The first Yt (also known as Cartwright) blood group system antigen, ie. Yt^a, was described 1956 by Eaton et al. This blood group antigen was proven to be inherited as a dominant character and independent from the other know systems at that time. In 1964, Giles and Metaxas reported the first example of an antibody that detected the product of the expected antithetical allele, Yt^b. This latter discovery raised the stature of the Yt system, which then became a chromosome marker of about the same potential usefulness as the Lutheran system.

The two antigens of the Yt system, Yt^a and Yt^b, are both expressed at birth, however in a slightly lower expression level than seen on adult cells. They were shown to be resistant to trypsin treatment, but sensitive to other protein cleaving enzymes. Antibodies to these antigens were implicated in cases of delayed transfusion reactions but were not reported to have caused hemolytic disease of the newborn. No examples of Yt(a-b-) individuals have been found despite numerous studies. From population studies, Yt^b appeared to be lacking, or of very low incidence, from Orientals, Amer-Indians and southern Africans; Yt^a was found lacking in approximately one per thousand individuals of European origin.

This system remained unexciting until it was found that both of these antigens were weak or absent from paroxysmal nocturnal hemoglobinuria (PNH) III red blood cells. With a rush of activity in the early 1990's, it was found that the Yt blood group system antigens represented amino acid substitutions on the GPI-linked glycoprotein, acetylcholinesterase (AchE). This protein probably exists as a dimer (pair) in the red cell membrane. Yt^a and Yt^b are equated to substitutions of a hisitidine and asparagine, respectively, at amino acid position 322 on the GPI-linked glycoprotein. AChE has been assigned a chromosome location at 7q22.

As of this date, there have been only two antigens associated with this system. Based on the present knowledge of the placement on AChE, it is far more likely that any new variants will be found investigating AChE peculiarities and their immune response than by standard serological methods.