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Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism

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

Posted 26 Apr 2018
bioRxiv DOI: 10.1101/307264 (published 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, attenuating 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. * CCV : clathrin-coated vesicles CHC : clathrin heavy chain CLC : clathrin light chain GLUT4 : glucose transporter 4 SNP : single nucleotide polymorphism GFP : green fluorescent protein FRAP : fluorescence recovery after photobleaching GSC : GLUT4 storage compartment HA : hemagglutinin FACS : fluorescence-activated cell sorting T2D : Type 2 diabetes AFR : African EUR : European EAS : East Asian AMR : Admixed American SAS : South Asian YRI : Yoruba from Nigeria CEU : North Americans with Caucasian European ancestry CHB : Han Chinese from Beijing MSA : multiple sequence alignment VCF : variant call format HG : hunter-gatherer EF : early farmer MFI : mean fluorescent intensity

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