Abstract: The invention relates to methods for the detection of the amount of a nucleic acid in a sample. The described methods exploit the ability to physically pair nucleic acid molecules in a sample that have a reference sequence with nucleic acid molecules in the sample that have a target sequence. The presence of unpaired target or reference sequence following such physical pairing indicates a difference in the amount of the target sequence versus the reference sequence. The methods are broadly applicable for the determination of differences in the amounts of nucleic acids in diagnostic and research applications.