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

ABSTRACT: 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.

SUBMITTER: Ding K

PROVIDER: S-EPMC2842919 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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

Ding Keyue K Kullo Iftikhar J IJ

Pharmacogenetics and genomics 20080301 3

<h4>Objective</h4>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.<h4>Methods</h4>The authors characterized the patterns of variation at the PCSK9 locus in African-Americans and ...[more]

PMID: 18300938

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Project description:BACKGROUND:Recent human transcriptomic analyses revealed a very large number of testis-enriched genes, many of which are involved in spermatogenesis. This comprehensive transcriptomic data lead us to the question whether positive selection was a decisive force influencing the evolution and variability of testis-enriched genes in humans. We used two methodological approaches to detect different levels of positive selection, namely episodic positive diversifying selection (i.e., past selection) in the human lineage within primate phylogeny, potentially driven by sperm competition, and recent positive directional selection in contemporary human populations, which would indicate adaptation to different environments. RESULTS:In the human lineage (after correction for multiple testing) we found that only the gene TULP2, for which no functional data are yet available, is subject to episodic positive diversifying selection. Using less stringent statistical criteria (uncorrected p-values), also the gene SPATA16, which has a pivotal role in male fertility and for which episodes of adaptive evolution have been suggested, also displays a putative signal of diversifying selection in the human branch. At the same time, we found evidence for recent positive directional selection acting on several human testis-enriched genes (MORC1, SLC9B1, ROPN1L, DMRT1, PLCZ1, RNF17, FAM71D and WBP2NL) that play important roles in human spermatogenesis and fertilization. Most of these genes are population-specifically under positive selection. CONCLUSION:Episodic diversifying selection, possibly driven by sperm competition, was not an important force driving the evolution of testis-enriched genes in the human lineage. Population-specific, recent positive directional selection suggests an adaptation of male reproductive genes to different environmental conditions. Positive selection acts on eQTLS and sQTLs, indicating selective effects on important gene regulatory functions. In particular, the transcriptional diversity regulated by sQTLs in testis-enriched genes may be important for spermatocytes to respond to environmental and physiological stress.

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

Publications

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

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