Skip to main content

Advertisement

SpringerLink
Log in

Significance of the Evolutionary α1,3-Galactosyltransferase (GGTA1) Gene Inactivation in Preventing Extinction of Apes and Old World Monkeys

  • Original Article
  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

The α1,3-galactosyltransferase (α1,3GT or GGTA1) gene displays unique evolutionary characteristics. This gene appeared early in mammalian evolution and is absent in other vertebrates. The α1,3GT gene is active in marsupials, nonprimate placental mammals, lemurs (prosimians) and New World monkeys, encoding the α1,3GT enzyme that synthesizes a carbohydrate antigen called “α-gal epitope.” The α-gal epitope is present in large numbers on cell membrane glycolipids and glycoproteins. The α1,3GT gene was inactivated in ancestral Old World monkeys and apes by frameshift single-base deletions forming premature stop codons. Because of this gene inactivation, humans, apes, and Old World monkeys lack α-gal epitopes and naturally produce an antibody called the “anti-Gal antibody” which binds specifically to α-gal epitopes and which is the most abundant antibody in humans. The evolutionary event that resulted in the inactivation of the α1,3GT gene in ancestral Old World primates could have been mediated by a pathogen endemic to Eurasia–Africa landmass that exerted pressure for selection of primate populations lacking the α-gal epitope. Once the α-gal epitope was eliminated, primates could produce the anti-Gal antibody, possibly as means of defense against pathogens expressing this epitope. This assumption is supported by the fossil record demonstrating an almost complete extinction of apes in the late Miocene and failure of Old World monkeys to radiate into multiple species before that period. A present outcome of this evolutionary event is the anti-Gal-mediated rejection of mammalian xenografts expressing α-gal epitopes in humans, apes, and Old World monkeys.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

α1,3GT:

α1,3-Galactosyltransferase

α-gal epitope:

The structure Galα1-3Galβ1-4GlcNAc-R

GGTA1 :

The α1,3-galactosyltransferase gene

Mya:

Million years ago

NWM:

New World monkeys

OWM:

Old World monkeys

References

  • Agustí J, Sanz de Siria A, Garcés M (2003) Explaining the end of the hominoid experiment in Europe. J Hum Evol 45:145–153

    Article  PubMed  Google Scholar 

  • Alba DM (2012) Fossil apes from the Vallès-Penedès Basin. Evol Anthropol 21:254–269

    Article  PubMed  Google Scholar 

  • Alba DM, Fortuny J, Moya-Sola S (2010) Enamel thickness in Middle Miocene great apes Anoiapithecus, Pierolapithecus and Dryopithecus. Proc R Soc B 277:2237–2245

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Almeida IC, Milani SR, Gorin PA, Travassos LR (1991) Complement-mediated lysis of Trypanosoma cruzi trypomastigotes by human anti- α-galactosyl antibodies. J Immunol 146:2394–2400

    CAS  PubMed  Google Scholar 

  • Andrews P (1992) Evolution and environment in the Hominoidea. Nature 360:641–646

    Article  CAS  PubMed  Google Scholar 

  • Andrews P, Martin L (1991) Hominoid dietary evolution. Philos Trans R Soc Lond B Biol Sci 334:199–209

    Article  CAS  PubMed  Google Scholar 

  • Andrews P, Harrison T, Delson E, Bernor RL, Martin L (1996) Distribution and biochronology of European and southwest Asian Miocene catarrhines. In: Bernor RL, Fahlbusch V, Mittman HW (eds) The evolution of western Eurasian Neogene mammal faunas. Columbia University Press, New York, pp 168–207

    Google Scholar 

  • Avila JL, Rojas M, Galili U (1989) Immunogenic Galα1–3Gal carbohydrate epitopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 142:2828–2834

    CAS  PubMed  Google Scholar 

  • Basu M, Basu S (1973) Enzymatic synthesis of blood group related pentaglycosyl ceramide by an α-galactosyltransferase. J Biol Chem 248:1700–1706

    CAS  PubMed  Google Scholar 

  • Begun DR (2002) The pliopithecoidea. In: Hartwig WC (ed) The primate fossil record. Cambridge University Press, Cambridge, pp 221–240

    Google Scholar 

  • Begun DR, Nargolwalla MC, Kordos L (2012) European Miocene hominids and the origin of the African ape and human clade. Evol Anthropol 21:10–23

