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Optimal sample size for calibrating DNA methylation age estimators.

ABSTRACT: Age is a fundamental parameter in wildlife management as it is used to determine the risk of extinction, manage invasive species, and regulate sustainable harvest. In a broad variety of vertebrates species, age can be determined by measuring DNA methylation. Animals with known ages are initially required during development, calibration, and validation of these epigenetic clocks. However, wild animals with known ages are frequently difficult to obtain. Here, we perform Monte-Carlo simulations to determine the optimal sample size required to create an accurate calibration model for age estimation by elastic net regression modelling of cytosine-phosphate-guanine methylation data. Our results suggest a minimum calibration population size of 70, but ideally 134 individuals or more for accurate and precise models. We also provide estimates to the extent a model can be extrapolated beyond a distribution of ages that was used during calibration. The findings can assist researchers to better design age estimation models and decide if their model is adequate for determining key population attributes.

SUBMITTER: Mayne B

PROVIDER: S-EPMC8518423 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Optimal sample size for calibrating DNA methylation age estimators.

Mayne Benjamin B Berry Oliver O Jarman Simon S

Molecular ecology resources 20210618 7

Age is a fundamental parameter in wildlife management as it is used to determine the risk of extinction, manage invasive species, and regulate sustainable harvest. In a broad variety of vertebrates species, age can be determined by measuring DNA methylation. Animals with known ages are initially required during development, calibration, and validation of these epigenetic clocks. However, wild animals with known ages are frequently difficult to obtain. Here, we perform Monte-Carlo simulations to ...[more]

PMID: 34053192

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Project description:BackgroundAge-related changes in DNA methylation (DNAm) play a critical role in regulating gene expression. However, most epigenome-wide association studies have predominantly focused on individuals of European descent. This study aims to characterize longitudinal changes in DNAm patterns in a cohort of elderly Brazilian participants.MethodsDNAm profiles were collected approximately nine years apart from 23 elderly Brazilian individuals using the Illumina Infinium MethyationEPIC BeadChip. Using mixed-effects models, we examined changes in DNAm patterns using both quantitative age and binary timepoint (e.g., baseline vs. follow-up) as predictors of interest to identify differentially methylated positions (DMPs). Significant DMPs were compared with a list of previously identified age-related DMPs. Differentially methylated regions (DMRs) were also identified using DMRcate. Gene ontology (GO) pathway enrichment analyses were performed to explore the functional significance of identified DMPs and DMRs.ResultsOf the 586,229 autosomal probes included in the differential methylation analyses, 2768 significant (FDR < 0.05) age-associated DMPs (aDMPs) and 2757 significant (FDR < 0.05) timepoint-associated DMPs (tpDMPs) were identified. Of the 2768 aDMPs, 1471 were replicated from previous studies. Of the 1297 non-replicated CpGs, 77.4% were exclusive to the EPIC array. The DMR analyses identified 305 age-associated DMRs (aDMRs) and 372 timepoint-associated DMRs (tpDMRs). Both aDMPs and aDMRs exhibited age-related hypermethylation within CpG islands and promoter regions of the genome, whereas hypomethylation predominantly occurred in interCGI and intergenic regions and introns. The GO enrichment analyses identified several neurological and cognition-related pathways enriched for hypermethylated CpG islands, many of which were mapped near transcription start sites and first exon regions.ConclusionsThis longitudinal study identified age-associated and timepoint-associated DMPs and DMRs in a sample of elderly Brazilians. Most of the non-replicated CpGs were found to be on the new EPIC array, suggesting that more age-related studies using the EPIC array are required to validate these CpGs. The GO pathway enrichment analyses identified age-related enrichment of several gene sets related to cognitive and physical decline in elderly populations. The enrichment of these sites could provide evidence for age-related neurodegeneration and cognitive decline in elderly populations.

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Optimal sample size for calibrating DNA methylation age estimators.

Publications

Optimal sample size for calibrating DNA methylation age estimators.

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