Molecular population genetics of PCSK9: a signature of recent positive selection

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that plays a key role in regulating plasma low density lipoprotein (LDL) cholesterol levels. Both rare mutations and common variants in the coding regions of PCSK9 affect LDL cholesterol levels and coronary heart disease risk, as well as response to lipid-lowering therapy.

The authors characterized the patterns of variation at the PCSK9 locus in African-Americans and European-Americans using resequenced data from the SeattleSNPs database (pga.gs.washington.edu). The authors performed a test of population differentiation and the long-range haplotype test to detect signatures of recent position selection on PCSK9.

A significantly high FST (a measure of population differentiation) between African-Americans and European-Americans was noted for single nucleotide polymorphism (SNP) rs505151 (FST=0.309). The long-range haplotype test was suggestive of non-neutral evolution of two SNPs, rs505151 and rs562556 that are associated with elevated LDL cholesterol levels ('gain-of-function' mutations). The modes of selection were different between African-Americans and European-Americans. The authors observed signals of recent positive selection on the ancestral allele of nonsynonymous SNP rs505151 (E670G, P=0.0227 and P=0.0001 in theoretical and empirical distribution, respectively) and the derived allele of nonsynonymous SNP rs562556 (I474V, P=0.0227 and 0.0001) in African-Americans, whereas in European-Americans the ancestral allele of SNP rs562556 (P=0.1320 and 0.0370) appeared to be under positive selection.

The authors' findings suggest that evolutionary dynamics may underlie the 'gain-of-function' mutations in PCSK9 that are associated with higher LDL cholesterol levels.