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The uromodulin gene locus shows evidence of pathogen adaptation through human evolution
- Source :
- Journal of the American Society of Nephrology
- Publication Year :
- 2016
-
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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology
- Accession number :
- edsair.doi.dedup.....45b1427f72fde2b8a7a725c13a1852ee