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Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers but our understanding of the effects of IBD on the mutational profile and clonal structure of the colon is limited. Here, we isolated and whole-genome sequenced 370 colonic crypts from 45 IBD patients, and compared these to 413 crypts from 41 non-IBD controls. We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon, and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We also found that non-synonymous mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients. With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia and point to potential therapeutic targets for IBD.

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