scholarly journals Contrasting determinants of mutation rates in germline and soma

2017 ◽  
Author(s):  
Chen Chen ◽  
Hongjian Qi ◽  
Yufeng Shen ◽  
Joseph Pickrell ◽  
Molly Przeworski
Keyword(s):  
Somatic Mutations ◽  
Gc Content ◽  
Replication Timing ◽  
Germline Mutations ◽  
Mutation Rates ◽  
Coding Region ◽  
Expression Levels ◽  
Strand Asymmetry ◽  
Number Of Factors ◽  
Somatic Tissues

AbstractRecent studies of somatic and germline mutations have led to the identification of a number of factors that influence point mutation rates, including CpG methylation, expression levels, replication timing and GC content. Intriguingly, some of the effects appear to differ between soma and germline: in particular, whereas mutation rates have been reported to decrease with expression levels in tumors, no clear effect has been detected in the germline. Distinct approaches were taken to analyze the data, however, so it is hard to know whether these apparent differences are real. To enable a cleaner comparison, we considered a statistical model in which the mutation rate of a coding region is predicted by GC content, expression levels, replication timing, and two histone repressive marks. We applied this model to both a set of germline mutations identified in exomes and to exonic somatic mutations in four types of tumors. Germline and soma share most determinants of mutations; notably, we detected an effect of expression levels on germline mutations as well as on somatic ones. However, whereas in somatic tissues, increased expression levels are associated with greater strand asymmetry and decreased mutation rates, in ovaries and testes, increased expression leads to greater strand asymmetry but increased mutation rates. This contrast points to differences in damage or repair rates during transcription in soma and germline.

scholarly journals Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression

2013 ◽  
Vol 98 (12) ◽  
pp. E2013-E2021 ◽  
Author(s):  
Maki Fukami ◽  
Takayoshi Tsuchiya ◽  
Heike Vollbach ◽  
Kristy A. Brown ◽  
Shuji Abe ◽  
...  
Keyword(s):  
Gc Content ◽  
Replication Timing ◽  
Nonhomologous End Joining ◽  
Coding Region ◽  
End Joining ◽  
Clinical Consequences ◽  
Underlying Mechanisms ◽  
Nonallelic Homologous Recombination ◽  
Genomic Disorders ◽  
Flanking Regions

Context: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. Objective: The aim of the study was to clarify such unsolved matters. Design, Setting, and Methods: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. Results: Novel rearrangements included simple duplication involving exons 1–10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, nonhomologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement-associated motifs. The rearrangements resided in early-replicating segments. Conclusions: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

scholarly journals Mutation bias shapes gene evolution in Arabidopsis thaliana

2020 ◽  
Author(s):  
J. Grey Monroe ◽  
Thanvi Srikant ◽  
Pablo Carbonell-Bejerano ◽  
Moises Exposito-Alonso ◽  
Mao-Lun Weng ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
De Novo ◽  
Gene Evolution ◽  
Gc Content ◽  
Mutation Rates ◽  
Rate Variation ◽  
Recent Theory ◽  
De Novo Mutations ◽  
Coding Region ◽  
Mutational Hotspots

Classical evolutionary theory maintains that mutation rate variation between genes should be random with respect to fitness 1–4 and evolutionary optimization of genic mutation rates remains controversial 3,5. However, it has now become known that cytogenetic (DNA sequence + epigenomic) features influence local mutation probabilities 6, which is predicted by more recent theory to be a prerequisite for beneficial mutation rates between different classes of genes to readily evolve 7. To test this possibility, we used de novo mutations in Arabidopsis thaliana to create a high resolution predictive model of mutation rates as a function of cytogenetic features across the genome. As expected, mutation rates are significantly predicted by features such as GC content, histone modifications, and chromatin accessibility. Deeper analyses of predicted mutation rates reveal effects of introns and untranslated exon regions in distancing coding sequences from mutational hotspots at the start and end of transcribed regions in A. thaliana. Finally, predicted coding region mutation rates are significantly lower in genes where mutations are more likely to be deleterious, supported by numerous estimates of evolutionary and functional constraint. These findings contradict neutral expectations that mutation probabilities are independent of fitness consequences. Instead they are consistent with the evolution of lower mutation rates in functionally constrained loci due to cytogenetic features, with important implications for evolutionary biology8.

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

scholarly journals Nucleotide excision repair is impaired by binding of transcription factors to DNA

2015 ◽  
Author(s):  
Radhakrishnan Sabarinathan ◽  
Loris Mularoni ◽  
Jordi Deu-Pons ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Nucleotide Excision Repair ◽  
Mutation Rate ◽  
Binding Sites ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Replication Timing ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Nucleotide Excision ◽  
Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

scholarly journals Periodic variation of mutation rates in bacterial genomes associated with replication timing

2017 ◽  
Author(s):  
Marcus M. Dillon ◽  
Way Sung ◽  
Michael Lynch ◽  
Vaughn S. Cooper
Keyword(s):  
Vibrio Fischeri ◽  
Bacterial Species ◽  
Replication Timing ◽  
Small Chromosome ◽  
Burkholderia Cenocepacia ◽  
Mutation Rates ◽  
Base Substitution ◽  
Large Chromosome ◽  
Bacterial Genomes ◽  
Substitution Mutation

ABSTRACTThe causes and consequences of spatiotemporal variation in mutation rates remains to be explored in nearly all organisms. Here we examine relationships between local mutation rates and replication timing in three bacterial species whose genomes have multiple chromosomes:Vibrio fischeri, Vibrio cholerae, andBurkholderia cenocepacia. Following five evolution experiments with these bacteria conducted in the near-absence of natural selection, the genomes of clones from each lineage were sequenced and analyzed to identify variation in mutation rates and spectra. In lineages lacking mismatch repair, base-substitution mutation rates vary in a mirrored wave-like pattern on opposing replichores of the large chromosome ofV. fischeriandV. cholerae, where concurrently replicated regions experience similar base-substitution mutation rates. The base-substitution mutation rates on the small chromosome are less variable in both species but occur at similar rates as the concurrently replicated regions of the large chromosome. Neither nucleotide composition nor frequency of nucleotide motifs differed among regions experiencing high and low base-substitution rates, which along with the inferred ~800 Kb wave period suggests that the source of the periodicity is not sequence-specific but rather a systematic process related to the cell cycle. These results support the notion that base-substitution mutation rates are likely to vary systematically across many bacterial genomes, which exposes certain genes to elevated deleterious mutational load.

scholarly journals In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas

2013 ◽  
Vol 20 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Rodrigo A Toledo ◽  
Yuejuan Qin ◽  
Subramanya Srikantan ◽  
Nicole Paes Morales ◽  
Qun Li ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Target Genes ◽  
Germline Mutations ◽  
Vascular Tumors ◽  
Wild Type ◽  
Pheochromocytoma Pc12 ◽  
Hereditary Tumors ◽  
Tumor Dna

Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.

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