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Serine protease inhibitors (SERPINs) are crucial in the regulation of diverse biological processes including inflammation and immune response.  SERPINB11 , located in the 18q21 gene cluster, is a polymorphic gene/pseudogene coding for a non-inhibitory SERPIN. In a genome-wide scan for recent selection,  SERPINB11  was identified as a potential candidate gene for adaptive evolution in Yoruba. The present study sought a better understanding of the evolutionary history of  SERPINB11 , with special focus on evaluating its selective signature. Through the resequencing of coding and noncoding regions of  SERPINB11  in 20 Yorubans and analyzing primate orthologous sequences, we identified a full-length  SERPINB11  variant encoding a non-inhibitory SERPIN as the putative candidate of selection – probably driven to higher frequencies by an adaptive response using preexisting variation. In addition, we detected contrasting evolutionary features of  SERPINB11  in primates: While primate phylogeny as a whole is under purifying selection, the human lineage shows evidence of positive selection in a few codons, all associated with the active  SERPINB11 . Comparative modeling studies suggest that positively selected codons reduce SERPINB11's ability to undergo the conformational changes typical of inhibitory SERPINs – suggesting that it is evolving towards a new non-inhibitory function in humans. Significant correlations between  SERPINB11  variants and the environmental variables, pastoralism and pathogen richness, have led us to propose a selective advantage through host-pathogen interactions, possibly linked to an adaptive response combating the emergence of infectious diseases in recent human evolution. This work represents the first description of a resurrected gene in humans, and may well exemplify selection on standing variation triggered by drastic ecological shifts.

Loss and Gain of Function in SERPINB11: An Example of a Gene under Selection on Standing Variation, with Implications for Host-Pathogen Interactions