Putative Origins of Cell-Free DNA in Humans: A Review of Active and Passive Nucleic Acid Release Mechanisms

Stefan Grabuschnig, Abel Jacobus Bronkhorst, Stefan Holdenrieder, Ingund Rosales Rodriguez, Klaus Peter Schliep, Daniel Schwendenwein, Vida Ungerer, Christoph Wilhelm Sensen*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Through various pathways of cell death, degradation, and regulated extrusion, partial or complete genomes of various origins (e.g., host cells, fetal cells, and infiltrating viruses and microbes) are continuously shed into human body fluids in the form of segmented cell-free DNA (cfDNA) molecules. While the genetic complexity of total cfDNA is vast, the development of progressively efficient extraction, high-throughput sequencing, characterization via bioinformatics procedures, and detection have resulted in increasingly accurate partitioning and profiling of cfDNA subtypes. Not surprisingly, cfDNA analysis is emerging as a powerful clinical tool in many branches of medicine. In addition, the low invasiveness of longitudinal cfDNA sampling provides unprecedented access to study temporal genomic changes in a variety of contexts. However, the genetic diversity of cfDNA is also a great source of ambiguity and poses significant experimental and analytical challenges. For example, the cfDNA population in the bloodstream is heterogeneous and also fluctuates dynamically, differs between individuals, and exhibits numerous overlapping features despite often originating from different sources and processes. Therefore, a deeper understanding of the determining variables that impact the properties of cfDNA is crucial, however, thus far, is largely lacking. In this work we review recent and historical research on active vs. passive release mechanisms and estimate the significance and extent of their contribution to the composition of cfDNA
Original languageEnglish
Article number 8062
Pages (from-to)1-24
Number of pages24
JournalInternational Journal of Molecular Sciences
Issue number21
Publication statusPublished - 1 Nov 2020


  • active release of cfDNA
  • cell-free DNA
  • circulating DNA
  • circulating tumor DNA
  • liquid biopsy
  • origins of cfDNA
  • passive release of cfDNA

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


  • BioTechMed-Graz


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