Genetic evidence of X–Y interchange in a human XX male

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Abstract
Of the hypotheses put forward to explain why occasional individuals with two X chromosomes are nonetheless male, the one that has attracted most attention is the possibility1 that one of the X chromosomes has obtained a small piece of Y chromosome which is sufficient to produce ‘maleness’. This hypothesis was based primarily on the observation that in two families with XX males2–4 both fathers were Xg(a+) and both probands Xg(a−). (Xg shows X-linked dominant inheritance.) This theory holds that an anomalous X–Y interchange at meiosis in the father resulted hi the paternal X chromosome's losing the Xg gene and acquiring a male-determining gene from the Y chromosome. While, for example, the frequencies of Xg phenotypes among XX males5,6 and the cytogenetic observation of a structural abnormality in one X7,8 are compatible with this hypothesis, direct evidence of it is lacking. Here we describe an XX male who expresses his father's allele for 12E7, a Y-linked marker, but fails to express his father's allele for Xg, an X-linked marker. These findings strongly suggest that anomalous X–Y interchange occurred in this case and perhaps in that of many other XX males. We suggest that a male-determining gene on the Y has also been translocated to the X and caused maleness in the proband. These results are discussed in the light of current models of X–Y chromosomal homology.