sex determination

sex determination Theories and myths about what might cause a child to be boy or girl, and what action might be taken to select one or the other, have no doubt been part of all human cultures. Of those that are recorded, we know that it was a common Hippocratic view, believed by Galen, that the right testicle and the right side of the womb produced male children, and the left counterparts, female. This was disputed by Aristotle, who contended that the male determined the sex of the offspring. And he proved to be correct: the sex of a child is determined by the father's sperm.

The germinal cell from which the sperm was formed contained, like all other cells in the man's body, 22 pairs of chromosomes plus another dissimilar pair of sex chromosomes — an X and a Y. The split that resulted in sperms meant that each sperm carried one of these two alternative chromosomes: either an X or a Y, and one copy of each of the other 22 chromosomes. The mother's germinal cells had 22 pairs plus paired X chromosomes, so that every ovum had an X. Fertilization may therefore result in an embryo carrying either two X chromosomes (one from the father, one from the mother), when development will be female (XX), or an X chromosome from the mother and a Y from the father chromosome, when development will be male (XY).

How does this happen? Sometimes the inheritance of the sex chromosomes is disturbed, and this provides clues to the normal mechanism. A person with only one X chromosome and no Y chromosome (XO) develops as a female, whereas an individual with one or more X chromosomes but also at least one Y chromosome develops as a male. An experiment by the French physiologist Jost provided the basis of our understanding of the processes underlying male or female development. He operated on fetal rabbits to remove their gonads at a stage before they had developed in either a male or female direction. All fetuses from whom the testis rudiment had been removed developed as though they were female, as also did those from whom the developing ovary was removed. Thus female development is the default. It is the presence of a testis which causes male development. The testis itself develops as a result of the presence of a Y chromosome. Thus the Y chromosome determines male development by the possession of some testis determining factor (TDF).

Analysis of individual people who have either inherited an altered Y chromosome and are still female, or who apparently have 2 XX chromosomes but are male, revealed that it was only a small region of the Y chromosome which was responsible as TDF. Pieces of the Y chromosome were either missing or located in another place, and it was therefore possible to identify the gene responsible, by a positional cloning approach. At the same time as this work was progressing a mouse was discovered with a Y chromosome with a mutation that made its TDF non-functional.

Other workers isolated a candidate human gene that fulfilled all the criteria for the TDF. The scientist who had isolated the mutant mice was able to show that the equivalent gene was mutated and that its normal expression was at a critical early stage of testis development. The final proof that this was the gene responsible for sex determination came when the two groups collaborated to make mice carrying an extra copy of the human gene. These mice developed as males.

This is therefore an example of a gene which causes a switch in developmental direction. We now need to know how this gene function is turned on at the critical point of gonad development and what downstream functions it itself controls to cause male development.

Martin Evans

See also genetics, human; germ cells; gonads; heredity.