Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

Abstract

Somatic mutations in non-malignant tissues accumulate with age and insult, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate mutations found in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to non-alcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side-by-side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Bcl6, Tbx3, or Smyd2 resulted in protection against NASH. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease. HighlightsO_LIMosaic Mboat7 mutations that increase lipotoxicity lead to clonal disappearance in NASH. C_LIO_LIIn vivo screening can identify genes that alter hepatocyte fitness in NASH. C_LIO_LIMosaic Gpam mutations are positively selected due to reduced lipogenesis. C_LIO_LIIn vivo screening of transcription factors and epifactors identified new therapeutic targets in NASH. C_LI