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.
Elife. 2019 Jun 4;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 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining , strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency 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.
CHC22 网格蛋白在人类胰岛素反应性葡萄糖转运蛋白 GLUT4 的细胞内膜运输中起着关键作用。我们对 CHC22 编码基因进行了群体遗传和系统发育分析，结果表明，该基因在脊椎动物的两个谱系中独立发生了基因丢失，这是在基因复制之后发生的。所有的脊椎动物都保留了编码 CHC17 网格蛋白的同源基因，该基因介导内吞作用。对于保留的脊椎动物，强烈的净化选择证据支持 CHC22 的功能。所有人类群体都维持着两种高频率的等位基因变异体，分别在 1316 位编码蛋氨酸或缬氨酸。功能研究表明，CHC22-V1316 在农耕人群中的频率高于狩猎采集人群，其细胞动力学与 M1316-CHC22 不同，并且在控制 GLUT4 膜运输方面的效果较差，改变了其胰岛素调节反应。这些分析表明，人类祖先的饮食变化影响了影响 CHC22 在代谢中作用的同种型的选择，并有可能对人类的胰岛素反应产生不同的影响。
