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Long-read mapping to repetitive reference sequences using Winnowmap2.

Chirag JainArang RhieNancy F HansenSergey KorenAdam M Phillippy
Published in: Nature methods (2022)
Approximately 5-10% of the human genome remains inaccessible due to the presence of repetitive sequences such as segmental duplications and tandem repeat arrays. We show that existing long-read mappers often yield incorrect alignments and variant calls within long, near-identical repeats, as they remain vulnerable to allelic bias. In the presence of a nonreference allele within a repeat, a read sampled from that region could be mapped to an incorrect repeat copy. To address this limitation, we developed a new long-read mapping method, Winnowmap2, by using minimal confidently alignable substrings. Winnowmap2 computes each read mapping through a collection of confident subalignments. This approach is more tolerant of structural variation and more sensitive to paralog-specific variants within repeats. Our experiments highlight that Winnowmap2 successfully addresses the issue of allelic bias, enabling more accurate downstream variant calls in repetitive sequences.
Keyphrases
  • single molecule
  • high resolution
  • high frequency
  • high density
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  • genome wide
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  • dna methylation
  • mass spectrometry
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