Compositions and methods for representational selection of nucleic acids from complex mixtures using hybridization

A method of analyzing a complex mixture of nucleic acids comprising:

• (a) providing a complex mixture of nucleic acids comprising genomic DNA sequence having a complexity of at least 1.7 Gbp;
• (b) providing a population of solid support-attached capture probes, said population comprising full length nucleic acids complementary to nucleic acids comprising a predetermined portion of the nucleic acid sequences collectively present in said complex mixture;
• (c) contacting said complex mixture of nucleic acids with said population of solid support-attached capture probes under conditions sufficient for hybridization of said nucleic acids with said capture probes, wherein the capture probes are randomly located on the solid support,
• (d) removing unhybridized nucleic acids from the solid support to separate desired sequences from undesired sequences within the complex mixture;
• thereby selecting a representational sample of nucleic acids having a complexity of at least 0.001% and at most 49% of said complex mixture, wherein the proportion of each sequence in said representational sample relative to all other sequences in said representational sample is substantially the same as the proportions of the sequences in said complex mixture;
• and
• (e) detecting individual nucleic acids in said representational sample to determine a sequence characteristic of said predetermined portion of the nucleic acid sequences collectively present in said complex mixture.