I am trying to deplete specific DNA sequences from a mixture by hybridizing with a biotinylated ssDNA fragment at 65 degrees, 180mM KCl and then capturing with streptavidin magnetic beads. The trouble is, I'm getting way too much background. The protocols for capturing biotinylated DNA with these beads typically employ 1M salt - why so high? I'd like to reduce it because I believe it's causing non-specific hybridization.

Alternatively I could raise the temperature (I used 15 minutes @ 42 degrees for the bead capture step) or add formamide, but I don't want to denature the streptavidin. Maybe I could add random hexamers or something. Has anyone tried these or come up with another solution?