Evolution of the CLTCL1 Gene Encoding CHC22 Clathrin Reveals Selection Influencing CHC22’s Role in Human Glucose Metabolism

Fumagalli, M.; Diekmann, Y.; Camus, S. M.; Burke, A.; Camus, M. D.; Norman, P. J.; Joseph, A.-P.; Abi-Rached, L.; Benazzo, A.; Rasteiro, R.; Topf, M.; Parham, P.; Thomas, M. G.; Brodsky, F. M.

doi:10.1101/307264

bioRxiv · 10.1101/307264

Evolution of the CLTCL1 Gene Encoding CHC22 Clathrin Reveals Selection Influencing CHC22’s Role in Human Glucose Metabolism

Fumagalli, M.·Diekmann, Y.·Camus, S. M.·Burke, A.·Camus, M. D.·Norman, P. J.·Joseph, A.-P.·Abi-Rached, L.·Benazzo, A.·Rasteiro, R.·Topf, M.·Parham, P.·Thomas, M. G.·Brodsky, F. M.

View original source ↗Export metadata ↓

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 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 CHC22s role in metabolism and have potential to differentially influence the human insulin response.

Source connections

Published article ↗

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Fumagalli, M., Diekmann, Y., Camus, S. M., Burke, A., Camus, M. D., Norman, P. J., Joseph, A.-P., Abi-Rached, L., Benazzo, A., Rasteiro, R., Topf, M., Parham, P., Thomas, M. G., Brodsky, F. M.. 2018-04-26. Evolution of the CLTCL1 Gene Encoding CHC22 Clathrin Reveals Selection Influencing CHC22’s Role in Human Glucose Metabolism. https://doi.org/10.1101/307264

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

X-Chromosomal STR-based analysis of genetic diversity, structure, and phylogeny in the Sri Lankan Vedda population

The Vedda people are regarded as the direct descendants of Sri Lanka's Mesolithic hunter-gatherers and represent one of South Asia's oldest surviving indigenous populations. X-chromosomal short tandem repeat (X-STR) analysis provides a powerful framework to examine their genetic distinctiveness, as the X chromosome exhibits sex-biased biparental inheritance and greater sensitivity to demographic and evolutionary forces compared to autosomal markers. However, no X-STR-based genetic investigations have yet been conducted on this population. In the present study, we successfully genotyped 50 unrelated Veddas individuals using a recently developed 16 X-STR multiplex PCR system optimized for Sri Lankan populations. Our analyses revealed a statistically significant genetic differentiation (2.43%) between the Veddas and the principal local ethnic groups; Sinhalese, Sri Lankan Tamils, Indian Tamils, and Moors exceeding previous estimates based on autosomal STR markers. Comparative analysis with 32 global populations positioned the Veddas as a genetically distinct and isolated group, separated from clusters representing South Asians, Europeans, Middle Easterners, and other indigenous populations such as Australian Aboriginals, Bhil Indians, and Kedayans, emphasizing their unique genetic heritage. Reduced allelic (115) and haplotype (62) counts, alongside significant linkage disequilibrium detected among eight pairs of X-STR loci, reflect the influence of genetic drift within this small, endogamous, and historically isolated population. These findings highlight the evolutionary and demographic distinctiveness of the Veddas and provide essential baseline data for future population genomic studies. Furthermore, the demonstrated high discriminatory power of the 16 X-STR loci supports their continued application in population genetics and anthropological research within this unique community.

genetics↗

bioRxiv2026

Fss1, a CTNS/PQ domain protein, has dual roles in promoting fertility in Schizosaccharomyces pombe

Sexual reproduction is critical in most eukaryotes, but many genes required for the process remain to be identified and characterized. A previous saturation mutagenesis study in Schizosaccharomyces pombe implicated several unnamed genes in having roles in sexual reproduction. In this work, we provide an initial characterization of 13 of these genes and an in-depth characterization of one gene, fss1 (facilitates starvation sex). Fss1 has high structural homology to the human PQ-loop repeat family PQLC2 transceptor (amino acid transporter plus membrane receptor), but likely lacks the ability to transport amino acids due to loss of a critical PQ motif. fss1{Delta} mutants have no defects in meiosis but have pronounced defects in packaging the products of meiosis into spores, particularly in nutrient-poor environments. The spore formation phenotypes are recessive as fss1{Delta} spores produced by a fss1+/fss1{Delta} heterozygote develop normally. Immuno-gold electron microscopy shows Fss1 localizes to vesicles that fuse to the ephemeral outer spore membrane as the spore wall matures below. Fss1 protein is also produced within spores and this population is required for normal vacuole morphology and timely germination. We propose a model in which Fss1 is a vesicle receptor that facilitates spore wall formation from diploid-expressed protein, while spore-expressed protein acts at the vacuole to promote an internal cellular environment that facilitates germination. This work expands our catalog of genes that contribute to sexual reproduction and identifies two previously unknown tasks in spore biology that are both facilitated by Fss1.

genetics↗

bioRxiv2026

Expression of tardigrade intrinsically disordered proteins in C. elegans reveals variable effects on aging and stress

Tardigrades survive extreme environmental stress by expressing intrinsically disordered proteins that stabilize cellular structures during cryptobiosis. Because these proteins protect cells from desiccation, oxidative stress, and DNA damage, they have attracted interest as potential therapeutics to enhance stress resilience in other organisms. However, most studies have relied on cultured cells or germline expression, leaving their effects in somatic tissues largely unexplored. Here, we generated Caenorhabditis elegans strains expressing four tardigrade intrinsically disordered proteins, Damage Suppressor (DSUP), cytoplasmic-abundant heat-soluble (CAHS), mitochondrial-abundant heat-soluble (MAHS), and Ramazzottius varieornatus late embryogenesis abundant (RvLEAM), throughout somatic tissues. Surprisingly, constitutive expression of each protein reduced lifespan, impaired motility and reproduction, and failed to improve resistance to most environmental stressors. DSUP toxicity was tissue- and developmental stage-dependent, indicating that both spatial and temporal expression influence its physiological effects. Despite these detrimental phenotypes, several proteins reduced protein aggregation during desiccation-associated stress, demonstrating context-dependent protective effects. Together, our findings reveal that tardigrade stress proteins impose physiological tradeoffs in vivo and underscore the importance of evaluating candidate stress-protective proteins in physiologically relevant somatic models before therapeutic translation.

genetics↗