The invention discloses an innovative method to deplete repetitive sequences from human DNA. The method comprises (a) providing a source DNA containing both unique and repetitive sequences and sonicating the source DNA to smaller fragments; (b) providing a driver DNA containing sequences complementary to the repetitive sequences of the source DNA and labeled with a non-radioactive label, (c) hybridizing the source DNA and the driver DNA in the presence of a molecule that binds the label to form a complex; (d) removing the hybridized repetitive sequences from the complex by using RNAase and electrophoresis or by incubating with a mixture of phenol, chloroform, and ethanol; and (e) recovering the remaining source DNA wherein said repetitive sequences being significantly removed.