Molecular basis of evolutionary loss of the alpha 1,3-galactosyltransferase gene in higher primates.
Galactose-alpha1,3-galactose (alphaGal) epitopes, the synthesis of which requires the enzyme product of alpha1,3-galactosyltransferase (alpha1,3GT), are sugar chains on the cell surface of most mammalian species. Notable exceptions are higher primates including Old World monkeys, apes, and humans. The alphaGal-negative species as well as mice with deletion of the alpha1,3GT gene produce abundant anti-alphaGal antibodies. The evolutionary loss of alphaGal epitopes has been attributed to point mutations in the coding region of the gene. Because no transcripts could be found in the higher primate species with Northern blot analysis, a potential alternative explanation has been loss of upstream regulation of the gene. Here, we have demonstrated that the rhesus promoter is functional. More importantly, a variety of full-length transcripts were detected with sensitive PCR-based methods in the tissues of rhesus monkeys, orangutans, and humans. Five crucial mutations were delineated in the coding region of the human and rhesus and three in the orangutan, any one of which could be responsible for inactivation of the alpha1,3GT gene. Two of the mutations were shared by all three higher primates. These findings, which elucidate the molecular basis for the evolutionary loss of alphaGal expression, may have implications in medical research.
Koike
Chihiro
C
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA. koikec@msx.upmc.edu
Fung
John J
JJ
Geller
David A
DA
Kannagi
Reiji
R
Libert
Therese
T
Luppi
Patrizia
P
Nakashima
Izumi
I
Profozich
Jennifer
J
Rudert
William
W
Sharma
Sugandha B
SB
Starzl
Thomas E
TE
Trucco
Massimo
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002417:Cattle; D002520:Cercopithecidae; D019143:Evolution, Molecular; D005091:Exons; D005700:Galactosyltransferases / Q000235:genetics*; D016678:Genome; D015894:Genome, Human; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011148:Pongo pygmaeus; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D012333:RNA, Messenger; D008156:Luciferases; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase