Genetic variants and evolutionary analyses of heparin cofactor II

Heparin cofactor II (HCII) belongs to serpin superfamily and it acts as a thrombin inhibitor in the coagulation cascade, in a glycosaminoglycan-dependent pathway using the release of a sequestered hirudin-like N-terminal tail for interaction with thrombin. This serpin belongs to multiple member group V2 of vertebrate serpin classification. However, there is no comprehensive study illustrating the exact phylogenetic history of HCII, to date. Herein, we explored phylogenetic traits of HCII genes. Structures of HCII gene from selected ray-finned fishes and lamprey varied in exon I and II with insertions of novel introns of which one in core domain for ray-finned fishes in exon II at the position 241c. We found HCII remain nested in the largest intron of phosphatidylinositol (PI) 4-kinase (PIK4CA) gene (genetic variants of this gene cause schizophrenia) at the origin of vertebrates, dated about 500MY old. We found that sequence features such as two acidic repeats (AR1-II), GAG-binding helix-D, three serpin motifs and inhibitory reactive center loop (RCL) of HCII protein are highly conserved in 55 vertebrates analyzed. We identified 985 HCII variants by analysis of 1092 human genomes with top three variation classes belongs to SNPs (84.3%), insertion (7.1%) and deletion (5.0%). We identified 37 deleterious mutations in the human HCII protein and we have described these mutations in relation to HCII sequence-structure-function relationships. These understandings may have clinical and medical importance as well.