    Article  PubMed  Google Scholar 

  • Betteridge A, Watkins WM (1983) Two α-3-d galactosyltransferases in rabbit stomach mucosa with different acceptor substrate specificities. Eur J Biochem 132:29–35

    Article  CAS  PubMed  Google Scholar 

  • Blake DD, Goldstein IJ (1981) An α-d-galactosyltransferase in Ehrlich ascites tumor cells: biosynthesis and characterization of a trisaccharide (α-d-galacto(1-3)-N-acetyllactosamine). J Biol Chem 256:5387–5393

    CAS  PubMed  Google Scholar 

  • Blanken WM, Van den Eijnden DH (1985) Biosynthesis of terminal Gal α1,3Gal β1,4GlcNAc-R oligosaccharide sequences on glycoconjugates. Purification and acceptor specificity of a UDP-Gal: N-acetyl-lactosaminide α1,3-galactosyltransferase from calf thymus. J Biol Chem 260:12927–12934

    CAS  PubMed  Google Scholar 

  • Britten RJ (1986) Rates of DNA sequence evolution differ between taxonomic groups. Science 231:1393–1398

    Article  CAS  PubMed  Google Scholar 

  • Buonomano R, Tinguely C, Rieben R, Mohacsi PJ, Nydegger UE (1999) Quantitation and characterization of anti-Galα1–3Gal antibodies in sera of 200 healthy persons. Xenotransplantation 6:173–180

    Article  CAS  PubMed  Google Scholar 

  • Chatterjee H, Ho S, Barnes I, Groves C (2009) Estimating the phylogeny and divergence times of primates using a supermatrix approach. BMC Evol Biol 9:259

    Article  PubMed Central  PubMed  Google Scholar 

  • Collins BH, Cotterell AH, McCurry KR, Alvarado CG, Magee JC, Parker W, Platt JL (1994) Cardiac xenografts between primate species provide evidence of the α-galactosyl determinant in hyperacute rejection. J Immunol 154:5500–5510

    Google Scholar 

  • Cooper DK, Good AH, Koren E, Oriol R, Malcolm AJ, Ippolito RM, Neethling FA, Ye Y, Romano E, Zuhdi N (1993) Identification of α-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl Immunol 1:198–205

    Article  CAS  PubMed  Google Scholar 

  • Dawkins R (2004) The ancestor’s tale: a pilgrimage to the dawn of life. Houghton Mifflin Harcourt Company, Boston

    Google Scholar 

  • Dor FJ, Tseng YL, Cheng J, Moran K, Sanderson TM, Lancos CJ, Shimizu A, Yamada K, Awwad M, Sachs DH, Hawley RJ, Schuurman HJ, Cooper DK (2004) α1,3-Galactosyltransferase gene-knockout miniature swine produce natural cytotoxic anti-Gal antibodies. Transplantation 78:15–20

    Article  CAS  PubMed  Google Scholar 

  • Fang J, Walters A, Hara H, Long C, Yeh P, Ayares D, Cooper DK, Bianchi J (2012) Anti-gal antibodies in α1,3-galactosyltransferase gene-knockout pigs. Xenotransplantation 19:305–310

    Article  PubMed Central  PubMed  Google Scholar 

  • Galili U (1993) Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotranplantation in humans. Immunol Today 14:480–482

    Article  CAS  PubMed  Google Scholar 

  • Galili U (2013) α1,3-galactosyltransferase knockout pigs produce the natural anti-Gal antibody and simulate the evolutionary appearance of this antibody in primates. Xenotransplantation 20:267–276

    Article  PubMed  Google Scholar 

  • Galili U, Swanson K (1991) Gene sequences suggest inactivation of α1-3 galactosyltransferase in catarrhines after the divergence of apes from monkeys. Proc Natl Acad Sci (USA) 88:7401–7404

    Article  CAS  Google Scholar 

  • Galili U, Rachmilewitz EA, Peleg A, Flechner I (1984) A unique natural human IgG antibody with anti-α-galactosyl specificity. J Exp Med 160:1519–1531

    Article  CAS  PubMed  Google Scholar 

  • Galili U, Macher BA, Buehler J, Shohet SB (1985) Human natural anti-α-galactosyl IgG. II. The specific recognition of α(1,3)-linked galactose residues. J Exp Med 162:573–582

