Compositions and methods for accurately identifying mutations

A method for detecting a true mutation in both strands of a native genomic double-stranded DNA molecule, the method comprising:

• (a) amplifying a double-stranded nucleic acid library, wherein the double-stranded nucleic acid library comprises a plurality of target nucleic acid molecules and a plurality of double-stranded cyphers, wherein:
• (i) the nucleic acid library comprises molecules having a formula of Xa-Y-Xb (in 5′ to 3′ order);
• (ii) Xa comprises a first cypher;
• (iii) Y comprises a target nucleic acid molecule comprising a double-stranded fragment of genomic DNA;
• (iv) Xb comprises a second cypher that is different from the first cypher;
• (v) each of the plurality of cyphers comprise a length ranging from about 5 nucleotides to about 50 nucleotides;
• (vi) the first cypher and second cypher uniquely tag the associated target nucleic acid;
• and
• (vii) the plurality of target nucleic acid molecules and plurality of double-stranded cyphers are amplified;
• (b) sequencing the amplified plurality of target nucleic acid molecules and plurality of cyphers to obtain sequence data comprising sequencing reads for both strands of the plurality of target nucleic acid molecules and the plurality of cyphers;
• (c) linking the sequence data for both strands of each of a plurality of the target nucleic acid molecules based on the respective first and second cyphers;
• and
• (d) detecting the true mutation, wherein the true mutation is a mutation present in substantially all sequencing reads of the linked sequence data for the target nucleic acid with the true mutation.