1. A computer-implemented method for classifying alignments of paired nucleic acid sequence reads, comprising: receiving a plurality of paired nucleic acid sequence reads, wherein each read is comprised of a first tag and a second tag separated by an insert region; determining potential alignments for the first and second tags of each read to a reference sequence, wherein each potential alignment satisfies a minimum threshold mismatch constraint; identifying potential paired alignments of the first and second tags of each read, wherein a distance between the first and second tags of each potential paired alignment is within an estimated insert size range; and calculating an alignment score for each potential paired alignment based on, a distance between the first and second tags, and a total number of mismatches for each tag.