Evolutionary constraint and population variation across coagulation genes

Hemostasis is a tightly regulated system in which disruption of coagulation genes can cause bleeding or thrombotic disorders. Despite extensive variant discovery, it remains unclear whether coagulation genes share uniform or gene-specific patterns of evolutionary constraint and population variation.

To characterize evolutionary constraint and population variation across coagulation genes using large-scale genomic data.

We performed a population-genomic analysis of 34 genes associated with inherited bleeding, fibrinolytic, and thrombotic disorders using Genome Aggregation Database (gnomAD) v4.1.1 data from more than 800,000 individuals. We evaluated gene-level constraint metrics, including loss-of-function observed/expected ratios, loss-of-function observed/expected upper bound fraction, missense constraint scores, and synonymous variation metrics. We quantified rare and very rare variant burden after normalization for coding sequence length, assessed predicted functional impact using CADD and REVEL scores, evaluated nucleotide-level evolutionary conservation using phylogenetic P value scores, and characterized ClinVar pathogenic, uncertain, and benign variants identified in gnomAD.

Hemostatic genes demonstrated a continuous spectrum of evolutionary constraint rather than uniform intolerance to genetic variation. Genes including F8, F9, F2, VWF, MYH9, SERPINC1, and PROS1 showed strong depletion of damaging variation, whereas GP6, GP1BB, F12, VKORC1, MCFD2, and LMAN1 showed greater tolerance. Rare variant density differed substantially across genes even after adjustment for coding sequence length. ClinVar pathogenic variants identified in gnomAD were enriched at evolutionarily conserved sites and displayed marked gene-specific differences in variant class distribution, particularly among missense variants.

The hemostatic system is shaped by heterogeneous evolutionary pressures, resulting in gene-specific patterns of constraint and variation tolerance. Integrating population genomics, evolutionary conservation, and clinical annotations provides a framework for understanding genetic variation across bleeding, thrombotic, and fibrinolytic disorders.