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The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation Through Human Evolution

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The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation Through Human Evolution BRIEF COMMUNICATION www.jasn.org The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution † ‡ Silvia Ghirotto,* Francesca Tassi,* Guido Barbujani,* Linda Pattini, Caroline Hayward, | Peter Vollenweider,§ Murielle Bochud,§ Luca Rampoldi, and Olivier Devuyst¶ *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; †Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy; ‡Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; §Department of Internal Medicine, Institute of Social and Preventive Medicine, Lausanne University Hospital Center, Lausanne, Switzerland; |Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and ¶Institute of Physiology, University of Zurich, Zurich, Switzerland ABSTRACT Common variants in the UMOD gene encoding uromodulin, associated with risk and in mouse models of autosomal dom- of hypertension and CKD in the general population, increase UMOD expression inant tubulointerstitial kidney disease and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal revealed intracellular aggregates of mu- lesions. To determine the effect of selective pressure on variant frequency, we in- tant uromodulin in the TAL cells, coupled vestigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human with a systematic decrease of uromodulin populations, in eight ancient human genomes, and in primate genomes. The T allele excretion in the urine.9–11 of rs4293393, associated with CKD risk, has high frequency in most modern popu- In parallel, multiple genome-wide lations and was the one detected in primate genomes. In contrast, we identified association studies (GWAS) and se- only the derived, C allele in Denisovan and Neanderthal genomes. The distribution quencing efforts have identified com- of the UMOD ancestral allele did not follow the ancestral susceptibility model ob- mon single nucleotide polymorphisms served for variants associated with salt-sensitive hypertension. Instead, the global (SNPs) in UMOD that are strongly asso- frequencies of the UMOD alleles significantly correlated with pathogen diversity ciated with eGFR and the risk for develop- (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections ing CKD in the general population.12–16 (UTIs). The inverse correlation found between urinary levels of uromodulin and The SNPs in UMOD were also associated markers of UTIs in the general population substantiates the link between UMOD with the risk of developing hypertension variants and protection against UTIs. These data strongly suggest that the UMOD and kidney stones.17,18 The top variants ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a from these GWAS studies consistently high frequency because of its protective effect against UTIs. map in the same linkage disequilibrium block encompassing the UMOD pro- J Am Soc Nephrol 27: 2983–2996, 2016. doi: 10.1681/ASN.2015070830 moter. Recently, we demonstrated that Received July 28, 2015. Accepted January 30, Uromodulin (Tamm–Horsfall protein) urinary tract infection (UTI),5 and regu- 2016. 6 is the most abundant protein excreted lates innate immunity. S.G. and F.T. are equal first authors; L.R. and O.D. in the urine.1,2 Uromodulin is exclusively The interest in uromodulin was boos- are equal senior authors. produced in the kidney by epithelial cells ted when genetic studies revealed that Published online ahead of print. Publication date lining the thick ascending limb (TAL) of mutations of the UMOD gene, which available at www.jasn.org. the loop of Henle, where it is sorted to the encodes uromodulin, can cause rare Correspondence: Dr. Luca Rampoldi, Division of apical plasma membrane and released forms of autosomal dominant tubuloin- Genetics and Cell Biology, San Raffaele Scientific into the tubular lumen by proteolytic terstitial kidney diseases.7,8 These disorders Institute, I-20132 Milan, Italy, or Dr. Olivier De- cleavage. Although the biologic role of may include impaired urinary concen- vuyst, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Swit- uromodulin remains mysterious, studies trating ability, hyperuricemia, and/or zerland. Email: [email protected] or olivier. in knockout mice have shown that uromo- gout, and they often lead to CKD and [email protected] dulin regulates NaCl transport processes ESRD between the second and fourth Copyright © 2016 by the American Society of operating in the TAL,3,4 protects against decade of life. Analyses in renal biopsies Nephrology J Am Soc Nephrol 27: 2983–2996, 2016 ISSN : 1046-6673/2710-2983 2983 BRIEF COMMUNICATION www.jasn.org these UMOD