    Article  CAS  PubMed  Google Scholar 

  • Galili U, Clark MR, Shohet SB, Buehler J, Macher BA (1987) Evolutionary relationship between the anti-Gal antibody and the Galα1,3Gal epitope in primates. Proc Natl Acad Sci USA 84:1369–1373

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffis JM (1988a) Interaction between human natural anti-α-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun 56:1730–1737

    CAS  PubMed Central  PubMed  Google Scholar 

  • Galili U, Shohet SB, Kobrin E, Stults CLM, Macher BA (1988b) Man, apes, and Old World monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J Biol Chem 263:17755–17762

    CAS  PubMed  Google Scholar 

  • Galili U, Tibell A, Samuelsson B, Rydberg L, Groth CG (1995) Increased anti-Gal activity in diabetic patients transplanted with fetal porcine islet cell clusters. Transplantation 59:1549–1556

    Article  CAS  PubMed  Google Scholar 

  • Galili U, Repik PK, Anaraki F, Mozdzanowska K, Washko G, Gerhard W (1996) Enhancement of antigen presentation of influenza virus hemagglutinin by the natural human anti-Gal antibody. Vaccine 14:321–328

    Article  CAS  PubMed  Google Scholar 

  • Good AH, Cooper DK, Malcolm AJ, Ippolito RM, Koren E, Neethling FA, Ye Y, Zuhdi N, Lamontagne LR (1992) Identification of carbohydrate structures which bind human anti-porcine antibodies: implication for discordant xenografting in man. Transplant Proc 24:559–562

    CAS  PubMed  Google Scholar 

  • Han W, Cai L, Wu B, Xiao Z, Cheng J, Wang PG (2012) The wciN gene encodes an α-1,3-galactosyltransferase involved in the biosynthesis of the capsule repeating unit of Streptococcus pneumoniae serotype 6B. Biochemistry 51:5804–5810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Henion TR, Macher BA, Anaraki F, Galili U (1994) Defining the minimal size of catalytically active primate α1,3galactosyltransferase: structure function studies on the recombinant truncated enzyme. Glycobiology 4:193–201

    Article  CAS  PubMed  Google Scholar 

  • Joziasse DH, Shaper JH, Van den Eijnden DH, Van Tunen AJ, Shaper NL (1989) Bovine α1, 3-galactosyltransferase: isolation and characterization of a cDNA clone. Identification of homologous sequences in human genomic DNA. J Biol Chem 264:14290–14297

    CAS  PubMed  Google Scholar 

  • Joziasse DH, Shaper JH, Jabs EW, Shaper NL (1991) Characterization of an α1-3-galactosyltransferase homologue on human chromosome 12 that is organized as a processed pseudogene. J Biol Chem 266:6991–6998

    CAS  PubMed  Google Scholar 

  • Joziasse DH, Shaper NL, Kim D, Van den Eijnden DH, Shaper JH (1992) Murine α1, 3-galactosyltransferase. A single gene locus specifies four isoforms of the enzyme by alternative splicing. J Biol Chem 267:5534–5541

    CAS  PubMed  Google Scholar 

  • Katayama A, Ogawa H, Kadomatsu K, Kurosawa N, Kobayashi T, Kaneda N, Uchimura K, Yokoyama I, Muramatsu T, Takagi H (1998) Porcine α-1,3-galactosyltransferase: full length cDNA cloning, genomic organization and analysis of splicing variants. Glycoconj J 15:583–589

    Article  CAS  PubMed  Google Scholar 

  • Koike C, Fung JJ, Geller DA, Kannagi R, Libert T, Luppi P, Nakashima I, Profozich J, Rudert W, Sharma S, Starzl TE, Trucco M (2002) Molecular basis of evolutionary loss of the α1,3-galactosyltransferase gene in higher primates. J Biol Chem 277:10114–10120

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koike C, Uddin M, Wildman DE, Gray EA, Trucco M, Starzl TE, Goodman M (2007) Functionally important glycosyltransferase gain and loss during catarrhine primate emergence. Proc Natl Acad Sci USA 104:559–564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koop BF, Goodman M, Xu P, Chan K, Slightom JL (1986) Primate eta-globin DNA sequences and man’s place among the great apes. Nature 319:234–238

