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.

非恶性组织中的体细胞突变随着年龄和损伤而积累，但这些突变是否在细胞或有机体水平上具有适应性尚不清楚。为了探究人类代谢疾病中的基因，我们对患有非酒精性脂肪性肝炎（NASH）的体细胞嵌合体小鼠进行了谱系追踪。 Mboat7 （一种膜脂酰基转移酶）嵌合体丢失的概念验证研究表明，脂肪变性的增加会加速克隆消失。接下来，我们在 63 个已知的 NASH 基因中诱导了混合嵌合，使我们能够并排追踪突变克隆。我们将这个体内追踪平台命名为 MOSAICS ，选择改善脂毒性的突变，包括在人类 NASH 中发现的突变基因。为了优先考虑新基因，对 472 个候选基因进行了额外筛选，确定了 23 个促进克隆扩增的体细胞扰动。在验证研究中，全肝删除Tbx3 、 Bcl6或Smyd2可预防肝脂肪变性。对小鼠和人类肝脏中克隆适应性的选择确定了调节代谢疾病的途径。