risk variants directly in- analyzed were homozygous for the T al- humans did not allow the derived allele crease the expression of uromodulin in lele, identifying it as the ancestral one to rise to high frequencies, as it proba- vitro and in vivo, while increased uromo- (Figure 1). bly did in archaic humans, or that the dulin expression causes salt-sensitive hy- We next evaluated the UMOD allelic evolutionary forces acting on archaic pertension and kidney lesions in mice status in the two ancient hominid and modern humans were somehow and humans (Table 1).19 Meta-analyses genomes at high coverage currently different. have shown that the UMOD variant available, namely the Denisova and the rs4293393, strongly associated with Neanderthal,22,23 from which present- Does the Ancestral Susceptibility eGFR and BP, is also the top variant as- day humans diverged some 550,000– Model Apply to UMOD Variants? sociated with uromodulin level in urine, 750,000 years ago, respectively,23,24 and Since the Tallele of rs4293393, associated confirming its biologic effect on pro- in anatomically modern human samples with risk for CKD and hypertension, is moter activity.16 spanning a period 3900–45,000 years the ancestral one and is associated with The unusually high frequency of the ago (Supplemental Table 1). This inves- salt retention, we hypothesized that the UMOD risk variants (70%–80% in Afri- tigation showed that only the ancestral, ancestral susceptibility model could be cans and Europeans and 92%–95% in T allele is present in the genomes of an- applied to the UMOD locus.25 This East Asians), combined with strong bi- atomically modern humans, whereas the model pertains to alleles that underwent ologic activity, suggests the action of archaic hominids were homozygous for ancient adaptations. With a shift in some sort of selective pressure.20 Based the derived, C allele (Figure 1). environment and lifestyle, the ancestral on known properties of uromodulin, Since the genomic region around alleles no longer confer a selective such pressures could be linked to salt rs4293393 is not among those identi- advantage but rather increase the risk avidity or, alternatively, to antimicrobial fied in the modern human genome as of of common diseases, while the derived, activity. The aims of the present study putative Neanderthal origin,23 an expla- protective alleles become neutral or were to characterize the ancestry of the nation for the observed pattern could be moderately advantageous and increase top risk UMOD promoter variant that the derived, C allele arose in the hu- in frequency. This model potentially ap- rs4293393, to explore whether the high man lineage after separation from the plies to variants influencing the risk of prevalence of this variant is due to selec- one leading to the chimpanzees (6 mil- hypertension, since ancient populations tive pressure, and to investigate the na- lion years ago), but before Neanderthals adapted to hot, humid areas by retaining ture of such a potential selection. and Denisovans separated from modern salt. In turn, these ancestral alleles favor- human lineage as distinct groups (Figure ing salt retention increase the risk of UMOD Variant in Nonhuman 1).23 The probability of being homozygous hypertension in modern populations Primates and Ancient Hominids for the derived allele of two individuals living in cooler, temperate climates. The top rs4293393 UMOD variant iden- randomly chosen from a population The ancestral susceptibility model tified in previous GWAS has two alleles: with the allele frequencies of current predicts a relatively recent change in T, the major allele associated with risk of European populations (about 0.20) is the selective pressure, approximately at hypertension and CKD, and C, the mi- 0.0016. Although a meaningful statisti- the time of modern human dispersal nor allele. To place the observed modern cal comparison cannot be based on two from Africa (about 50,000–70,000 years human variation in its evolutionary individuals only, this low probability ago).26 It is supported by a change of context, we evaluated the allelic status suggests that archaic hominids did allelic frequencies along the latitude, re- of rs4293393 in 25 individuals from have a higher frequency of the derived flecting environmental adaptations, with thefourchimpanzeesubspecies,21 and rs4293393 allele than modern Euro- African populations showing higher fre- in available genomes of other nonhu- peans. In turn, this supports the possibil- quencies of the ancestral (risk) allele, man primates. All the individuals ity that the recent evolution of modern and non-African populations showing Table 1. The rs4293393 promoter variant of the UMOD gene Documented Urinary GWAS Potential
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