Sequence, phylogenetic and variant analyses of antithrombin III

Area of Science:

• Molecular Evolution
• Genomics
• Biochemistry

Background:

• Antithrombin III (ATIII) is crucial for anticoagulation, inhibiting blood clotting proteinases with heparin and heparan sulfate cofactors.
• While ATIII's physiological, biochemical, and structural aspects are studied, its molecular evolution remains underexplored.

Purpose of the Study:

• To investigate the molecular phylogenetic analyses of Antithrombin III (ATIII) genes across 50 vertebrate genomes.
• To combine gene structure, synteny, and sequence-structural features to understand ATIII's evolutionary trajectory.

Main Methods:

• Phylogenetic analysis of ATIII genes from 50 vertebrate genomes.
• Comparative analysis of gene structures, synteny, and protein sequence-structural features.
• Compilation and analysis of ATIII variants from 1092 human genomes (1000G project).

Main Results:

• ATIII gene has been conserved on the same genomic loci for over 450 million years in vertebrates.
• Ray-finned fishes exhibit an additional intron at position 262c, which is lost in tetrapods and coelacanth.
• Key protein features like heparin binding sites, hD helix, salt bridges, N-glycosylation sites, serpin motifs, and the reactive center loop (RCL) are highly conserved.
• Analysis of 1092 human genomes revealed 1997 ATIII variants, primarily single nucleotide polymorphisms (SNPs, 76.2%), deletions (11.8%), and insertions (8.1%).

Conclusions:

• ATIII exhibits remarkable evolutionary conservation in its gene loci and critical protein domains.
• Intron loss in tetrapods and coelacanth, and variations in ray-finned fishes, highlight evolutionary divergence.
• Identified human ATIII variants have potential medical significance for understanding anticoagulation disorders.