非恶性组织中的体细胞突变随着年龄和损伤累积，但这些突变在细胞或有机体水平上是否是适应性的还不清楚。为了研究人类代谢疾病的基因，我们在患有体细胞性状、接受非酒精性脂肪性肝炎（NASH）治疗的小鼠中进行了谱系追踪。通过Mboat7亏损的谱系敲除验证研究表明，增加脂肪肝的程度可以加速克隆消失。接下来，我们在63个已知NASH基因中诱导了集体体细胞状突变，从而可以并排追踪突变克隆。我们将这种追踪平台命名为MOSAICS，并筛选出解除脂毒性的突变，包括在人类NASH中鉴定出的突变基因。为了优先考虑新基因，我们通过对472个候选者的额外筛选，鉴定出23个体细胞机制的干扰，促进了克隆扩展。在验证研究中，删除Tbx3、Bcl6或Smyd2可以在肝脏中全面保护免受脂肪肝的侵害。在小鼠和人类肝脏中选择克隆健康可以确定调节代谢疾病的途径。版权所有 ©2023 Elsevier Inc.。

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic 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 Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.Copyright © 2023 Elsevier Inc. All rights reserved.