Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

Genome Research
Kun SunY M Dennis Lo

Abstract

Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented and possess information related to their tissues of origin. Pathologies causing death of cells from particular tissues result in perturbations in the relative distribution of DNA from the affected tissues. Such tissue-of-origin analysis is particularly useful in the development of liquid biopsies for cancer. It is therefore of value to accurately determine the relative contributions of the tissues to the plasma DNA pool in a simultaneous manner. In this work, we report that in open chromatin regions, cfDNA molecules show characteristic fragmentation patterns reflected by sequencing coverage imbalance and differentially phased fragment end signals. The latter refers to differences in the read densities of sequences corresponding to the orientation of the upstream and downstream ends of cfDNA molecules in relation to the reference genome. Such cfDNA fragmentation patterns preferentially occur in tissue-specific open chromatin regions where the corresponding tissues contributed DNA into the plasma. Quantitative analyses of such sign...Continue Reading

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Citations

Nov 2, 2019·Clinical Chemistry·Ellen Heitzer
Jan 5, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sarah T K SinY M Dennis Lo
Oct 16, 2019·Journal of Clinical Pathology·Giuditta BenincasaClaudio Napoli
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Jan 6, 2021·International Journal of Molecular Sciences·Qiyuan HanNatalia Y Tretyakova
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Jul 27, 2021·Journal of the American Heart Association·Teodora R KolarovaRaj Shree
Sep 3, 2021·Genome Research·Diana S C HanY M Dennis Lo

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