Cell-type-resolved somatic variant discovery from bulk long-read sequencing
Year: 2026
Type: preprint
Abstract: Somatic mutations arise throughout life, with functional consequences tied to the cell populations in which they occur. Genome-wide studies measure somatic variations in bulk tissue, whereas single-cell approaches resolve cell identity but provide limited sensitivity for complex alleles. Here we developed SniffCell, which uses DNA methylation carried on native long reads to assign somatic variant-supporting molecules to methylation-resolvable cell types. SniffCell builds cell-type-discriminatory methylation signatures across eight tissues, assigns long reads to cell types, and provides cell-type-specific variant calling. Across peripheral blood mononuclear cells and brain benchmarks, SniffCell recovered sorted cell identities and validated cell-type-specific variant assignments using purified immune-cell, neuronal, and oligodendrocyte fractions. In blood, SniffCell recovered lineage-restricted antigen receptor rearrangements and localized a somatic tandem-repeat expansion to T cells. In the frontal cortex, SniffCell identified recurrent neuron-specific tandem-repeat expansions in genes including FGF14, LRRC7 and SH3RF3 . Across three brain cohorts comprising 172 donors, recurrent neuron-associated expansions were enriched for GAA-rich motifs. In donors with matched blood, and diverged more strongly from the inherited repeat length, whereas oligodendrocyte-associated alleles more often tracked it. SniffCell transforms native bulk long-read genomes into a cell-type-aware resource for somatic variant discovery and reveals recurrent somatic instability in human tissues at cell-type resolution.
Source: medRxiv
Authors: Yilei Fu, Caoimhe Morley, Lauren M. Masters, Adam C. English, Yiming Zhu, Abraham G. Moller, Luis F. Paulin, Ben Thompson, Ester Kalef-Ezra, George Weissenberger, Helen Shen, Melissa Meredith, Arianna Manini, Dominic Horner, Xylena Reed, Donna Muzny, Zane Jaunmuktane, Ziad M. Khan, Heer Mehta, Winston Timp, Kimberley Billingsley, Graham S. Erwin, Christos Proukakis, Fritz J. Sedlazeck
Institutions: Baylor College of Medicine, Aligning Science Across Parkinson's, UCL Queen Square Institute of Neurology, University College London, National Institutes of Health, Data Tecnica International (United States), National Institute of Neurological Disorders and Stroke, National Institute on Aging, Johns Hopkins University, Rice University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G623564305
OpenAlex ID: W7208711132