    Article  CAS  PubMed  Google Scholar 

  • Lai L, Kolber-Simonds D, Park KW, Cheong HT, Greenstein JL, Im GS, Samuel M, Bonk A, Rieke A, Day BN, Murphy CN, Carter DB, Hawley RJ, Prather RS (2002) Production of α-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 295:1089–1092

    Article  CAS  PubMed  Google Scholar 

  • Lantéri M, Giordanengo V, Vidal F, Gaudray P, Lefebvre J-C (2002) A complete α1,3-galactosyltransferase gene is present in the human genome and partially transcribed. Glycobiology 12:785–792

    Article  PubMed  Google Scholar 

  • Larsen RD, Rajan VP, Ruff MM, Kukowska-Latallo J, Cummings D, Lowe JB (1989) Isolation of a cDNA encoding a murine UDP-galactose:β-d-galactosyl-1,4-N-acetyl-d-glucosaminide α-1,3-galactosyltransferase: expression cloning by gene transfer. Proc Natl Acad Sci USA 86:8227–8231

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Larsen RD, Rivera-Marrero CA, Ernst LK, Cummings RD, Lowe JB (1990) Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:β-D-Gal(1,4)-D-GlcNAc α(1,3)-galactosyltransferase cDNA. J Biol Chem 265:7055–7061

    CAS  PubMed  Google Scholar 

  • Lüderitz O, Simmons DA, Westphal G (1965) The immunochemistry of Salmonella chemotype VI O-antigens. The structure of oligosaccharides from Salmonella group U (o 43) lipopolysaccharides. Biochem J 97:820–826

    PubMed Central  PubMed  Google Scholar 

  • Merceron G, Kaiser TM, Kostopoulos DS, Schulz E (2010) Ruminant diets and the Miocene extinction of European great apes. Proc R Soc B 277:3105–3112

    Article  PubMed Central  PubMed  Google Scholar 

  • Miller ER, Benefit BR, McCrossin ML, Plavcan JM, Leakey MG, El-Barkooky AN, Hamdan MA, Abdel Gawad MK, Hassan SM, Simons EL (2009) Systematics of early and middle Miocene Old World monkeys. J Hum Evol 57:195–211

    Article  CAS  PubMed  Google Scholar 

  • Mourant AE, Kopec AC, Domaniewska-Sobczak O (1976) The distribution of blood groups and other polymorphisms, vol 1, 2nd edn. Oxford Press, London, p 1050

    Google Scholar 

  • Perez SI, Tejedor MF, Novo NM, Aristide L (2013) Divergence times and the evolutionary radiation of New World monkeys (Platyrrhini, Primates): an analysis of fossil and molecular data. PLoS ONE 8:e68029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, Ball S, Specht SM, Polejaeva IA, Monahan JA, Jobst PM, Sharma SB, Lamborn AE, Garst AS, Moore M, Demetris AJ, Rudert WA, Bottino R, Bertera S, Trucco M, Starzl TE, Dai Y, Ayares DL (2003) Production of α1,3-galactosyltransferase-deficient pigs. Science 299:411–414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pilbeam D (1984) The descent of hominoids and hominids. Sci Am 250:84–96

    Article  CAS  PubMed  Google Scholar 

  • Posekany KJ, Pittman HK, Bradfield JF, Haisch CE, Verbanac KM (2002) Induction of cytolytic anti-Gal antibodies in α-1,3-galactosyltransferase gene knockout mice by oral inoculation with Escherichia coli O86:B7 bacteria. Infect Immun 70:6215–6222

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pothoulakis C, Galili U, Castagliuolo I, Kelly S, Nikulasson PK, Brasitus TA, Lamont JY (1996) Human anti-Gal IgG binds to the same receptors and mimics the effects of C. difficile Toxin A in rat colon. Gastroenterology 98:641–649

    CAS  Google Scholar 

  • Ramasamy R, Field MC (2012) Terminal galactosylation of glycoconjugates in Plasmodium falciparum asexual blood stages and Trypanosoma brucei bloodstream trypomastigotes. Exp Parasitol 130:314–320

    Article  CAS  PubMed  Google Scholar 

  • Repik PM, Strizki JM, Galili U (1994) Differential host dependent expression of α-galactosyl epitopes on viral glycoproteins: a study of Eastern equine encephalitis virus as a model. J Gen Virol 75:1177–11781

