Comparative genomics and diversifying selection of the clustered vertebrate protocadherin genes.
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, beta, 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.
Wu
Qiang
Q
Department of Human Genetics, University of Utah, Salt Lake City, 84112, USA. qwu@genetics.utah.edu
D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000235:genetics*; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D003062:Codon; D018076:DNA, Complementary / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons; D014644:Genetic Variation; D023281:Genomics / Q000379:methods*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D002679:Pan troglodytes; D010641:Phenotype; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D051381:Rats; D015027:Zebrafish
D015820:Cadherins; D003062:Codon; D018076:DNA, Complementary; C502403:FAT1 protein, human; C502405:Fat1 protein, rat; C502406:fat1 protein, mouse
Genetics. 2000 May;155(1):431-49
10790415
Am J Hum Genet. 2003 Mar;72(3):621-35
12577201
J Mol Biol. 1994 Feb 4;235(5):1501-31
8107089
Nature. 2004 Apr 1;428(6982):493-521
15057822
Mol Cell Biol. 1999 May;19(5):3225-36
10207048
Genetics. 1998 Mar;148(3):929-36
9539414
Br J Psychiatry. 2002 Oct;181:295-7
12356655
Trends Ecol Evol. 2000 Dec 1;15(12):496-503
11114436
Science. 2002 May 17;296(5571):1308-13
11964443
Mol Biol Evol. 2000 Jun;17(6):975-8
10833204
Genome Res. 2002 Jun;12(6):996-1006
12045153
J Cell Sci. 1995 Dec;108 ( Pt 12):3765-73
8719883
Genome Res. 2001 Mar;11(3):389-404
11230163
Neuron. 1998 Jun;20(6):1137-51
9655502
Genetics. 2003 Jul;164(3):1229-36
12871927
Mol Biol Evol. 2001 Apr;18(4):503-13
11264401
Mol Biol Evol. 1989 Sep;6(5):447-59
2796726
Genomics. 2000 Jan 1;63(1):75-87
10662547
J Neurosci. 2003 Jun 15;23(12):5096-104
12832533
Genome Res. 2004 Jan;14(1):79-89
14672974
Genet Res. 2003 Apr;81(2):115-21
12872913
Gene. 2004 Oct 13;340(2):197-211
15475161
Genome Res. 2004 Mar;14(3):354-66
14993203
J Cell Biol. 2001 Jul 9;154(1):231-43
11449003
Genome Res. 2004 Apr;14(4):591-602
15060000
Nat Rev Genet. 2003 Jan;4(1):20-8
12509750
Genetics. 2000 Nov;156(3):1299-308
11063703
Cell. 1999 Jun 11;97(6):779-90
10380929
J Biol Chem. 2004 Nov 19;279(47):49508-16
15347688
Neuron. 1999 Jul;23(3):427-30
10433255
Comput Appl Biosci. 1997 Oct;13(5):555-6
9367129
Electrophoresis. 1997 Dec;18(15):2714-23
9504803
Nucleic Acids Res. 2003 Jul 1;31(13):3537-9
12824361
Curr Opin Struct Biol. 2003 Dec;13(6):690-8
14675546
Genomics. 1995 Oct 10;29(3):631-40
8575755
Proc Natl Acad Sci U S A. 1963 Oct;50:703-10
14077501
Am J Hum Genet. 2001 Feb;68(2):444-56
11170892
Mol Biol Evol. 1998 Jan;15(1):50-60
9491604
J Mol Evol. 1994 Sep;39(3):306-14
7932792
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
Mol Cell. 2002 Jul;10(1):21-33
12150904
Genes Dev. 2002 Aug 1;16(15):1890-905
12154121
Genomics. 2004 Apr;83(4):717-26
15028293
Nature. 1988 Sep 8;335(6186):167-70
3412472
Proc Natl Acad Sci U S A. 1989 Feb;86(3):958-62
2492668
Neuron. 2002 Dec 5;36(5):843-54
12467588
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11820-4
10518534