Methods for genotyping with selective adaptor ligation

A method for reducing the complexity of a genomic DNA sample comprising:

• (a) fragmenting the sample with a restriction enzyme that has a recognition sequence that comprises at least one variable position to obtain fragments, wherein the at least one variable position is in the single-stranded overhang generated by cleavage with the restriction enzyme and cleavage generates four different overhang sequences;
• (b) ligating a selective adaptor to the fragments to generate adaptor-ligated fragments, wherein the selective adaptor is complementary to two of the four different overhang sequences;
• and
• (c) amplifying at least some of the adaptor-ligated fragments by polymerase chain reaction using a primer complementary to the selective adaptor.

A method for genotyping a plurality of known sequence variants in a genomic DNA sample comprising:

• i. obtaining a reduced complexity amplified sample wherein a subset of the DNA is amplified, by a method comprising:
• (a) fragmenting the genomic DNA sample with a restriction enzyme that has a recognition sequence that comprises at least one variable position, wherein the at least one variable region is in the single-stranded overhang generated by cleavage with the restriction enzyme to obtain restriction fragments;
• (b) ligating at least one selective adaptor to a subset of the restriction fragments to generate adaptor-ligated fragments, wherein the at least one selective adaptor is perfectly complementary to a first subset of the single-stranded overhangs generated in step (a) and is not perfectly complementary to a second subset of the single-stranded overhangs generated in step (a);
• and
• (c) amplifying a subset of the adaptor-ligated fragments by polymerase chain reaction using a primer complementary to the at least one selective adaptor to obtain a reduced complexity amplified sample;
• ii. fragmenting the reduced complexity amplified sample to obtain fragments and labeling the fragments to obtain labeled fragments;
• iii. hybridizing the labeled fragments to an array of allele specific probes that are specific for one allele of a known sequence variant to obtain a hybridization pattern;
• and
• iv. analyzing the hybridization pattern to determine the genotype of a plurality of known sequence variants in the genomic DNA sample.