A method of generating a polynucleotide sample of reduced complexity from multiple polynucleotide samples, optionally wherein the multiple polynucleotide samples are genomic DNA samples derived from different subjects, comprising: fragmenting polynucleotides in each of the multiple polynucleotide samples; generating asymmetrically tagged polynucleotides; combining the asymmetrically tagged polynucleotides to generate a pooled library, wherein the asymmetrically tagged polynucleotides each comprise: a polynucleotide having a first end and second end; a first adapter sequence on the first end of the polynucleotide comprising a polynucleotide sample-specific multiplexer identifier, wherein the MID is a tag or combination of tags the identity of which can be used to identify the sample from which the polynucleotide is derived; and a second adapter sequence on the second end of the polynucleotide; wherein the first adapter sequence and the second adapter sequence are not identical; circularizing the asymmetrically tagged polynucleotides in the pooled library intramolecularly to produce a circularized pooled library; and performing an inverse polymerase chain reaction (iPCR) with an iPCR primer pair on the circularized pooled library to generate amplicons, wherein the iPCR primer pair targets a polynucleotide region of interest, wherein each amplicon comprises; the ROI; the MID; the first adapter sequence, and the second adapter sequence,; thereby generating a polynucleotide sample of reduced complexity from the multiple polynucleotide samples. fragmenting polynucleotides in each of the multiple polynucleotide samples; generating asymmetrically tagged polynucleotides; combining the asymmetrically tagged polynucleotides to generate a pooled library, wherein the asymmetrically tagged polynucleotides each comprise: a polynucleotide having a first end and second end; a first adapter sequence on the first end of the polynucleotide comprising a polynucleotide sample-specific multiplexer identifier, wherein the MID is a tag or combination of tags the identity of which can be used to identify the sample from which the polynucleotide is derived; and a second adapter sequence on the second end of the polynucleotide; a polynucleotide having a first end and second end; a first adapter sequence on the first end of the polynucleotide comprising a polynucleotide sample-specific multiplexer identifier, wherein the MID is a tag or combination of tags the identity of which can be used to identify the sample from which the polynucleotide is derived; and a second adapter sequence on the second end of the polynucleotide; wherein the first adapter sequence and the second adapter sequence are not identical; circularizing the asymmetrically tagged polynucleotides in the pooled library intramolecularly to produce a circularized pooled library; and performing an inverse polymerase chain reaction (iPCR) with an iPCR primer pair on the circularized pooled library to generate amplicons, wherein the iPCR primer pair targets a polynucleotide region of interest, wherein each amplicon comprises; the ROI; the MID; the first adapter sequence, and the second adapter sequence,; the ROI; the MID; the first adapter sequence, and the second adapter sequence,; thereby generating a polynucleotide sample of reduced complexity from the multiple polynucleotide samples.