A brief history of sex determination
The differences in physiology between males and females of several species have in all likelihood always been noticed. Various explanations have been offered including astronomical signs such as the presence or absence of a halo around the moon during conception, and the ‘heat’ of the father in determining the sex of the child. While examples of this sort are numerous and often entertaining, the modern view of sex determination arose in the early 20th century. The prevailing belief around this time was that sex was determined by external environmental stimuli, such as nutrition, as opposed to internal genetic causes.
The first hints that there was a genetic basis of sex determination came from the cytological work of Hermann Henking, Clarence McClung, Nettie Stevens and E. B. Wilson. These experiments provided important correlative evidence of the presence and absence of specific chromosomes with being male and female. For example, using the mealworm beetle, Tenebrio Molitor, Nettie Stevens identified that male mealworms made sperm with either 10 chromosomes of a large size or 9 large chromosomes and 1 small chromosome. Crucially, when she looked in the somatic cells of males and females, she found that females have 20 large chromosomes, while males have 19 large chromosomes and 1 small chromosome. She concluded that ‘this result suggests that there may be in many cases some intrinsic difference affecting sex. The large unpaired chromosome in males was later termed the X and the small chromosome, if present, was termed the Y chromosome. Shortly thereafter, Theophilus Painter conducted careful cytological work in human testicular tissue, discovering that humans too had a difference in their chromosomal complement between males and females. Specifically, in males, he found one X and one Y chromosomes where females had two X chromosomes.
These discoveries were significant in identifying the potential causes of sex determination in mammals and in other species. However, particularly in mammals, a key question remained regarding the role of the Y chromosome in sex determination. Two chromosomal abnormalities observed in human populations helped settle this question. First, it was shown that patients with Klinefelter syndrome, who display male sexual characteristics, have a XXY karyotype. Second, it was discovered that patients with Turner syndrome, who display female sexual development, have a X karyotype. These results strongly confirmed that, in humans, the presence of a Y chromosome was a dominant determinant of male sexual differentiation and the presence of a single X chromosome was sufficient for female development.
While identifying the importance of the genetic underpinnings of sex determination, a key question remained untouched. Namely, does the organism make cell-autonomous decisions resulting in the various sexual differentiation characteristics or is there a specific organ that is primarily affected by the genetic difference that is then responsible for the sexual differentiation of the rest of the embryo?
The key experiment in determining the causal role of the gonad and the hormones it produces in development was conducted by Alfred Jost in 1947. In a technically challenging experiment, Jost removed gonads from rabbits in utero and then allowed them to develop. He noted that, while the removal of gonads from female rabbits at any stage had no impact of the development of female characteristics, the removal of male gonads had a time-sensitive phenotype. Specifically, late removal of the gonads from male rabbits (day 23 onward) had no influence on the development of male characteristics. However, removing the gonad at earlier stages in male rabbits caused them to develop as phenotypical females. Later work showed that the two hormones produced by the testis that were instrumental in producing male sexual development were testosterone and Anti-Mullerian Hormone. This was a convincing argument that, in mammals, the gonad was the central organ involved in governing the sexual differentiation of the rest of the organism.
Sexual development, in mammals, can be thought of as a hierarchy with three levels. Genetic sex is set at fertilization when an X-bearing egg is fertilized by an X- or Y- bearing sperm. In a process known as primary sex determination, this genetic difference leads to a difference in gonadal sex, i.e. the development of either an ovary in XX embryos, or a testis in XY embryos. The gonads then produce the hormones necessary to direct the sexual differentiation of the rest of the embryo.
In mice, genetic sex is determined at fertilization by an X or a Y bearing sperm. In a process known as primary sex determination, this genetic difference governs the differentiation of the gonad to an ovary (XX) or a testis (XY). The gonads produce the hormones necessary for the sexually dimorphic differentiation of the rest of the mouse in a process known as secondary sex differentiation. Picture of mice are from.
Although the dominant role of the Y-chromosome in determining testis differentiation in mammals was made in 1960, it took 3 decades to identify the gene on the Y chromosome that was responsible for this behavior. After a few missteps, the transcription factor Sry was identified as the testis determining factor. The key data came from analyzing three XX individuals who had developed as males. These three individuals shared a 35kb region of the Y-chromosome in which the gene Sry was present. In addition, conservation across mammals, testis specific ex