Dynamic evolution of clonal epialleles revealed by methclone

Abstract

We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at

CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data

“…The joint methylation status of individual sequencing reads, often referred to as epialleles (epigenetic alleles), captures the ‘phased information’ of CpG sites, and can represent the methylation haplotype (9,14,32). With the advancement of base-resolution sequencing techniques (such as WGBS), epialleles have recently been studied in several major lines of DNA methylation research (14,25,26,31–35), such as tumor clones and their phylogeny (26,33,34), intratumor heterogeneity (25,35), solid tissue studies (31), and tissue deconvolution of cfDNAs (14).…”

“…With the advancement of base-resolution sequencing techniques (such as WGBS), epialleles have recently been studied in several major lines of DNA methylation research (14,25,26,31–35), such as tumor clones and their phylogeny (26,33,34), intratumor heterogeneity (25,35), solid tissue studies (31), and tissue deconvolution of cfDNAs (14). Most of these studies proposed new measures based on epialleles, such as proportion of discordant reads (PDR) (25), Epipolymorphism (31), methylation entropy (32), and methylated haplotype load (MHL) (14). These measures are intrinsically population-averaged metric at the marker level, designed for assessing discordancy, diversity, and co-methylation level of joint methylation states over a pile of reads, not for classifying individual reads.…”

Toward understanding and exploiting tumor heterogeneity

“…Epigenetic marks are therefore unique in their ability to provide information about the previous, present and potential future states of a cell. They can also provide a built-in ‘barcode’ that can measure a tumor’s epigenetic clonality 6 .…”

Genetic and epigenetic heterogeneity in acute myeloid leukemia

“…Each case of AML is a complex mosaic of cells containing different combinations of genetic lesions and epigenetic variants [4-6]. Clonal evolution within each AML patient appears to be a dynamic process whereby there is continuous acquisition and loss of specific mutations, sometimes occurring in different timepoints.…”