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Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-alpha and -beta gene clusters.

Rie Miki·Kotaro Hattori·Yusuke Taguchi·Motoki N Tada·Tomoko Isosaka·Yuko Hidaka·Takahiro Hirabayashi·Ryota Hashimoto·Hiroshi Fukuzako·Takeshi Yagi
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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.

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AllelesAmino Acid SequenceAmino Acid SubstitutionAsian PeopleBrainCadherinsChromosome MappingChromosomes, Human, Pair 5Conserved SequenceDNAEvolution, MolecularExonsGene ConversionGene FrequencyGenetic VariationHaplotypesHumansLinkage DisequilibriumMolecular Sequence DataMultigene FamilyPhylogenyPolymerase Chain ReactionPolymorphism, Single NucleotideProtein Structure, TertiarySequence Analysis, DNASequence DeletionSequence Homology, Amino AcidComparative StudyJournal ArticleResearch Support, Non-U.S. Gov't

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Rie Miki, Kotaro Hattori, Yusuke Taguchi, Motoki N Tada, Tomoko Isosaka, Yuko Hidaka, Takahiro Hirabayashi, Ryota Hashimoto, Hiroshi Fukuzako, Takeshi Yagi. 2005-04-11. Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-alpha and -beta gene clusters.. https://doi.org/10.1016/j.gene.2004.11.044

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