Directional and balancing selection on proprotein convertase subtilisin/kexin type 6 (PCSK6)

The selective pressures challenging the human population leave genetic signatures. This study was designed to detect positive and balancing selection on the proprotein convertase subtilisin/kexin type 6 (PCSK6) gene by four different approaches (FDIST, BayeScan, EHH, iHS). The outlier programs FDIST and BayeScan found 27 overlapping single nucleotide polymorphisms (SNPs) under selection, of which twelve are under strong positive directional selection and 15 under balancing selection. In the EHH analysis, all SNPs detected under positive selection show a slow decay of the derived extended haplotype. The integrated haplotype scores (iHS) for eight loci under positive selection were found to be larger than one. Based on these results, we provide a short overview of PCSK6-related mechanisms potentially associated with the detected positive or balancing selection patterns. Positive selection possibly reflects the key role of PCSK6 in tumorigenesis, in nociception, in rheumatoid arthritis and osteoarthritis, in the cardiovascular circulatory as well as in blood pressure regulation. Balancing selection acting on the PCSK6 locus might be explained by its involvement in vertebral left-right asymmetry and therefore in human handedness. Whereas until now the exact nature of the selective pressures acting on PCSK6 remained incompletely understood, the results of this study provide for the first time insights into the enzyme’s evolutionary significance owing to its functional manifoldness.