Originally published as Genetics Published Articles Ahead of Print on March 2, 2005.

Genetics, Vol. 169, 2179-2188, April 2005, Copyright © 2005
doi:10.1534/genetics.104.037606

Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes

Qiang Wu1

Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112

1 Address for correspondence: Department of Human Genetics, University of Utah, 15N 2030E, Salt Lake City, UT 84112.
E-mail: qwu{at}genetics.utah.edu

To explain the mechanism for specifying diverse neuronal connections in the brain, Sperry proposed that individual cells carry chemoaffinity tags on their surfaces. The enormous complexity of these connections requires a tremendous diversity of cell-surface proteins. A large number of neural transmembrane protocadherin (Pcdh) proteins is encoded by three closely linked human and mouse gene clusters ({alpha}, ß, and {gamma}). To gain insight into Pcdh evolution, I performed comprehensive comparative cDNA and genomic DNA analyses for the three clusters in the chimpanzee, rat, and zebrafish genomes. I found that there are species-specific duplications in vertebrate Pcdh genes and that additional diversity is generated through alternative splicing within the zebrafish "variable" and "constant" regions. Moreover, different codons (sites) in the mammalian Pcdh ectodomains (ECs) are under diversifying selection, with some under diversity-enhancing positive Darwinian selection and others, including calcium-binding sites, under strong purifying selection. Interestingly, almost all positively selected codon positions are located on the surface of ECs 2 and 3. These diversified residues likely play an important role in combinatorial interactions of Pcdh proteins, which could provide the staggering diversity required for neuronal connections in the brain. These results also suggest that adaptive selection is an additional evolutionary factor for increasing Pcdh diversity.




This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
W.-P. Yu, V. Rajasegaran, K. Yew, W.-l. Loh, B.-H. Tay, C. T. Amemiya, S. Brenner, and B. Venkatesh
Elephant shark sequence reveals unique insights into the evolutionary history of vertebrate genes: A comparative analysis of the protocadherin cluster
PNAS, March 11, 2008; 105(10): 3819 - 3824.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
D. T. Gerrard and A. Meyer
Positive Selection and Gene Conversion in SPP120, a Fertilization-Related Gene, during the East African Cichlid Fish Radiation
Mol. Biol. Evol., October 1, 2007; 24(10): 2286 - 2297.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. S. Braun, M. Kretzler, T. Heider, J. Floege, L. B. Holzman, W. Kriz, and M. J. Moeller
Differentially Spliced Isoforms of FAT1 Are Asymmetrically Distributed within Migrating Cells
J. Biol. Chem., August 3, 2007; 282(31): 22823 - 22833.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
K. Tsuritani, T. Irie, R. Yamashita, Y. Sakakibara, H. Wakaguri, A. Kanai, J. Mizushima-Sugano, S. Sugano, K. Nakai, and Y. Suzuki
Distinct class of putative "non-conserved" promoters in humans: Comparative studies of alternative promoters of human and mouse genes
Genome Res., July 1, 2007; 17(7): 1005 - 1014.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Kaneko, H. Kato, Y. Kawamura, S. Esumi, T. Hirayama, T. Hirabayashi, and T. Yagi
Allelic Gene Regulation of Pcdh-{alpha} and Pcdh-{gamma} Clusters Involving Both Monoallelic and Biallelic Expression in Single Purkinje Cells
J. Biol. Chem., October 13, 2006; 281(41): 30551 - 30560.
[Abstract] [Full Text] [PDF]