Urea transporter evolution: deep conservation, recent adaptation in mammals, and maintenance of the Jka/Jkb polymorphism in the past ~ 110,000 years

Urea is a central metabolite and many organisms encode membrane integral urea transporters (UTs). Here, we combined motif homology searches, phylogenetics, and molecular evolution with paleogenomics to investigate the evolutionary dynamics of UTs from prokaryotes to human populations. We discovered previously unknown combinations of UT domains with other functional modules in metazoa, protists, and bacteria, suggesting a wider range of functions and regulatory mechanisms for UTs than previously understood. The early origin of UT domains allowed the identification of specific residues that have remained conserved across billions of years. Contestually, we found evidence that UT-B was a target of positive selection in mammals. In particular, selection targeted UT-B in bats, primates and rodents, possibly as the result of a pressure exerted by blood pathogens. In human populations, a single variant (Asp280Asn) in the UT-B protein is responsible for the common Kidd blood group antigens. Here we provide direct evidence for the temporal stability of the Asp280Asn polymorphism over ~ 110,000 years in Europe and Asia. While we previously proposed this variant to be under balancing selection, this study is the first to use ancient DNA to track its allele frequency through deep time. This novel application of paleogenomics confirms that the polymorphism was maintained at stable frequencies over time, in different European sub-regions, and across continents. Our data show how paleogenomics can provide information on the selective processes in humans, not only limited to directional selection, but also to balancing selection.