Revising angiotensinogen from phylogenetic and genetic variants perspectives

Angiotensinogen (AGT) belongs to the serpin superfamily. It acts as the unique substrate of all angiotensin peptides, which generates a spectrum of angiotensin peptides in the renin-angiotensin system and regulates hypertension. This serpin belongs to the multiple member group V2 of the intron encoded vertebrate serpin classification. Despite huge advancements in the understanding of angiotensinogen based on biochemical properties and its roles in the RAS, phylogenetic history of AGT remains forgotten. To date, there is no comprehensive study illustrating the phylogenetic history of AGT. Herein, we investigated phylogenetic traits of AGT gene across vertebrates. Gene structures of AGT gene from selected ray-finned fishes varied in exon I and II with insertions of two novel introns in the core domain for ray-finned fishes at the position 77c and 233c. We that found AGT loci is conserved from lampreys to human and estimated to be older than 500 MY. By comparing AGT protein in 57 vertebrate genomes, we illustrated that the reactive center loop (RCL) of AGT protein became from inhibitory (in lampreys, GTEAKAETVVGIMPI†SMPPT) to non-inhibitory (in human, EREPTESTQQLNKPE†VLEVT) during period of 500 MY. We identified 690 AGT variants by analysis of 1092 human genomes with top three variation classes belongs to SNPs (89.7%), somatic SNVs (5.2%) and deletion (2.9%). There are 32 key residues out of 121 missense variants, which are deleterious for AGT protein, computed by combination of SIFT and PolyPhen V2 methods. These results may have clinical implications for understanding hypertension.