engleski

Cell-type deconvolution from cell-free DNA fragmentaton patterns

Circulating cell-free DNA (cfDNA) present in the plasma of healthy individuals is believed to mostly be a product of apoptosis of cells of the hematopoietic lineage. Differences in the distribution of tissues of origin of circulating cfDNA between healthy and disease states or specific physiological conditions can be informative of the underlying biological mechanisms contributing to specific states and have the substantial potential of improving the diagnostics of various diseases. Several approaches for identification of the tissue of origin from cfDNA have been developed, including methods based on the analysis of nucleosome patterns or transcription factor binding sites inferred from cfDNA fragmentation patterns, DNA methylation, or ChIP-seq of cfDNA. However, methods that rely only on cfDNA fragmentation patterns can usually differentiate between hematopoietic vs non-hematopoietic tissues of origin but are less sensitive to differences in the changes of proportions of different blood cells. To increase the sensitivity of the method to subtle changes in proportions of cells of origin of cfDNA, whose cfDNA fragmentation patterns are highly similar, we developed a novel approach based on the comparison of average fragmentation patterns of cfDNA in tissue-specific regulatory regions and the cfDNA signal intensity. We tested our approach on a whole genome sequencing dataset of individuals before and after exercising. Vigorous exercise has been shown to increase the concentration of cfDNA in plasma and the cell types that increase after exercise are largely unknown. We analyzed the cfDNA patterns before and after exercise using our approach and identified the cell types that increase after exercise. This method can be used to study other conditions that may be associated with changes in the release of cell-free DNA from specific blood cell types.

Cell type deconvolution ; cfDNA

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