Somatic NFKBIZ v ariant modulates inflammation at single-cell resolution

The human body is a somatic mosaic, with normal tissue colonized by cell populations carrying distinct mutations. Intriguingly, in tissues affected by chronic disease, such as inflammatory bowel disease (IBD), disease-specific drivers of clonal expansion emerge. IBD is characterized by chronic intestinal inflammation and increased cancer risk. This inflammatory environment exerts selective pressure promoting the growth of clones carrying somatic mutations in IL-17 inflammatory pathway genes. While many such mutations have been implicated in downregulating inflammation and protecting against colitis-associated colorectal cancer, their presence has yet to be characterized at single-cell resolution in solid human tissue. We used SComatic to identify somatic single nucleotide variants in single-cell RNA-sequenced colorectal samples from IBD patients ( n =204). Among them, we found a novel missense mutation predicted to be highly pathogenic in the ankyrin repeat domain of NFKBIZ , which is critical for promoter binding in the IL-17 pathway. NFKBIZ is a key regulator of intestinal inflammation and a known driver of clonal expansion in IBD. Notably, while NFKBIZ variants are highly prevalent in IBD, they are rarely found in colitis-associated cancer, suggesting this adaptation in chronically inflamed tissue is protective against cancer. Strikingly, we found that the variant appears exclusively in epithelial cells. In this compartment, it exhibited a high variant allele frequency of 0.727, suggesting substantial remodeling of colonic epithelium during chronic inflammation. Functionally, the variant appeared to disrupt IL-17-mediated signaling, as its presence was associated with reduced expression of DUOX2 , a known IL-17 target gene that causes DNA damage and is frequently upregulated in colonic inflammation in IBD. This shows, for the first time at single-cell resolution in native human tissue, previously hypothesized protective mechanisms driven by somatic NFKBIZ mutations. Our work reveals how protective clones emerge in specific cell types in response to chronic inflammation, highlighting how epithelial remodeling can influence IBD disease progression and treatment response.