An Epigenetic Aging Clock for Cattle Using Portable Sequencing Technology.
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ABSTRACT:
SUBMITTER: Hayes BJ
PROVIDER: S-EPMC8637324 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceNeighborhood deprivation is associated with age-related disease, mortality, and reduced life expectancy. However, biological pathways underlying these associations are not well understood.ObjectiveTo evaluate the association between neighborhood deprivation and epigenetic measures of age acceleration and genome-wide methylation.Design, setting, and participantsThis cross-sectional study used data from the Sister Study, a prospective cohort study comprising 50 884 women living in the US and Puerto Rico aged 35 to 74 years at enrollment who had a sister with breast cancer but had not had breast cancer themselves. Cohort enrollment occurred between July 2003 and March 2009. Participants completed a computer-assisted telephone interview on demographic, socioeconomic, lifestyle, and residential factors and provided anthropometric measures and peripheral blood samples at a home examination. DNA methylation data obtained for 2630 non-Hispanic White women selected for a case-cohort study in 2014 were used in this cross-sectional analysis. DNA methylation was measured using the HumanMethylation450 BeadChips in whole blood samples collected at baseline. Data analysis for this study was performed from October 17, 2019, to August 27, 2020.ExposuresEach participants' primary address was linked to an established index of neighborhood deprivation.Main outcomes and measuresEpigenetic age was estimated using 4 epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge). Age acceleration was determined using residuals from regressing chronologic age on each of the 4 epigenetic age metrics. Linear regression was used to estimate associations between neighborhood deprivation and epigenetic age acceleration as well as DNA methylation at individual cytosine-guanine sites across the genome.ResultsMean (SD) age of the 2630 participants was 56.9 (8.7) years. Those with the greatest (>75th percentile) vs least (≤25th percentile) neighborhood deprivation had higher epigenetic age acceleration estimated by Hannum (β = 0.23; 95% CI, 0.01-0.45), PhenoAge (β = 0.28; 95% CI, 0.06-.50), and GrimAge (β = 0.37; 95% CI, 0.12-0.62). Increasing US quartiles of neighborhood deprivation exhibited a trend with Hannum, PhenoAge, and GrimAge. For example, GrimAge showed a significant dose-response (P test for trend <.001) as follows: level 2 vs level 1 (β = 0.30; 95% CI, 0.17-0.42), level 3 vs level 1 (β = 0.35; 95% CI, 0.19-0.50), and level 4 vs level 1 (β = 0.37; 95% CI, 0.12-0.62). Neighborhood deprivation was found to be associated with 3 cytosine-phosphate-guanine sites, with 1 of these annotated to a known gene MAOB (P = 9.71 × 10-08).Conclusions and relevanceThe findings of this study suggest that residing in a neighborhood with a higher deprivation index appears to be reflected by methylation-based markers of aging.
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Project description:In this issue of Molecular Cell, Gross et al. (2016) find a CpG DNA methylation signature in blood cells of patients with chronic well-controlled HIV infection that correlates with accelerated aging.
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Project description:Epigenetic clocks are DNA methylation-based chronological age prediction models that are commonly employed to study age-related biology. The difference between the predicted and observed age is often interpreted as a form of biological age acceleration, and many studies have measured the impact of environmental and disease-associated factors on epigenetic age. Most epigenetic clocks are fit using approaches that minimize the error between the predicted and observed chronological age, and as a result, they may not accurately model the impact of factors that moderate the relationship between the actual and epigenetic age. Here, we compare epigenetic clocks that are constructed using penalized regression methods to an evolutionary framework of epigenetic aging with the epigenetic pacemaker (EPM), which directly models DNA methylation as a function of a time-dependent epigenetic state. In simulations, we show that the value of the epigenetic state is impacted by factors such as age, sex, and cell-type composition. Next, in a dataset aggregated from previous studies, we show that the epigenetic state is also moderated by sex and the cell type. Finally, we demonstrate that the epigenetic state is also moderated by toxins in a study on polybrominated biphenyl exposure. Thus, we find that the pacemaker provides a robust framework for the study of factors that impact epigenetic age acceleration and that the effect of these factors may be obscured in traditional clocks based on linear regression models.
| S-EPMC10791860 | biostudies-literature
Project description:Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats-a model with unique physical, physiological, and biochemical advantages-by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.
