title: Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2.
abstract: The superfamily of serine protease inhibitors (SERPINs) plays a key role in controlling the activity of proteinases in diverse biological processes. alpha1-antitrypsin (SERPINA1), the most studied member of this family, is encoded by a gene located within the proximal 14q32.1 SERPIN subcluster, together with the highly homologous alpha1-antitrypsin-like sequence (SERPINA2), which was previously proposed to be a pseudogene. Here, we performed a resequencing study encompassing both SERPINA1 and SERPINA2 as well as the adjacent gene coding for corticosteroid-binding globulin (SERPINA6) in samples from Europe and West Africa. In the African sample, we found that a common haplotype carrying a 2-kb deletion in the SERPINA2 gene is associated with remarkable long-range homozygozity as if it was quickly driven to high frequency by natural selection acting on an advantageous variant. An analysis of the HapMap Phase I data for the Yoruba sample confirmed that variation in this subcluster carries a strong signal of positive selection. We also show that the SERPINA2 gene is expressed and probably encodes a functional SERPIN. Finally, comparisons with orthologous sequences in nonhuman primates showed that SERPINA2 is present in some great apes, but in chimpanzees it was lost by a deletion event independent from that observed in humans. In agreement with the "less is more" hypothesis, we propose that loss of SERPINA2 is an ongoing process associated with a selective advantage during recent primate evolution, possibly because of a role in fertility or in host-pathogen interactions.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal. sseixas@ipatimup.pt
authors.forename: Susana
authors.initials: S
authors.lastname: Seixas
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Suriano
authors.forename: Filipa
authors.initials: F
authors.lastname: Carvalho
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Jorge
authors.initials: J
authors.lastname: Rocha
authors.forename: Anna
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D000349:Africa; D000818:Animals; D002883:Chromosomes, Human, Pair 14; D005060:Europe; D006239:Haplotypes; D015186:Hominidae / Q000235:genetics; D006801:Humans; D005810:Multigene Family; D002679:Pan troglodytes / Q000235:genetics; D011487:Protein Conformation; D011544:Pseudogenes; D012641:Selection, Genetic; D015843:Serpins; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; C519531:SERPINA2 protein, human; D015843:Serpins; D000515:alpha 1-Antitrypsin