Abstract
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.
Highlights
Serine protease inhibitors (SERPINs), a superfamily of proteins found in all domains of life (Eukarya, Eubacteria, and Archaea), have preserved their tertiary structure throughout evolution
In the database from a genome-wide scan (GWS) for recent positive selection based on the integrated haplotype score (iHS) statistic [16] and relying on HapMap phase II data, we found a significant p-value (p = 0.040607) for SERPINB11 in the YRI
34 single nucleotide polymorphisms (SNPs) with significant iHS scores (File S1) were identified the vicinity (200 kb window) of SERPINB11. These SNPs were organized into two major clusters and located in distinct linkage disequilibrium (LD) blocks; the first cluster, occupied a 34kb block encompassing a large SERPINB11 segment; the second cluster was in a 30-kb block downstream of SERPINB11 (Figure 2, Figure S1 and File S1)
Summary
Serine protease inhibitors (SERPINs), a superfamily of proteins found in all domains of life (Eukarya, Eubacteria, and Archaea), have preserved their tertiary structure throughout evolution. SERPINs neutralize serine or cysteine proteases by a unique suicide substrate-like inhibitory mechanism that entails a dramatic rearrangement in protein folding. SERPINs are able to entrap proteases by presenting a pseudosubstrate in an exposed reactive center loop (RCL). Upon RCL cleavage, SERPINs initiate a major conformational change from ‘‘stressed’’ to ‘‘relaxed’’ (S-toR – transition) leading to distortion and permanent inactivation of the protease catalytic site [1,2,3,4]. The vast majority of SERPINs are important in regulating proteolytic cascades in biological processes such as blood coagulation, development, apoptosis, and inflammation. The 37 SERPINs known in humans belong to nine phylogenetic clades (A–I) defined by similarities in protein sequence and gene structure [2,5,6,7]
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