Plasma contains ultrashort single-stranded DNA in addition to nucleosomal cell-free DNA

Jordan Cheng(University of California, Los Angeles), Marco Morselli(University of California, Los Angeles), Wei-Lun Huang(National Cheng Kung University), You Jeong Heo(University of California, Los Angeles), Thalyta Pinheiro-Ferreira(University of California, Los Angeles), Feng Li(University of California, Los Angeles), Wei Fang(University of California, Los Angeles), David Chia(University of California, Los Angeles), Yong Kim(University of California, Los Angeles), Hua‐Jun He(National Institute of Standards and Technology), Kenneth D. Cole(National Institute of Standards and Technology), Wu‐Chou Su(National Cheng Kung University), Matteo Pellegrini(University of California, Los Angeles), David T. Wong(University of California, Los Angeles)
iScience
June 8, 2022
10.1016/j.isci.2022.104554
Cited by 49Open Access
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Abstract

Plasma cell-free DNA is being widely explored as a biomarker for clinical screening. Currently, methods are optimized for the extraction and detection of double-stranded mononucleosomal cell-free DNA of ∼160bp in length. We introduce uscfDNA-seq, a single-stranded cell-free DNA next-generation sequencing pipeline, which bypasses previous limitations to reveal a population of ultrashort single-stranded cell-free DNA in human plasma. This species has a modal size of 50nt and is distinctly separate from mononucleosomal cell-free DNA. Treatment with single-stranded and double-stranded specific nucleases suggests that ultrashort cell-free DNA is primarily single-stranded. It is distributed evenly across chromosomes and has a similar distribution profile over functional elements as the genome, albeit with an enrichment over promoters, exons, and introns, which may be suggestive of a terminal state of genome degradation. The examination of this cfDNA species could reveal new features of cell death pathways or it can be used for cell-free DNA biomarker discovery.

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