1. ¹Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
2. ²Department of Clinical Medicine, Trinity College Dublin and Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

Correspondence: Dr AW Ryan, Department of Clinical Medicine, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. Tel: +353 1 896 3273; Fax: +353 1 896 3503; E-mail: aryan12@tcd.ie

Received 31 March 2008; Revised 25 June 2008; Accepted 25 June 2008; Published online 20 August 2008.

Abstract

Electrophoretic analysis of protein variation at the coagulation F13B locus has previously revealed three alleles, with alleles 1, 2, and 3 each being at high frequency in European, African, and Asian populations, respectively. To determine if this unusual pattern of interpopulation differentiation reflects local natural selection or neutral genetic drift, we re-sequenced 4.6 kb of the gene, encompassing all exons, splice junctions, and 1.4 kb of the promoter, in African, European, and Asian samples. These analyses revealed three major lineages, which correspond to the common protein alleles and differ from each other at a non-synonymous substitution in exon 3 and a novel splice acceptor in intron K. There is previous evidence that these lineages are not functionally equivalent; we therefore carried out case–control analyses and confirmed that variability at F13B modulates susceptibility and/or survivorship in coronary artery disease (P<0.05) and type II diabetes within the coronary artery disease cohort (P<0.01). Tajima's D and Fu and Li's tests did not indicate significant departures from neutral expectations. However, publicly available data from SeattleSNPs and HapMap do indicate highly unusual levels of population differentiation (P=0.003) and an excess of allele-specific, extended haplotype homozygosity within the African population (P=0.0125). Possible causes of this putative signal of selection include hematophagous organisms, infection by pathogens that cause disseminated intravascular coagulation, and metabolic or dietary factors.