Inheritance of the Sex‐Determining Factor in the Absence of a Complete Y Chromosome in 46,XX Human Males

Sex determination in mammals depends on the presence or absence of a testisdetermining factor (TDF) located on the Y chromosome. In humans, it has been proposed that TDF is localized on the short arm of the Y chromosome.' Approximately 1 in 20,000 phenotypic males have a 46,XX genotype;* these men are infertile and have small testes. Many XX males have visible translocations of Y chromosomal material to one of the X chromosomes. High resolution cytogenetic analyses of these X:Y translocations indicate that the Y fragment is probably a derivative of the tip of the short arm of the Y chrom~some.~ Some 46,XX males have no visible translocation, however. Do these individuals also have Y-derived sequences in their genome? We have studied seven 46,XX males, three with, and four without, visible translocations of Y material, by Southern analysis. The results are summarized in TABLE 1. All six individuals were negative for the Y centromeric probe Y97: consistent with the absence of a complete Y chromosome. The genomic probe p75/79 was previously subcloned from cosmid Y75 from a human Y libraryS and recognizes a 2.0 kb Eco RI fragment localized on the short arm of the Y chromosome by somatic cell genetics and on the tip of the Y short arm by in situ hybridization. The 3 XX males with visible translocations were positive for the Yspecific 2.0 kb Eco RI fragment recognized by ~75179. Even in the absence of a visible translocation, DNA from the other 3 XX males also contained the 2.0 kb Eco RI fragment. In addition, DNA from two XX males with visible translocations was hybridized with p52d,6 which recognizes Y short arm sequences centromeric to p75/79. One is positive, and one is negative for p52d, indicating that variable amounts of Y material were translocated. It appears that XX males inherit a small, though variable portion of DNA from the proximal end of the short arm of the Y chromosome, which appears to contain the sex-determining region. The simple explanation for the mode of inheritance in cases with visible translocation is that Y material has been added onto the paternal X chromosome. Could XX males, however, with no visible translocations arise by way of crossing-over between the X and Y chromosome just outside the pseudoautosomal region (a region of shared X, Y homology with one obligate crossover per meiosis), which is located at the proximal end of the X and Y short arms? We are currently using a probe localized on the lower boundary of the pseudoautosomal region to investigate this possible mode of inheritance of the sex-determining factor in 46,XX human males. In brief summary, 46,XX males have Y short arm-derived material containing a presumptive sex-determining factor termed the testis-determining factor,