The subject invention relates to improvements in nucleic acid isolation, and more particularly, relates to modifications to the subtractive hybridization method and to reagents such as oligonucleotides that are useful when performing the method. The present invention provides a modified subtractive hybridization method termed Selectively Primed Adaptive Driver-RDA ("SPAD-RDA"), which utlises a driver-versus-driver subtraction control performed in parallel with the driver-versus-tester subtraction step. The products of the driver control subtraction from each round can be used as the driver of the subsequent round.