Unravelling genome-wide mosaic microsatellite mutations at single-cell resolution
Wang, C.; Fan, W.; Wang, W.; Xia, Y.; Lu, J.; Ma, X.; Yu, J.; Zheng, Y.; Luo, Y.; Li, W.; Yang, Q.; Lin, M.; Liu, H.; Lan, Y.; Li, C.; Liu, X.; HE, D.; Cai, S.; Yu, X.; Zhou, D.; Kellis, M.; Xiong, X.; Xie, Q.; Dou, Y.
Show abstract
Short tandem repeats (STRs), or microsatellites, are highly mutable genomic elements that modulate gene regulations and are implicated in a range of human diseases. However, detecting mosaic STR mutations at single-cell resolution remains challenging due to both technical and biological complexities. To address this, we developed BayesMonSTR, a robust algorithm that enables accurate detection of mosaic STR mutations. Using this tool in single-cell analysis of human tissues, we reveal an accumulation of longer mosaic STR insertions and deletions (indels) in aging mitotic and post-mitotic cells. Strikingly, prefrontal cortex (PFC) neurons accumulate a higher burden of STR mutations than B cells or lung epithelium, with aged neurons exhibiting a particularly pronounced increase in longer STR deletions. These mutations are enriched at transcription start sites (TSSs) and active enhancers of highly expressed genes. Our work establishes a foundation for genome-wide, hypothesis-free discovery of disease-associated mosaic STR mutations and reveals a previously unexplored landscape of mosaic STR variation in development and aging.
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