Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism.

Abstract

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 <i>CLTCL1</i> gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous <i>CLTC</i> gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining <i>CLTCL1</i>, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency <i>CLTCL1</i> 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.