Sex determination and differentiation (human)
Human sex determination refers to the processes by which an individual becomes either a male or female during development.
The Jost Paradigm
Under typical circumstances, the sex of an individual will be determined and expressed through the following mechanisms:
- Chromosomal Sex (genetic): Presence or absence of Y chromosome
- Gonadal Sex (Primary Sex Determination): Controlled by presence or absence of testis determining factor (TDF)
- Phenotypic Sex (Secondary Sex Differentiation): Determined by the hormonal products produced by the gonads.
Sex determination at the chromosome level
For the majority of individuals, sex determination is as simple as the presence or absence of a Y chromosome. Those individuals with a Y chromosome (including XXY, XXXY, etc.) will develop into males, and those without one will become female. Some individuals, however, will undergo what is referred to as primary sex reversal, whereby the X and Y chromosomes [cross over] and exchange genetic material. This relatively rare occurrence (approximately 1 in 20000 births) can lead to males with two X chromosomes and females with a Y chromosome.
Testis determining gene
During the late 1980s and early 1990s, coinciding with the mapping of the human genome, researchers began to look for the specific gene on the Y chromosome that, up until then, had been known as the testis determining factor (TDF). Through the study of individuals that underwent primary sex reversal (that is, XX males and XY females), researchers determined that the TDF must lie on the Y chromosome in a location that would permit its exchange to the X chromosome during cross over. In 1985, Dr. David C. Page published an article in Nature boldly stating that the TDF was the ZFY gene on the Y chromosome. However, Dr. MS Palmer later discovered a ZFY analogue on the X chromosome, providing evidence that ZFY was in fact not the TDF. Eventually, Dr. Peter Koopman was able to prove that the SRY gene is the TDF from studies on XX males.. The fact that SRY supports the following evidence further supports this claim:
- SRY is Y specific, and there is no analogue on the X chromosome.
- SRY is deleted or mutated in XY females
- It undergoes expression within the testis at the time of testis differentiation.
- Its sequence suggests that its protein has a DNA binding motif because it has high homology to an 80 amino acid long DNA binding region (HMG box).
SRY a repressor?
Recently, it has been suggested by some that the SRY gene acts as a repressor or inhibitor of another gene, “Z”, that is involved in female development. Previously, it was stated that the SRY sequence suggests the presence of a DNA binding motif. Also, the idea that SRY is a repressor is further supported by the fact that a small percentage of sex reversal cases cannot be explained by the absence of SRY and could be due to a mutation in some gene “Z” that prevents the binding of SRY and its subsequent antagonist action.
Other sex determination genes
- DAX1: Exerts its effects early on in development. There is some debate over what its role is in the development of testis. It is a candidate for gene “Z”.
- SOX9: mutations in this gene cause severe dwarfism, and a bone disorder called campomelic dysplasia, which occurs in many sex reversed males. 
Sex differentiation refers to the expression of phenotypic attributes specific to the sex of an individual. While gonad development is a result of the presence or absence of the sex determination gene SRY on the Y chromosome, sex differentiation is determined by the hormonal products produced by the gonads.
Müllerian inhibiting substance
Jost also observed that while testosterone was required for Wolffian duct development, the regression of the Müllerian duct was due to another substance. This was later determined to be Müllerian inhibiting substance (MIS), a 140 kD dimeric glycoprotein that is produced by sertoli cells. MIS blocks the development of Müllerian ducts, promoting their regression.
5-alpha dihydrotestosterone (DHT)
Testosterone is converted to the more potent DHT by 5-alpha reductase. DHT is necessary to exert androgenic effects farther from the site of testosterone production, where the concentrations of testosterone are too low to have any potency. A 5-alpha reductase deficiency results in an androgen disorder characterized by female phenotype or severely undervirilized male phenotype with development of the epididymis, vas deferens, seminal vesicle, and ejaculatory duct, but also a pseudovagina.
The following disorders are caused by a malfunction in the sex determination and differentiation process:
- Congenital Adrenal Hyperplasia - Inability of adrenal to produce sufficient cortisol, leading to increased production of testosterone resulting in severe masculinization of 46 XX females.
- Persistent Müllerian Duct Syndrome - A rare type of pseudohermaphrititism that occurs in 46 XY males, caused by either a mutation in the Müllerian inhibiting substance (MIS) gene, on 19p13, or its type II receptor, 12q13. Results in a retention of Müllerian ducts and unilateral or bilateral undescended testes.
- Male Pseudohermaphroditism - Failure of androgen production or inadequate androgen response, which can cause incomplete masculinization in XY males. Varies from mild failure of masculinization with undescended testes to complete sex reversal and female phenotype.
- Page DC, de la Chapelle A, Weissenbach J (1985). "Chromosome Y-specific DNA in related human XX males". Nature. 315 (6016): 224–6. PMID 2987697. Unknown parameter
- Palmer MS (1989). "Sex determining genes". Science Progress. 73: 245–61. PMID 2678463.
- Koopman, P (1995). "The molecular biology of SRY and its role in sex determination in mammals". Reproduction, Fertility, and Development. 7 (4): 713–22. PMID 8711208.
- Koopman P (1999). "Sry and Sox9: mammalian testis-determining genes". Cellular and Molecular Life Sciences. 55 (6–7): 839–56. PMID 10412367. Unknown parameter
- Pop R, Zaragoza MV, Gaudette M, Dohrmann U, Scherer G (2005). "A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion". Human Genetics. 117 (1): 43–53. PMID 15806394. Unknown parameter
- MacLaughlin and Donahoe N (2004). "Mechanisms of Disease: Sex Determination and Differentiation". New England Journal of Medicine. 350: 367–378. PMID 14736929.