Comprehensive benchmarking of somatic mutation detection by the SMaHT Network

作者：Tim H. H. Coorens, Jihyeon Oh, Yujin Choi, Nam Seop Lim, Boxun Zhao, Adam Voshall, A. Abyzov, L. Antonacci-Fulton, Sam Aparicio, K. Ardlie, T. Bell, James T. Bennett, Bradley E. Bernstein, Thomas G Blanchard, Alan P. Boyle, Jason D. Buenrostro, Kathleen H. Burns, Fei Chen, Rui Chen, S. Choudhury, H. Doddapaneni, E. Eichler, Gilad D. Evrony, Melissa A. Faith, T. Fazzio, Robert S. Fulton, Manuel Garber, N. Gehlenborg, S. Germer, G. Getz, Richard A. Gibbs, Raquel G Hernandez, Fulai Jin, J. Korbel, D. Landau, Heather A. Lawson, Niall J. Lennon, Heng Li, Yan Li, Po-Ru Loh, Gabor T. Marth, Michael J. McConnell, R. E. Mills, Stephen B. Montgomery, P. Natarajan, Peter J. Park, R. Satija, F. Sedlazeck, Diane D. Shao, Hui Shen, Andrew B. Stergachis, Hunter R. Underhill, Alexander E. Urban, M. VonDran, Christopher A. Walsh, Ting Wang, Tao Wu, Chenghang Zong, E. A. Lee, F. Vaccarino · 发表于：bioRxiv · 年份：2025 · DOI：10.1038/s41586-025-09096-7 · 被引用次数：48 · 研究领域：Medicine、Biology

Somatic mosaicism is increasingly recognized as a fundamental feature of human biology, yet the detection of somatic mutations remains challenging. The SMaHT Network conducted four large-scale benchmarking experiments involving cell-lines and donor tissues, to evaluate sequencing technologies, experimental approaches, and computational methods for detecting different types of somatic mutations, generating community resource with >1,000× short-read and 100-400× long-read data for each of the nine analyzed samples. We determined effective strategies for utilizing short- and long-reads sequencing for mutation detection and demonstrated that using donor-specific assemblies and human pangenome improved calling, extending mutation catalogs to challenging genomic regions. We benchmarked six duplex technologies and showed that single-cell sequencing resolves cell type-specific mutational patterns and heterogeneity. Our results indicate that bulk, single-cell, and duplex analyses are complementary – and leveraging all three provides comprehensive characterization of mosaicism within tissues. Together, these findings provide a roadmap for accurate, genome-wide somatic mutation discovery and analysis.