Spatial co-fragmentation pattern of cell-free DNA recapitulates in vivo chromatin organization and identifies tissue-of-origin

Three-dimensional chromatin organization varies across different cell types and is essential for gene regulation. However, current technologies are unable to assess in vivo genome-wide chromatin organization non-invasively. Here, we showed that long-range correlations in the fragment length of cell-free DNA (cfDNA) estimated from whole-genome sequencing recapitulate three-dimensional chromatin organization. The inferred organization is highly concordant with that measured by Hi-C in white blood cells from healthy donors, and is not explained by technical bias or sequence composition. Furthermore, the inferred organization reflects the differing genome organizations in the various cell types contributing to cfDNA, allowing quantification of cfDNA tissue-of-origin that is concordant with previous methods, but at much lower required DNA input. Our results, demonstrated in cfDNA from healthy individuals and cancer patients, may enable noninvasive monitoring of in vivo genome organization and accurate quantification of cell death in different clinical conditions. Compare two-dimensional fragmentation pattern in cell free DNA with Hi-C at white blood cell and then deconvolute the signals to reference cell types