Recent positive selection can also drive increased population differentiation. The VST statistic9 for population differentiation (Fig. 4) is distinct from haplotype-based measures of recent positive selection as it allows assessment of all loci, not just those with biallelic genotype calls (for example, unclusterable events and multiallelic CNVs). The CNV with the highest value of VST between CEU and YRI is an intronic deletion of the PDLIM3 gene, which encodes an abundant protein in skeletal and cardiac muscle. We noted that also among the top five most highly differentiated loci was an intronic VNTR of the gene encoding ACTN2, the sarcomeric protein binding-partner of PDLIM3. Four other pathways with two genes under recent selection have been identified in SNP-based selection scans40,43 (EDAR and EDA2R, SLC24A5 and SLC45A2, NRG and ERBB4, and LARGE and DMD). The possibility that these two highly differentiated CNVs in genes encoding interacting proteins contribute to population44 or individual differences in cardiac or skeletal muscle phenotypes warrants further investigation. Mutations in ACTN3, the close paralogue of ACTN2, alter muscle function in humans and mice45,and a recent study has highlighted an enrichment of genes involved in muscle development among signals of recent positive selection46.
