A method of sample analysis is described comprising providing a sample comprising a plurality of endblocked polynucleotides, digesting the sample with one or more defined nucleic acid-directed endonuclease that targets a sequence of interest to produce a digested sample of polynucleotide fragments, wherein one or more of the fragments in the digested sample comprises: a sequence of interest and at least one ligatable end that has been generated by endonuclease cleavage; (c) enriching for fragments that contain the sequence of interest, wherein the one or more sequences of interest are enriched greater than 55 times, or greater than 750 times, their relative abundance in the sample; and (d) analyzing the enriched sample.