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bioRxiv · 10.1101/2022.04.27.489683

Improved sequence mapping using a complete reference genome and lift-over

Chen, N.-C.·Paulin, L. F.·Sedlazeck, F. J.·Koren, S.·Phillippy, A. M.·Langmead, B.
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Abstract

Complete, telomere-to-telomere genome assemblies promise improved analyses and the discovery of new variants, but many essential genomic resources remain associated with older reference genomes. Thus, there is a need to translate genomic features and read alignments between references. Here we describe a new method called levioSAM2 that accounts for reference changes and performs fast and accurate lift-over between assemblies using a whole-genome map. In addition to enabling the use of multiple references, we demonstrate that aligning reads to a high-quality reference (e.g. T2T-CHM13) and lifting to an older reference (e.g. GRCh38) actually improves the accuracy of the resulting variant calls on the old reference. By leveraging the quality improvements of T2T-CHM13, levioSAM2 reduces small-variant calling errors by 11.4-39.5% compared to GRC-based mapping using real Illumina datasets. LevioSAM2 also improves long-read-based structural variant calling and reduces errors from 3.8-11.8% for a PacBio HiFi dataset. Performance is especially improved for a set of complex medically-relevant genes, where the GRC references are lower quality. The software is available at https://github.com/milkschen/leviosam2 under the MIT license.

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Chen, N.-C., Paulin, L. F., Sedlazeck, F. J., Koren, S., Phillippy, A. M., Langmead, B.. 2022-04-28. Improved sequence mapping using a complete reference genome and lift-over. https://doi.org/10.1101/2022.04.27.489683

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