CHC22 clathrin plays a key role in intracellular membrane traffic of the insulinresponsive 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