Department of Life Sciences, Imperial College London, Ascot, United Kingdom; Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom; Research Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London, United Kingdom; UCL Genetics Institute, University College London, London, United Kingdom
Stephane M Camus
Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom
Yoan Diekmann
Research Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London, United Kingdom; UCL Genetics Institute, University College London, London, United Kingdom
Alice Burke
Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom
Marine D Camus
Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom
Paul J Norman
Division of Bioinformatics and Personalized Medicine, University of Colorado, Aurora, United States; Department of Microbiology and Immunology, University of Colorado, Aurora, United States
Agnel Joseph
Institute of Structural and Molecular Biology, Birkbeck College and University College London, London, United Kingdom
Laurent Abi-Rached
Aix-Marseille Univ, IRD, MEPHI, IHU Méditerranée Infection, CNRS, Marseille, France
Andrea Benazzo
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
School of Biological Sciences, University of Bristol, Bristol, United Kingdom
Iain Mathieson
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Maya Topf
Institute of Structural and Molecular Biology, Birkbeck College and University College London, London, United Kingdom
Peter Parham
Department of Structural Biology, Stanford University, Stanford, CA, United States; Department of Microbiology and Immunology, Stanford University, Stanford, CA, United States
Mark G Thomas
Research Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London, United Kingdom; UCL Genetics Institute, University College London, London, United Kingdom
Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom; Institute of Structural and Molecular Biology, Birkbeck College and University College London, London, United Kingdom
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.
