Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Joshua Moss, Judith Magenheim, Daniel Neiman, Hai Zemmour, Netanel Loyfer, Amit Korach, Yaacov Samet, Myriam Maoz, Henrik Druid, Peter Arner, Keng Yeh Fu, Endre Kiss, Kirsty L. Spalding, Giora Landesberg, Aviad Zick, Albert Grinshpun, A. M.James Shapiro, Markus Grompe, Avigail Dreazan Wittenberg, Benjamin GlaserRuth Shemer*, Tommy Kaplan, Yuval Dor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

524 Scopus citations


Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.

Original languageAmerican English
Article number5068
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2018

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© 2018, The Author(s).


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