In trod u ct io n
It is now some 32 years since the search for the male sex determining gene(s), TDF in man and Tdy in mouse, was initiated in earnest by three papers published in 1959 showing that, in both these species, the Y chromosome is necessary for testis Since that point, tracking down TDF and Tdy has proceeded through an intimate interplay of studies in man and mouse. Karyotype/phenotype correlations in human individuals with abnormal Y chromosomes affecting sexual phenotype have been central in this process by progressively eliminating large sections of the human Y as candidate regions harbouring TDF. Thus, in 1966> Jacobs and Ross(4) were able to demonstrate that TDFmust reside on Yp (the short arm of the human Y chromosome), hence greatly rcducing the area of the Y under consideration. Over the next 10 to 20 years, various pretenders to the TDF and Tdy crown perished, the most notable being the malespecific H-Y antigen(') and the conserved, sex-specific repetitive Bkm DNA sequence first described in the snake the banded kraid6). The creation of male mice failing to express H-Y antigen(') excluded the formcr and the lack of Bkm sequences on the human Y chromosome the latter.
Sex-Reversed XX Males and XY Females
Men carrying two X chromosomes and no Y and women carrying a single X and Y chromosome have proved crucial in delineating the key region of the Y carrying TDF. The hypothesis first advanced in 1966 by Ferguson-Smith(*) to explain these sex-reversed individuals, proved to be a milestone in understanding the aetiology of their sexual phenotype. Ferguson-Smith proposed that sex-reversal could be explained most simply by rare illegitimate X-Y recombination (outside the pseudoautosomal pairing region of the sex chromosomes where genetic exchange is normally permitted) leading to the transfer of TDF to the paternal X and its loss from the paternal Y. The reciprocal gametes carrying these sex chromosomes would, therefore, give rise respectively to XX males with testes and XY females lacking differentiated gonads (Fig. 1).
It was reasoned that variation in the position of the recombination breakpoint in Yp in different patients X XX male