title: Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-alpha and -beta gene clusters.
abstract: The human protocadherin (Pcdh) gene clusters are located on chromosome 5q31. Single-nucleotide polymorphisms (SNPs) were detected in the Pcdh-alpha and -beta variable exons, and in the Pcdh-alpha 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-alpha variable exons, but only 1.2 times more common in the Pcdh-beta variable exons. The nonsynonymous SNPs were high in the ectodomain (EC) 1 encoding region of Pcdh-alpha but not of Pcdh-beta. One 48-kb region of extensive linkage disequilibrium (LD) is reported that has two haplotypes extending from the alpha1 to alpha7 genes in the Pcdh-alpha cluster. Here we identified 15 amino acid exchanges in these two major haplotypes; therefore, the two haplotypes encode different sets of Pcdh-alpha proteins in the brain. The distribution of cSNPs was different for each EC region of Pcdh-alpha or -beta. 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-alpha and Pcdh-beta clusters generated the cSNPs. Within the cSNPs, gene conversions were found in Pcdh-alpha4 in the major haplotype, and in Pcdh-beta9. These gene conversions were caused by the unequal crossing-over of homologous sequence regions. Thus, nonsynonymous variations in the Pcdh-alpha and -beta genes are possible contributors to the variations in human brain function.
authors.affiliation: KOKORO Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Suita 565-0871, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Miki
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hattori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Taguchi
authors.forename: Motoki N
authors.initials: MN
authors.lastname: Tada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Isosaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hidaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirabayashi
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuzako
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yagi
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D044466:Asian People; D001921:Brain / Q000502:physiology; D015820:Cadherins / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D017124:Conserved Sequence; D004247:DNA / Q000097:blood / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons; D005785:Gene Conversion; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D015820:Cadherins; D004247:DNA