Abstract: Disclosed herein are methods for isolating DNA, such as cell-free DNA (cfDNA) or DNA from a tissue sample, e.g., in which the DNA is partitioned into hypermethylated and hypomethylated partitions. After differential tagging of the partitions, portions of the hypomethylated partition are pooled with the hypermethylated partition or pooled separately. Epigenetic and sequence-variable target regions are captured from the pool comprising DNA from the hypermethylated and hypomethylated partitions, and sequence-variable target regions are captured from the pool comprising DNA from the hypomethylated partition. This approach can reduce costs and/or bandwidth by limiting sequencing of epigenetic target regions from the hypomethylated partition, which may be less informative than other DNA.

Abstract: Disclosed herein are methods for isolating DNA, such as cell-free DNA (cfDNA) or DNA from a tissue sample, e.g., in which the DNA is partitioned into hypermethylated and hypomethylated partitions. After differential tagging of the partitions, portions of the hypomethylated partition are pooled with the hypermethylated partition or pooled separately. Epigenetic and sequence-variable target regions are captured from the pool comprising DNA from the hypermethylated and hypomethylated partitions, and sequence-variable target regions are captured from the pool comprising DNA from the hypomethylated partition. This approach can reduce costs and/or bandwidth by limiting sequencing of epigenetic target regions from the hypomethylated partition, which may be less informative than other DNA.