• Yue Yin, Jia Li, Jin Li, Minjung Lee, Sibo Zhao, Linlang Guo, Jianfang Li, Mutian Zhang, Yun Huang, Xiao-Nan Li, Zhenzhong Deng, and Deqiang Sun.
• Texas A&M University College of Medicine.
• Brief. Bioinformatics. 2020 Dec 15.

AbstractThe cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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