THE CHROMOSOMAL BASIS OF MAMMALIAN SEX DETERMINATION

In 1916, Bridges described the sex chromosomes of the fruit fly Drosophila melanogaster, ascribing the sex
determining mechanism to the X:autosome ratio, i.e.,2:2 in females (XX), 1:2 in males (XY). When the human
X and Y chromosomes were first described by Painter (177), it was initially thought that humans would have a
similar mechanism. Another 30 years elapsed before the first sex chromosome aneuploid mammals were
discovered, which overturned this hypothesis and conclusively demonstrated that mammalian sex determination
is dependent on the Y chromosome. In humans, XXY individuals develop testes (103) and XO individuals
develop ovaries (75). Consequently, if sex were determined by the X:autosome ratio, the reverse would
have been true. In the following three decades it became increasingly obvious that development of testes is associated with the presence of a single Y-linked gene locus, dubbed TDF (testis determining factor) in humans and Tdy in mice. For simplicity, we will refer to both as TDY. As in all genetic analysis, this understanding arose out of the examination of mutations both in human and mouse that led to varying degrees of sex reversal, i.e., the chromosomal sex does not correlate with the observed sex. However, sterility is also usually a consequence of sex-reversing mutations, and therefore, such cases are generally sporadic, making conventional pedigree-based positional mapping difficult or impossible. Identification of TDY therefore had to rely on the study of sporadic cases of sex reversal