Detection of outlier methylation from bisulfite sequencing data with novel Bioconductor package BOREALIS

作者：Gavin R. Oliver, Garrett Jenkinson, Rory J. Olson, Laura Schultz‐Rogers, Eric W. Klee · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.05.19.492700 · 被引用次数：6 · 研究领域：Epigenetics and DNA Methylation、Genetic Syndromes and Imprinting、Genomics and Rare Diseases

Abstract DNA sequencing results in genetic diagnosis of 18-40% of previously unsolved cases, while the incorporation of RNA-Seq analysis has more recently been shown to generate significant numbers of previously unattainable diagnoses. Multiple inborn diseases resulting from disorders of genomic imprinting are well characterized and a growing body of literature suggest the causative or correlative role of aberrant DNA methylation in diverse rare inherited conditions. Therefore, the systematic application of genomic-wide methylation-based sequencing for undiagnosed cases of rare disease is a logical progression from current testing paradigms. Following the rationale previously exploited in RNA-based studies of rare disease, we can assume that disease-associated methylation aberrations in an individual will demonstrate significant differences from individuals with unrelated phenotypes. Thus, aberrantly methylated sites will be outliers from a heterogeneous cohort of individuals. Based on this rationale, we present BOREALIS: B isulfite-seq O utlie R M E thylation A t Sing L e-S I te Re S olution. BOREALIS uses a beta binomial model to identify outlier methylation at single CpG site resolution from bisulfite sequencing data. This method addresses a need unmet by standard differential methylation analyses based on case-control groups. Utilizing a heterogeneous cohort of 94 rare disease patients undiagnosed following DNA-based testing we show that BOREALIS can successfully identify...