1. The uromodulin gene locus shows evidence of pathogen adaptation through human evolution
- Author
-
Linda Pattini, Peter Vollenweider, Olivier Devuyst, Francesca Tassi, Luca Rampoldi, Guido Barbujani, Silvia Ghirotto, Caroline Hayward, Murielle Bochud, University of Zurich, Rampoldi, L, Ghirotto, S, Tassi, F, Barbujani, G, Pattini, L, Hayward, C, Vollenweider, P, Bochud, M, and Devuyst, O
- Subjects
Genetic Markers ,0301 basic medicine ,Tamm–Horsfall protein ,Population ,030232 urology & nephrology ,Socio-culturale ,610 Medicine & health ,Genome ,10052 Institute of Physiology ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Uromodulin ,Animals ,Humans ,Allele ,education ,Denisovan ,Gene ,Allele frequency ,Genetics ,education.field_of_study ,Urinary tract infection, chronic kidney disease, genetic renal disease, kidney tubule, tubular epithelium ,Urinary tract infection ,2727 Nephrology ,kidney tubule ,biology ,Genetic Variation ,genetic renal disease ,General Medicine ,biology.organism_classification ,030104 developmental biology ,Genetic Loci ,Nephrology ,Urinary Tract Infections ,biology.protein ,570 Life sciences ,Human genome ,tubular epithelium ,chronic kidney disease - Abstract
Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.
- Published
- 2016