In the beginning the dogma was that sex determination in man followed the Drosophila pattern in which XO is male, XXY female, and the Y chromosome has no direct influence on the determination of sex. On the grounds of specific anomalies with which they presented, females with Turner Syndrome were sex chromatin tested and found to be chromatin negative [1]. This result, confirmed in 1956 by the male frequency of red-green colour blindness in these subjects which indicated that they carried only one X chromosome in spite of their female phenotype, suggested that therefore they might be XO, and, so, hinted that sex determination in man might not follow the then accepted pattern [2]. In 1959 chromosome studies confirmed that XOs were female [3] and showed that subjects with the symmetrical XXY sex-chromosome anomaly were with Klinefelter syndrome [4]. In the same year, by showing that XOs were females also in mice [5] it became accepted that the Y chromosome was the determiner of the formation of the testis in the mammalian embryo, and so was the key element in primary sexual differentation. It would seem appropriate to call this formal model of chromosomal sex determination the Malandrium pattern [6].

In 1966 Jacobs and Ross [7], from work on males with Y chromosome deletions narrowed down the testis determining function of the Y chromosome to its short arm. Then, in 1975, Wachtel and collaborators [8] were the first to formulate a hypothesis on the sex determining gene, or, more precisely on the nature of its product. They suggested that this developmental role might be played by the H-Y antigen, a weak histocompatibility antigen which had been known to be involved in the rejection of male skin grafted onto otherwise histocompatible female mice. The idea had run into technical difficulties and a major problem was related to the significance that should be attached to the results of two different ways for demonstrating the antigen, namely the cell-mediated cytotoxicity test or the serological test. Efforts were made to keep the H-Y hypothesis alive, largely because there was a certain elegance about it [9, 10]. However eventually XX male mice, lacking H-Y by either test, spelt the end of the candidature of H-Y as the testis determining mechanism [11, 12].