MBE Advance Access originally published online on November 29, 2006
Molecular Biology and Evolution 2007 24(2):587-598; doi:10.1093/molbev/msl187
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Research Articles |
Sequence Diversity at the Proximal 14q32.1 SERPIN Subcluster: Evidence for Natural Selection Favoring the Pseudogenization of SERPINA2
* Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
Department of Human Genetics, University of Chicago
Faculty of Medicine, University of Porto, Porto, Portugal
Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
|| Department of Zoology and Anthropology, Faculty of Sciences, University of Porto, Porto, Portugal
E-mail: sseixas{at}ipatimup.pt.
Accepted for publication November 27, 2006.
The superfamily of serine protease inhibitors (SERPINs) plays a key role in controlling the activity of proteinases in diverse biological processes. 
1-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 1-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.
Key Words: natural selection • pseudogenization • SERPIN