Abstract: Provided herein are methods and systems for aligning next-generation sequence reads to a reference genome such that genetic conditions or diseases, including rare variants or mutations, may be identified. Provided herein are methods of mapping a query sequence. In some aspects, the methods include receiving a set of alignments of a query to a reference sequence, each alignment in the set of alignments corresponding to the query aligning to a subsequence of the reference, wherein each alignment is assigned an initial mapping probability.