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More than one-half billion people are obese, anddespite progress in genetic research, much ofthe high heritability of obesity remains enigmatic.Here, we identify a Trim28-dependent networkcapable of triggering obesity in a non-Mendelian,"on/off" manner. Trim28 +/D9 mutant mice exhibit abi-modal body-weight distribution, with isogenicanimals randomly emerging as either normal orobese and few intermediates. We find that theobese-"on" state is characterized by reducedexpression of an imprinted gene network includingNnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissuetranscriptome analyses in children indicate thathumans too cluster into distinct sub-populations,stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and manand thus carry important implications for complextrait genetics, evolution, and medicine. |