scholarly journals LFMD: detecting low-frequency mutations in high-depth genome sequencing data without molecular tags

2019 ◽  
Author(s):  
Rui Ye ◽  
Xuehan Zhuang ◽  
Jie Ruan ◽  
Yanwei Qi ◽  
Yitai An ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Low Frequency ◽  
Sequencing Data ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Drug Resistance Prediction ◽  
Theory Of Aging ◽  
Mitochondrial Heterogeneity ◽  
Duplex Sequencing ◽  
Next Generation Sequencing Ngs

AbstractAs next-generation sequencing (NGS) and liquid biopsy become more prevalent in research and in the clinic, there is an increasing need for better methods to reduce cost and improve sensitivity and specificity of low-frequency mutation detection (where the Alternative Allele Frequency, or AAF, is less than 1%). Here we propose a likelihood-based approach, called Low-Frequency Mutation Detector (LFMD), which combines the advantages of duplex sequencing (DS) and the bottleneck sequencing system (BotSeqS) to maximize the utilization of duplicate reads. Compared with the existing state-of-the-art methods, DS, Du Novo, UMI-tools, and Unified Consensus Maker, our method achieves higher sensitivity, higher specificity (< 4 × 10−10 errors per base sequenced) and lower cost (reduced by ~70% at best) without involving additional experimental steps, customized adapters or molecular tags. LFMD is useful in areas where high precision is required, such as drug resistance prediction and cancer screening. As an example of LFMD’s applications, mitochondrial heterogeneity analysis of 28 human brain samples across different stages of Alzheimer’s Disease (AD) showed that the canonical oxidative damage related mutations, C:G>A:T, are significantly increased in the mid-stage group. This is consistent with the Mitochondrial Free Radical Theory of Aging, suggesting that AD may be linked to the aging of brain cells induced by oxidative damage.

scholarly journals The Exacerbation of Aging and Oxidative Stress in the Epididymis of Sod1 Null Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 151 ◽  
Author(s):  
Anaīs Noblanc ◽  
Alicia Klaassen ◽  
Bernard Robaire
Keyword(s):  
Oxidative Damage ◽  
Oxygen Species ◽  
Superoxide Dismutase 1 ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Theory Of Aging ◽  
Accumulation Of Damage ◽  
Effects Of Aging ◽  
And Oxidative Stress

There is growing evidence that the quality of spermatozoa decreases with age and that children of older fathers have a higher incidence of birth defects and genetic mutations. The free radical theory of aging proposes that changes with aging are due to the accumulation of damage induced by exposure to excess reactive oxygen species. We showed previously that absence of the superoxide dismutase 1 (Sod1) antioxidant gene results in impaired mechanisms of repairing DNA damage in the testis in young Sod1−/− mice. In this study, we examined the effects of aging and the Sod−/− mutation on mice epididymal histology and the expression of markers of oxidative damage. We found that both oxidative nucleic acid damage (via 8-hydroxyguanosine) and lipid peroxidation (via 4-hydroxynonenal) increased with age and in Sod1−/− mice. These findings indicate that lack of SOD1 results in an exacerbation of the oxidative damage accumulation-related aging phenotype.

scholarly journals Increased yields of duplex sequencing data by a series of quality control tools

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Gundula Povysil ◽  
Monika Heinzl ◽  
Renato Salazar ◽  
Nicholas Stoler ◽  
Anton Nekrutenko ◽  
...  
Keyword(s):  
Low Frequency ◽  
Variant Calling ◽  
Data Loss ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Consensus Sequences ◽  
Sequencing Errors ◽  
Data Output ◽  
Reverse Strand ◽  
Duplex Sequencing

Abstract Duplex sequencing is currently the most reliable method to identify ultra-low frequency DNA variants by grouping sequence reads derived from the same DNA molecule into families with information on the forward and reverse strand. However, only a small proportion of reads are assembled into duplex consensus sequences (DCS), and reads with potentially valuable information are discarded at different steps of the bioinformatics pipeline, especially reads without a family. We developed a bioinformatics toolset that analyses the tag and family composition with the purpose to understand data loss and implement modifications to maximize the data output for the variant calling. Specifically, our tools show that tags contain polymerase chain reaction and sequencing errors that contribute to data loss and lower DCS yields. Our tools also identified chimeras, which likely reflect barcode collisions. Finally, we also developed a tool that re-examines variant calls from raw reads and provides different summary data that categorizes the confidence level of a variant call by a tier-based system. With this tool, we can include reads without a family and check the reliability of the call, that increases substantially the sequencing depth for variant calling, a particular important advantage for low-input samples or low-coverage regions.

scholarly journals Effects of Caloric Restriction on Cardiac Oxidative Stress and Mitochondrial Bioenergetics: Potential Role of Cardiac Sirtuins

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Ken Shinmura
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Oxidative Damage ◽  
Caloric Restriction ◽  
Functional Decline ◽  
Cellular Damage ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Stress Theory

The biology of aging has not been fully clarified, but the free radical theory of aging is one of the strongest aging theories proposed to date. The free radical theory has been expanded to the oxidative stress theory, in which mitochondria play a central role in the development of the aging process because of their critical roles in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function associated with the accumulation of oxidative damage might be responsible, at least in part, for the decline in cardiac performance with age. In contrast, lifelong caloric restriction can attenuate functional decline with age, delay the onset of morbidity, and extend lifespan in various species. The effect of caloric restriction appears to be related to a reduction in cellular damage induced by reactive oxygen species. There is increasing evidence that sirtuins play an essential role in the reduction of mitochondrial oxidative stress during caloric restriction. We speculate that cardiac sirtuins attenuate the accumulation of oxidative damage associated with age by modifying specific mitochondrial proteins posttranscriptionally. Therefore, the distinct role of each sirtuin in the heart subjected to caloric restriction should be clarified to translate sirtuin biology into clinical practice.

scholarly journals A midlife crisis for the mitochondrial free radical theory of aging

2014 ◽  
Vol 3 (1) ◽  
Author(s):  
Jeffrey A Stuart ◽  
Lucas A Maddalena ◽  
Max Merilovich ◽  
Ellen L Robb
Keyword(s):  
Free Radical ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Midlife Crisis ◽  
Theory Of Aging

The inflammatory process in aging

2000 ◽  
Vol 10 (3) ◽  
pp. 207-222 ◽  
Author(s):  
Hae Young Chung ◽  
Hyon Jeen Kim ◽  
Kyung Jin Jung ◽  
Ji Sung Yoon ◽  
Mi Ae Yoo ◽  
...  
Keyword(s):  
Free Radical ◽  
Inflammatory Process ◽  
Redox State ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Functional Changes ◽  
Related Disease ◽  
Progressive Loss ◽  
Theory Of Aging ◽  
Aging Phenomena

Aging processes are time-dependent, deteriorative functional changes. These functional changes lead to a progressive loss of the organism’s ability to withstand both internal and environmental stresses, causing the failure of cellular homeostasis. Among the modern hypotheses, the ‘Oxidative Stress Hypothesis’ offers the best mechanistic elucidation of aging phenomena. Based on the ‘Free Radical Theory of Aging’, this hypothesis has gained popularity among researchers in the field of gerontology as well as other biomedical fields. Its primary premise proposes that aging and its related disease processes are the net result of free radical-induced damage, asserting further that an organism’s inability to produce counterbalancing antioxidative defences, i.e. defences that offset disturbances in the redox state, underlies its cause.

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