Work

Evolutionary constraint and population variation across coagulation genes

Year: 2026

Type: article

Abstract: Background 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. Methods We performed a population-genomic analysis of 34 genes associated with inherited bleeding, fibrinolytic, and thrombotic disorders using gnomAD v4.1.1 data from more than 800,000 individuals. We evaluated gene-level constraint metrics, including loss-of-function (LoF) observed/expected ratios, LOEUF, 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 phyloP scores, and characterized ClinVar pathogenic, uncertain, and benign variants identified in gnomAD. Results 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. Conclusions 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.

Source: Research and Practice in Thrombosis and Haemostasis

DOI: 10.1016/j.rpth.2026.106980

Authors: Omid Seidizadeh, Himani Chand, Andrea Cairo, Flora Peyvandi

Institutions: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan

Language: English

Topic: Genomics and Rare Diseases

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,250