Evolution of alpha 1,3galactosyltransferase and of the alpha-Gal epitope.

Abstract

Most of the genes studied in humans have homologues in other mammals; however, theα1,3galactosyltransferase (α1,3GT) gene represents a unique exception. Whereas it is highly active in nonprimate mammals, prosimians and New World monkeys (i.e., monkeys of South America), producing one of the most abundant cell surface carbohydrate epitopes, the epitope Galα1–3Galβ1α4GlcNAc-R (termed the α-gal or α-galactosyl epitope), this gene is completely inactive in Old World primates (i.e., humans, apes and Old World monkeys). As discussed below, the inactivation of α1,3GT in ancestral primates was likely to be associated with a catastrophic evolutionary event that led primates of the Old World (i.e., primates of Asia and Africa) into almost complete extinction. Because of this event, humans, apes and Old World monkeys produce very large amounts of a natural antibody against the α-gal epitope. This antibody, termed anti-Gal, constitutes 1% of circulating immunoglobulins and it prevents transplantation of organs or tissues from nonprimate mammals (e.g., pigs) into humans because it readily binds to the α-gal epitopes on such xenografts. It is impossible to determine the actual evolutionary events which have led to inactivation of the α1,3GT gene and suppression of α-gal epitope expression in ancestral Old World primates. However, information on the expression of this epitope in various species, the structure of the α1,3GT pseudogene in primates and the fossil record of primates, enable us to speculate on both the evolutionary period in which α1,3GT gene inactivation occurred, as well as possible causes for this event.