    Article  CAS  PubMed  Google Scholar 

  • Salzano FM (1957) The blood groups of South American Indians. Am J Phys Anthropol 15:555–579

    Article  CAS  PubMed  Google Scholar 

  • Sandrin M, Vaughan HA, Dabkowski PL, McKenzie IFC (1993) Anti-pig IgM antibodies in human serum react predominantly with Galα1–3Gal epitopes. Proc Natl Acad Sci USA 90:11391–11395

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sandrin M, Dabkowski PL, Henning MM, Mouhtouris E, McKenzie IFC (1994) Characterization of cDNA clones for pig α(1,3)galactosyl transferase: the enzyme generating the Gal α(1,3)Gal epitope. Xenotransplantation 1:81–88

    Article  Google Scholar 

  • Schneider P, Schnur LF, Jaffe CL, Ferguson MA, McConville MJ (1994) Glycoinositol-phospholipid profiles of four serotypically distinct Old World Leishmania strains. Biochem J 304:603–609

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schrago CG (2007) On the time scale of New World primate diversification. Am J Phys Anthropol 132:344–354

    Article  PubMed  Google Scholar 

  • Simon PM, Neethling FA, Taniguchi S, Goode PL, Zopf D, Hancock WW, Cooper DK (1998) Intravenous infusion of Galα1–3Gal oligosaccharides in baboons delays hyperacute rejection of porcine heart xenografts. Transplantation 65:346–353

    Article  CAS  PubMed  Google Scholar 

  • Steiper ME, Young NM (2006) Primate molecular divergence dates. Mol Phylogenet Evol 41:384–394

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi Y, Porter CD, Strahan KM, Preece AF, Gustafsson K, Cosset FL, Weiss RA, Collins MK (1996) Sensitization of cells and retroviruses to human serum by (α1-3) galactosyltransferase. Nature 379:85–88

    Article  CAS  PubMed  Google Scholar 

  • Teranishi K, Manez R, Awwad M, Cooper DK (2002) Anti- Gal α1-3Gal IgM and IgG antibody levels in sera of humans and Old World non-human primates. Xenotransplantation 9:148–154

    Article  PubMed  Google Scholar 

  • Ungar PS, Kay RF (1995) The dietary adaptations of European Miocene catarrhines. Proc Natl Acad Sci USA 92:4579–4581

    Article  Google Scholar 

  • Welsh RM, O’Donnell CL, Reed DJ, Rother RP (1998) Evaluation of the Galα1–3Gal epitope as a host modification factor eliciting natural humoral immunity to enveloped viruses. J Virol 72:4650–4656

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu Y, Lorf T, Sablinski T, Gianello P, Bailin M, Monroy R, Kozlowski T, Awwad M, Cooper DK, Sachs DH (1998) Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galα1–3Galβ1-4Glc-R immunoaffinity column. Transplantation 65:172–179

    Article  CAS  PubMed  Google Scholar 

  • Zakhour M, Ruvoën-Clouet N, Charpilienne A, Langpap B, Poncet D, Peters T, Bovin N, Le Pendu J (2009) The α-Gal epitope of the histo-blood group antigen family is a ligand for bovine norovirus Newbury 2 expected to prevent cross-species transmission. PLoS Pathog 5:e1000504

    Article  PubMed Central  PubMed  Google Scholar 

  • Zalmout IS, Sanders WJ, Maclatchy LM, Gunnell GF, Al-Mufarreh YA, Ali MA, Nasser AA, Al-Masari AM, Al-Sobhi SA, Nadhra AO, Matari AH, Wilson JA, Gingerich PD (2010) New Oligocene primate from Saudi Arabia and the divergence of apes and Old World monkeys. Nature 466:360–364

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UMass Medical School, Worcester, MA, USA

    Uri Galili

  2. 910 South Michigan Avenue, Apt. 1404, Chicago, IL, 60605, USA

    Uri Galili

Authors
  1. Uri Galili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uri Galili.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galili, U. Significance of the Evolutionary α1,3-Galactosyltransferase (GGTA1) Gene Inactivation in Preventing Extinction of Apes and Old World Monkeys. J Mol Evol 80, 1–9 (2015). https://doi.org/10.1007/s00239-014-9652-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-014-9652-x

Keywords

Search

Navigation