Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-α and -β gene clusters

The human protocadherin (Pcdh) gene clusters are located on chromosome 5q31. Single-nucleotide polymorphisms (SNPs) were detected in the Pcdh-α and -β variable exons, and in the Pcdh-α constant exon, in samples from 104 individuals. Among coding SNPs (cSNPs), nonsynonymous (amino acid exchange) SNPs were 2.2 times more common than synonymous (silent) changes in the Pcdh-α variable exons, but only 1.2 times more common in the Pcdh-β variable exons. The nonsynonymous SNPs were high in the ectodomain (EC) 1 encoding region of Pcdh-α but not of Pcdh-β. One 48-kb region of extensive linkage disequilibrium (LD) is reported that has two haplotypes extending from the α1 to α7 genes in the Pcdh-α cluster. Here we identified 15 amino acid exchanges in these two major haplotypes; therefore, the two haplotypes encode different sets of Pcdh-α proteins in the brain. The distribution of cSNPs was different for each EC region of Pcdh-α or -β. The frequency of cSNPs was negatively correlated with the paralogous sequence diversity. These results suggested that gene conversion events in homologous regions of the Pcdh-α and Pcdh-β clusters generated the cSNPs. Within the cSNPs, gene conversions were found in Pcdh-α4 in the major haplotype, and in Pcdh-β9. These gene conversions were caused by the unequal crossing-over of homologous sequence regions. Thus, nonsynonymous variations in the Pcdh-α and -β genes are possible contributors to the variations in human brain function.