Compositions and methods for accurately identifying mutations

A method of determining an error-corrected sequence of a double-stranded target nucleic acid molecule, comprising:

• (a) ligating the double-stranded target nucleic acid molecule to at least one cypher polynucleotide, to form a cypher-target nucleic acid complex, wherein the at least one cypher polynucleotide comprises:
• (i) a random or partially-random identifier sequence that alone or in combination with an end of the target nucleic acid molecule uniquely labels the double-stranded target nucleic acid molecule;
• and
• (ii) a nucleotide sequence that tags each strand of the cypher-target nucleic acid complex such that each strand of the cypher-target nucleic acid complex has a distinct nucleotide sequence relative to its complementary strand;
• (b) amplifying each strand of the cypher-target nucleic acid complex to produce a plurality of cypher-target amplification products from each of a first strand and a complementary second strand of the cypher-target nucleic acid complex;
• (c) sequencing the cypher-target amplification products to produce a plurality of first-strand sequencing reads and a plurality of second-strand sequencing reads;
• and
• (d) comparing the first-strand sequencing reads with the second-strand sequencing reads, and generating an error-corrected sequence of the double-stranded target nucleic acid molecule by distinguishing erroneous nucleotides in one strand that lack a matched base change in the complementary strand.