Biology subjects

Georges, S. J.

Publications and source records attributed to Georges, S. J..

2 recordsLinked to original sources

bioRxiv2026

A Rare T-Cell Factor 4 Lineage-negative Epithelial Stem Cell Supports Wound Repair and APC-deletion-induced Colon Tumorigenesis

To maintain barrier homeostasis, the colonic and intestinal epithelial lining is continually renewed by rapidly proliferating epithelial crypt base columnar (CBC) stem cells that reside at the base of crypts. Using mouse lineage tracing, immunohistochemistry, and single-cell sequencing, we have identified a rare, non-CBC, T-cell factor 4 lineage-negative (Tcf4 Lin-) stem cell population that gives rise to secretory and absorptive precursors. Following endoscopic biopsy-induced injury, Tcf4 Lin- stem cells are recruited to the wound bed and to the site of expanding crypts and function in barrier restoration and wound repair. We show that in a Tcf4-haploinsufficient background, the Tcf4 Lin-, but not the Tcf4 Lin+, cell population represents the cell of origin for colon tumors driven by deletion of Apc. Our results provide a foundation for understanding Apc-allele-specific differences during colon tumorigenesis and identify a new stem-cell population that may prove valuable in the treatment of diseases caused by intestinal barrier homeostasis defects.

cell biology↗

bioRxiv2025

Comprehensive benchmarking of somatic single-nucleotide variant and indel detection at ultra-low allele fractions using short- and long-read data

Mosaic mutations in normal tissues occur at low variant allele fractions (VAFs), complicating detection. To benchmark strategies, the SMaHT Network created a cell-line mixture (1:49) and produced ultra-deep whole-genome sequencing using short and long reads (five centers, 180-500x each). We assembled a reference of 44,008 mosaic SNVs and 2,059 Indels, cross-validation between platforms to expose limits of short-read analysis. We also partitioned the genome by mappability to examine the impact of genomic context, added a negative reference set, and accounted for culture-derived mutations. When seven institutions applied eleven algorithms to mixture data, call sets were largely discordant across tools and replicates, partly reflecting stochastic presence of low-VAF mutations in biological replicants. For >2% VAF SNVs, sensitivity and precision approached [~]80% at [≥]300x, with little gain from additional sequencing. This work provides a comprehensive framework for reliable detection of low-VAF mutations in non-cancer tissues and a valuable resource for the community.

bioinformatics↗