Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism

Matteo Fumagalli Stephane M Camus Yoan Diekmann Alice Burke Marine D Camus Paul J Norman Agnel Joseph Laurent Abi-Rached Andrea Benazzo Rita Rasteiro Iain Mathieson Maya Topf Peter Parham Mark G Thomas Frances M Brodsky

eLife 2019;8:e41517 DOI: 10.7554/eLife.41517

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22’s role in metabolism and have potential to differentially influence the human insulin response.

 It is also possible that some forms of polar bear CHC22 are super-active at GLUT4 sequestration, providing a route to maintain high blood glucose, as occurs through other mutations in the cave fish (Riddle et al., 2018).

Regulators of fundamental membrane traffic pathways have diversified through gene duplication in many species over the timespan of eukaryotic evolution. Retention and loss can, in some cases, be correlated with special requirements resulting from species differentiation

The genetic diversity that we report here may reflect evolution towards reversing a human tendency to insulin resistance and have relevance to coping with increased carbohydrate in modern diets.