-origin-specific signatures of de novo mutations

2016 ◽  
Vol 48 (8) ◽  
pp. 935-939 ◽  
Author(s):  
Jakob M Goldmann ◽  
Wendy S W Wong ◽  
Michele Pinelli ◽  
Terry Farrah ◽  
Dale Bodian ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutations ◽  
Parent Of Origin

scholarly journals Author Correction: Parent-of-origin-specific signatures of de novo mutations

2018 ◽  
Vol 50 (11) ◽  
pp. 1615-1615 ◽  
Author(s):  
Jakob M Goldmann ◽  
Wendy S W Wong ◽  
Michele Pinelli ◽  
Terry Farrah ◽  
Dale Bodian ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutations ◽  
Parent Of Origin

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.

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 Next-Generation Sequencing Technologies and Neurogenetic Diseases

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 361
Author(s):  
Hui Sun ◽  
Xiao-Rong Shen ◽  
Zi-Bing Fang ◽  
Zong-Zhi Jiang ◽  
Xiao-Jing Wei ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Single Molecule ◽  
De Novo ◽  
Neurological Diseases ◽  
Genetic Diseases ◽  
Spinocerebellar Ataxias ◽  
Next Generation ◽  
De Novo Mutations ◽  
Coverage Area ◽  
Generation Sequencing

Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.

scholarly journals Comparison of the frequencies of ENU-induced point mutations in male germ cells and inherited germline mutations in their offspring

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Kenichi Masumura ◽  
Tomoko Ando ◽  
Naomi Toyoda-Hokaiwado ◽  
Akiko Ukai ◽  
Takehiko Nohmi ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Genetic Diseases ◽  
Point Mutations ◽  
Gene Mutations ◽  
Next Generation ◽  
Male Germ Cells ◽  
Gene Coding ◽  
Whole Exome ◽  
And Control

Abstract Background Gene mutations induced in germ cells may be transmitted to the next generation and cause adverse effects such as genetic diseases. Certain mutations may result in infertility or death in early development. Thus, the mutations may not be inheritable. However, the extent to which point mutations in male germ cells are transmitted to the next generation or eliminated during transmission is largely unknown. This study compared mutation frequencies (MFs) in sperm of N-ethyl-N-nitrosourea (ENU)-treated gpt delta mice and de novo MFs in the whole exome/genome of their offspring. Results Male gpt delta mice were treated with 10, 30, and 85 mg/kg of ENU (i.p., weekly × 2) and mated with untreated females to generate offspring. We previously reported a dose-dependent increase in de novo MFs in the offspring estimated by whole exome sequencing (WES) (Mutat. Res., 810, 30–39, 2016). In this study, gpt MFs in the sperm of ENU-treated mice were estimated, and the MFs per reporter gene were converted to MFs per base pair. The inherited de novo MFs in the offspring (9, 26 and 133 × 10− 8/bp for 10, 30, and 85 mg/kg ENU-treated groups, respectively) were comparable to those of the converted gpt MFs in the sperm of ENU-treated fathers (6, 16, and 69 × 10− 8/bp). It indicated that the gpt MFs in the ENU-treated father’s sperm were comparable to the inherited de novo MFs in the offspring as estimated by WES. In addition, de novo MFs in the offspring of 10 mg/kg ENU-treated and control fathers were estimated by whole genome sequencing (WGS), because WES was not sufficiently sensitive to detect low background MF. The de novo MF in the offspring of the ENU-treated fathers was 6 × 10− 8/bp and significantly higher than that of the control (2 × 10− 8/bp). There were no significant differences in de novo MFs between gene-coding and non-coding regions. WGS analysis was able to detect ENU-induced characteristic de novo base substitutions at a low dose group. Conclusions Despite a difference between exome/genome and exogenous reporter genes, the results indicated that ENU-induced point mutations in male germ cells could be transmitted to the next generation without severe selection.

scholarly journals Male-driven de novo mutations in haploid germ cells

2013 ◽  
Vol 19 (8) ◽  
pp. 495-499 ◽  
Author(s):  
M.-C. Gregoire ◽  
J. Massonneau ◽  
O. Simard ◽  
A. Gouraud ◽  
M.-A. Brazeau ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
De Novo Mutations

scholarly journals Transcriptional and mutational signatures of the aging germline

2021 ◽  
Author(s):  
Evan Witt ◽  
Christopher B Langer ◽  
Li Zhao
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Cell Types ◽  
Mutational Load ◽  
De Novo Mutations ◽  
Genome Maintenance ◽  
Mutational Signatures ◽  
Evolutionary Innovation ◽  
Complex Biological Process ◽  
Older Males

Aging is a complex biological process which is accompanied by changes in gene expression and mutational load. In many species including humans, old fathers pass on more paternally-derived de novo mutations, however, the cellular basis and cell types driving this pattern are still unclear. To understand the root causes of this phenomenon, we performed single-cell RNA-sequencing (scRNA-seq) on testes from young and old male Drosophila, as well as genomic sequencing (DNA-seq) on somatic tissue from the same flies. We found that early germ cells from old and young flies have similar mutational loads, but older flies are less able to remove mutations during spermatogenesis. This indicates that germline mutations arise from primarily non-replicative factors, and that the increased mutational load of older males is due to differences in genome maintenance activities such as repairs to DNA damage. We also found that T>A mutations are enriched in older flies, and transcription-related enrichment terms are depleted in older males. Early spermatogenesis-enriched genes have lower dN/dS than late spermatogenesis-enriched genes, supporting the hypothesis that late spermatogenesis is the source of evolutionary innovation. This transcriptional disruption is reflected in the decreased expression of genome maintenance genes in early germ cells of older flies, as well as potentially aberrant transcription of transposable elements in the aging germline. Our results provide novel insights into the transcriptional and mutational signatures of the male germline.

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