MBE Advance Access originally published online on March 9, 2005
Molecular Biology and Evolution 2005 22(6):1433-1443; doi:10.1093/molbev/msi130
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Molecular Evolution of Cadherin-Related Neuronal Receptor/Protocadherin 
(CNR/Pcdh) Gene Cluster in Mus musculus Subspecies
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* KOKORO Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; Department of Biology, Graduate School of Science, Osaka University; CREST of Japan Science and Technology Agency; Mouse Genomics Resource Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka-ken 411-8540, Japan; || Mammalian Genetics Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka-ken, 411-8540, Japan; and ¶ Laboratory of Neurobiology and Behavioral Genetics, National Institute for Physiological Sciences, Okazaki, Japan
E-mail: yagi{at}fbs.osaka-u.ac.jp.
The mouse cadherin-related neuronal receptor/protocadherin (CNR/Pcdh) gene clusters are located on chromosome 18. We sequenced single-nucleotide polymorphisms (SNPs) of the CNR/Pcdh
-coding region among 12 wild-derived and four laboratory strains; these included the four major subspecies groups of Mus musculus: domesticus, musculus, castaneus, and bactrianus. We detected 883 coding SNPs (cSNPs) in the CNR/Pcdh variable exons and three in the constant exons. Among all the cSNPs, 586 synonymous (silent) and 297 nonsynonymous (amino acid exchanged) substitutions were found; therefore, the Ka/Ks ratio (nonsynonymous substitutions per synonymous substitution) was 0.51. The synonymous cSNPs were relatively concentrated in the first and fifth extracellular cadherin domain-encoding regions (ECs) of CNR/Pcdh. These regions have high nucleotide homology among the CNR/Pcdh paralogs, suggesting that gene conversion events in synonymous and homologous regions of the CNR/Pcdh cluster are related to the generation of cSNPs. A phylogenetic analysis revealed gene conversion events in the EC1 and EC5 regions. Assuming that the common sequences between rat and mouse are ancestral, the GC content of the third codon position has increased in the EC1 and EC5 regions, although biased substitutions from GC to AT were detected in all the codon positions. In addition, nonsynonymous substitutions were extremely high (11 of 13, Ka/Ks ratio 5.5) in the laboratory mouse strains. The artificial environment of laboratory mice may allow positive selection for nonsynonymous amino acid variations in CNR/Pcdh during inbreeding. In this study, we analyzed the direction of cSNP generation, and concluded that subspecies-specific nucleotide substitutions and region-restricted gene conversion events may have contributed to the generation of genetic variations in the CNR/Pcdh genes within and between species.
Key Words: CNR • protocadherin • SNP • gene conversion
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