Conceptually, selection of somatic mutations that increase clone fitness can predict therapeutic efficacy-BUT some mutations cause conflict between clone and organism. Thanks to our key UK collaborators David Savage, Peter Campbell, Matt Hoare, and contributors from @cri-utsw.bsky.social 8/8

Consistently, Tbx3 KO protected against, and overexpression worsened fatty liver. This is because Tbx3 KO resulted in more VLDL-triglyceride secretion, which moves lipids from the liver to the rest of the body. Consequently, mice suffered from high blood triglyceride levels. 7/8

Loss of function TBX3 mutant clones expand in mice and humans with fatty livers. This suggests that these mutations protect hepatocytes from lipid-induced toxicity. 6/8

The second paper/concept is that some somatic mutations can appear to benefit the clone or organ, but have negative effects for the organism. Congrats to Greg Mannino on his first paper! 5/8 www.jci.org/articles/vie...

Consistently, liver-wide CIDEB inhibition was more protective against disease mechanisms that led to more clone expansion, suggesting that patients with more or larger CIDEB mutant clones might expect greater benefit from CIDEB inhibition. 4/8

CIDEB mutant clones expand more in the context of some fatty liver diets, but not others. This suggests that CIDEB mutations are protective of hepatocytes, but to varying degrees depending on diet type or genetic cause of disease. 3/8

These illustrate 2 concepts about somatic mutations and how they inform therapeutic strategies. The 1st concept is that some mutations predict effective therapies that benefit the individual as well as the clone. Congrats Qiyu Zeng @satishpatel.bsky.social 2/8 www.sciencedirect.com/science/arti...