title: Molecular evolution of GYPC: evidence for recent structural innovation and positive selection in humans.
abstract: GYPC encodes two erythrocyte surface sialoglycoproteins in humans, glycophorin C and glycophorin D (GPC and GPD), via initiation of translation at two start codons on a single transcript. The malaria-causing parasite Plasmodium falciparum uses GPC as a means of invasion into the human red blood cell. Here, we examine the molecular evolution of GYPC among the Hominoidea (Greater and Lesser Apes) and also the pattern of polymorphism at the locus in a global human sample. We find an excess of nonsynonymous divergence among species that appears to be caused solely by accelerated evolution of GYPC in the human lineage. Moreover, we find that the ability of GYPC to encode both GPC and GPD is a uniquely human trait, caused by the evolution of the GPC start codon in the human lineage. The pattern of polymorphism among humans is consistent with a hitchhiking event at the locus, suggesting that positive natural selection affected GYPC in the relatively recent past. Because GPC is exploited by P. falciparum for invasion of the red blood cell, we hypothesize that selection for evasion of P. falciparum has caused accelerated evolution of GYPC in humans (relative to other primates) and that this positive selection has continued to act in the recent evolution of our species. These data suggest that malaria has played a powerful role in shaping molecules on the surface of the human red blood cell. In addition, our examination of GYPC reveals a novel mechanism of protein evolution: co-option of untranslated region (UTR) sequence following the formation of a new start codon. In the case of human GYPC, the ancestral protein (GPD) continues to be produced through leaky translation. Because leaky translation is a widespread phenomenon among genes and organisms, we suggest that co-option of UTR sequence may be an important source of protein innovation.
authors.affiliation: Department of Biological Sciences, Northern Arizona University, USA. jason.wilder@nau.edu
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wilder
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Hewett
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Gansner
mesh_terms: D001483:Base Sequence; D003062:Codon / Q000235:genetics; D019143:Evolution, Molecular; D006021:Glycophorins / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010442:Peptide Chain Initiation, Translational / Q000235:genetics; D011110:Polymorphism, Genetic; D012641:Selection, Genetic / Q000235:genetics*
chemical_list: D003062:Codon; D006021:Glycophorins
references.citation: Proc Natl Acad Sci U S A. 1979 Oct;76(10):5269-73
references.pmid: 291943
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2358-62
references.pmid: 16461900
references.citation: Nature. 1991 Jun 20;351(6328):652-4
references.pmid: 1904993
references.citation: Trends Genet. 2002 Nov;18(11):559-63
references.pmid: 12414185
references.citation: Genetics. 2002 Mar;160(3):1179-89
references.pmid: 11901132
references.citation: Biochem J. 1988 Mar 1;250(2):407-14
references.pmid: 2833242
references.citation: Genetics. 2000 May;155(1):431-49
references.pmid: 10790415
references.citation: Annu Rev Genet. 2005;39:197-218
references.pmid: 16285858
references.citation: J Exp Med. 2002 Dec 2;196(11):1523-8
references.pmid: 12461087
references.citation: Vox Sang. 1972 Jan;22(1):73-84
references.pmid: 5011657
references.citation: Genetics. 2006 Nov;174(3):1431-9
references.pmid: 16951063
references.citation: Gene. 2002 Oct 16;299(1-2):1-34
references.pmid: 12459250
references.citation: J Biol Chem. 1993 Jan 25;268(3):2260-7
references.pmid: 8420995
references.citation: Genetics. 1993 Mar;133(3):693-709
references.pmid: 8454210
references.citation: Mol Cell Biochem. 1973 Dec 15;2(2):197-218
references.pmid: 4272551
references.citation: Mol Biol Evol. 2002 Mar;19(3):223-9
references.pmid: 11861881
references.citation: Theor Popul Biol. 1975 Apr;7(2):256-76
references.pmid: 1145509
references.citation: Immunol Cell Biol. 1994 Feb;72(1):23-7
references.pmid: 8157284
references.citation: Genetics. 2000 Jul;155(3):1405-13
references.pmid: 10880498
references.citation: Methods Enzymol. 1974;31:168-72
references.pmid: 4278921
references.citation: Genetics. 2004 Oct;168(2):1041-51
references.pmid: 15514074
references.citation: Am J Hematol. 2004 Jan;75(1):1-5
references.pmid: 14695625
references.citation: Mol Biol Evol. 2003 Jan;20(1):18-20
references.pmid: 12519901
references.citation: Blood. 2001 Dec 1;98(12):3489-91
references.pmid: 11719395
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12819-24
references.pmid: 16126901
references.citation: Bioinformatics. 2003 Dec 12;19(18):2496-7
references.pmid: 14668244
references.citation: Nat Med. 2003 Jan;9(1):87-92
references.pmid: 12469115
references.citation: Mol Biol Evol. 2007 Aug;24(8):1586-91
references.pmid: 17483113
references.citation: Trends Parasitol. 2001 Jun;17(6):297-9
references.pmid: 11378038
references.citation: Trends Parasitol. 2008 Nov;24(11):517-24
references.pmid: 18805736
references.citation: Mol Biol Evol. 2003 Nov;20(11):1795-804
references.pmid: 12949139
references.citation: Gene. 1995 Jul 4;159(2):225-30
references.pmid: 7622054
references.citation: Mol Biol Evol. 2005 Apr;22(4):1107-18
references.pmid: 15689528
references.citation: Genetics. 2002 Feb;160(2):765-77
references.pmid: 11861577
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2518-23
references.pmid: 14983041
references.citation: Br J Haematol. 1995 Mar;89(3):440-8
references.pmid: 7734343
references.citation: Blood. 1996 Sep 15;88(6):2364-5
references.pmid: 8822964
references.citation: Mol Biol Evol. 2005 Dec;22(12):2472-9
references.pmid: 16107592
references.citation: Genetics. 2003 Aug;164(4):1495-509
references.pmid: 12930755
references.citation: Infect Immun. 2009 Apr;77(4):1689-99
references.pmid: 19204093
references.citation: Genetics. 2000 Jul;155(3):1415-27
references.pmid: 10880499
references.citation: Genetics. 1989 Nov;123(3):585-95
references.pmid: 2513255
references.citation: Int J Parasitol. 2004 Dec;34(13-14):1413-29
references.pmid: 15582519