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DNA methylation, a covalent modification, fundamentally shapes mammalian gene regulation and cellular identity. This review examines methylation's biochemical underpinnings, genomic distribution patterns, and analytical approaches. We highlight three distinctive aspects that separate methylation from other epigenetic marks: its remarkable stability as a silencing mechanism, its capacity to maintain distinct states independently of DNA sequence, and its effectiveness as a quantitative trait linking genotype to disease risk. We also explore the phenomenon of methylation clocks and their biological significance. The review addresses technical considerations across major assay types—both array-based technologies and sequencing approaches—with emphasis on data normalization, quality control, cell proportion inference, and the specialized statistical models required for next-generation sequencing analysis. 

Abstract MotivationUnderstanding causal effects is a fundamental goal of science and underpins our ability to make accurate predictions in unseen settings and conditions. While direct experimentation is the gold standard for measuring and validating causal effects, the field of causal graph theory offers a tantalizing alternative: extracting causal insights from observational data. Theoretical analysis has shown that this is indeed possible, given a large dataset and if certain conditions are met. However, biological datasets, frequently, do not meet such requirements but evaluation of causal discovery algorithms is typically performed on synthetic datasets, which they meet all requirements. Thus, real-life datasets are needed, in which the causal truth is reasonably known. In this work we first construct such a large-scale real-life dataset and then we perform on it a comprehensive benchmarking of various causal discovery methods. ResultsWe find that the PC algorithm is particularly accurate at estimating causal structure, including the causal direction which is critical for biological applicability. However, PC does only produces cause-effect directionality, but not estimates of causal effects. We propose PC-NOTEARS (PCnt), a hybrid solution, which includes the PC output as an additional constraint inside the NOTEARS optimization. This approach combines PC algorithm’s strengths in graph structure prediction with the NOTEARS continuous optimization to estimate causal effects accurately. PCnt achieved best aggregate performance across all structural and effect size metrics. Availability and implementationhttps://github.com/zhu-yh1/PC-NOTEARS.