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      Evolutionary analysis of the contact system indicates that kininogen evolved adaptively in mammals and in human populations.

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          Abstract

          Activation of the contact system leads to the cleavage of kininogen by plasma kallikrein resulting in kinin release and in the initiation of the intrinsic pathway of coagulation. Proteolysis of kininogen also generates antimicrobial peptides (AMPs) and can be induced by diverse pathogens. Thus, the contact system is regarded as a branch of innate immunity. We performed an evolutionary analysis of contact system genes by analyzing both inter- and intraspecies diversity. Results indicated that mammalian kininogen genes evolved adaptively. Positively selected sites are located in all protein domains with the exclusion of the bradykinin region and also involve AMP sequences (including the highly effective NAT26 peptide); positively selected sites also occur at alternative cleavage sites for neutrophil-released kinins. Population genetic analysis in humans indicated that a region of the kininogen gene (KNG1) has been a target of long-standing multiallelic balancing selection and that the coalescence time of the haplotype phylogeny dates back to the split between the humans and chimpanzees. No selection signature was detected in the Pan troglodytes KNG1 gene or in human genes encoding other components of the contact system. The selection targets in human KNG1 might be accounted for by variants with transcriptional regulatory activity. Results herein indicate a continuum in selective pressure acting on different timescales and targeting KNG1. This is in line with evidences suggesting a central role for kininogen in modulating of immune response and with its being a target of an extremely diverse array of pathogen species.

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          Author and article information

          Journal
          Mol. Biol. Evol.
          Molecular biology and evolution
          1537-1719
          0737-4038
          Jun 2013
          : 30
          : 6
          Affiliations
          [1 ] Bioinformatics, Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy. rachele.cagliani@bp.lnf.it
          Article
          mst054
          10.1093/molbev/mst054
          23505046
          56e1de94-f4ae-4863-8608-049774462c69
          History

          KNG1,balancing selection,contact system genes,innate immunity,positive selection

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