| S-EPMC7661040 | biostudies-literature
Project description:Most traits in livestock, crops and humans are polygenic, that is, a large number of loci contribute to genetic variation. Effects at these loci lie along a continuum ranging from common low-effect to rare high-effect variants that cumulatively contribute to the overall phenotype. Statistical methods to calculate the effect of these loci have been developed and can be used to predict phenotypes in new individuals. In agriculture, these methods are used to select superior individuals using genomic breeding values; in humans these methods are used to quantitatively measure an individual's disease risk, termed polygenic risk scores. Both fields typically use SNP array genotypes for the analysis. Recently, genotyping-by-sequencing has become popular, due to lower cost and greater genome coverage (including structural variants). Oxford Nanopore Technologies' (ONT) portable sequencers have the potential to combine the benefits genotyping-by-sequencing with portability and decreased turn-around time. This introduces the potential for in-house clinical genetic disease risk screening in humans or calculating genomic breeding values on-farm in agriculture. Here we demonstrate the potential of the later by calculating genomic breeding values for four traits in cattle using low-coverage ONT sequence data and comparing these breeding values to breeding values calculated from SNP arrays. At sequencing coverages between 2X and 4X the correlation between ONT breeding values and SNP array-based breeding values was > 0.92 when imputation was used and > 0.88 when no imputation was used. With an average sequencing coverage of 0.5x the correlation between the two methods was between 0.85 and 0.92 using imputation, depending on the trait. This suggests that ONT sequencing has potential for in clinic or on-farm genomic prediction, however, further work to validate these findings in a larger population still remains.
| S-EPMC8673642 | biostudies-literature
Project description:DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig's increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.
| S-EPMC8599541 | biostudies-literature
Project description:Cattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the biological age of oocytes. Both epigenetic clock studies and epigenome-wide association studies revealed that blood and oocytes differ substantially with respect to aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood; however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.
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Project description:Reprogramming technology has enabled the fate conversion of terminally differentiated somatic cells into pluripotent stem cells or into another differentiated state. A dynamic reorganization of epigenetic regulation takes place during cellular reprogramming. Given that reprogramming does not require changes in the underlying genome, the technology can be used to actively modify epigenetic regulation. Although reprogramming has been investigated mostly at the cellular level in vitro, studies have reported that somatic cells are reprogrammable in multicellular organisms in vivo. In vivo reprogramming provides a potential strategy for regenerative medicine. Notably, recent studies using in vivo reprogramming technology to alter epigenetic regulation at organismal levels have revealed unappreciated epigenetic mechanisms in various biological phenomena, including cancer development, tissue regeneration, aging, and rejuvenation in mammals. Moreover, in vivo reprogramming technology can be applied to abrogate epigenetic aberrations associated with aging and cancer, which raises the possibility that the technology could provide a potential strategy to control the fate of detrimental cells such as senescent cells and cancer cells in vivo. Here, we review recent progress and future perspectives of in vivo reprogramming.
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Project description:DNA re-identification is used for a broad suite of applications, ranging from cell line authentication to forensics. However, current re-identification schemes suffer from high latency and limited access. Here, we describe a rapid, inexpensive, and portable strategy to robustly re-identify human DNA called 'MinION sketching'. MinION sketching requires as few as 3 min of sequencing and 60-300 random SNPs to re-identify a sample enabling near real-time applications of DNA re-identification. Our method capitalizes on the rapidly growing availability of genomic reference data for cell lines, tissues in biobanks, and individuals. This empowers the application of MinION sketching in research and clinical settings for periodic cell line and tissue authentication. Importantly, our method enables considerably faster and more robust cell line authentication relative to current practices and could help to minimize the amount of irreproducible research caused by mix-ups and contamination in human cell and tissue cultures.
| S-EPMC5705215 | biostudies-literature
Project description:BackgroundMycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis settings. To support this informatically, previous work led to the development of the widely used TBProfiler webtool, which predicts resistance to 14 drugs from WGS data. However, for accurate and rapid high throughput of samples in clinical or epidemiological settings, there is a need for a stand-alone tool and the ability to analyse data across multiple WGS platforms, including Oxford Nanopore MinION.ResultsWe present a new command line version of the TBProfiler webserver, which includes hetero-resistance calling and will facilitate the batch processing of samples. The TBProfiler database has been expanded to incorporate 178 new markers across 16 anti-tuberculosis drugs. The predictive performance of the mutation library has been assessed using > 17,000 clinical isolates with WGS and laboratory-based drug susceptibility testing (DST) data. An integrated MinION analysis pipeline was assessed by performing WGS on 34 replicates across 3 multi-drug resistant isolates with known resistance mutations. TBProfiler accuracy varied by individual drug. Assuming DST as the gold standard, sensitivities for detecting multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) were 94% (95%CI 93-95%) and 83% (95%CI 79-87%) with specificities of 98% (95%CI 98-99%) and 96% (95%CI 95-97%) respectively. Using MinION data, only one resistance mutation was missed by TBProfiler, involving an insertion in the tlyA gene coding for capreomycin resistance. When compared to alternative platforms (e.g. Mykrobe predictor TB, the CRyPTIC library), TBProfiler demonstrated superior predictive performance across first- and second-line drugs.ConclusionsThe new version of TBProfiler can rapidly and accurately predict anti-TB drug resistance profiles across large numbers of samples with WGS data. The computing architecture allows for the ability to modify the core bioinformatic pipelines and outputs, including the analysis of WGS data sourced from portable technologies. TBProfiler has the potential to be integrated into the point of care and WGS diagnostic environments, including in resource-poor settings.
| S-EPMC6591855 | biostudies-literature