XY sex-determination system

Human male XY chromosomes after G-banding

In humans, half of spermatozoa carry X chromosome and the other half Y chromosome.[5] A single gene (SRY) present on the Y chromosome acts as a signal to set the developmental pathway towards maleness. Presence of this gene starts off the process of virilization. This and other factors result in the sex differences in humans.[6] The cells in females, with two X chromosomes, undergo X-inactivation, in which one of the two X chromosomes is inactivated. The inactivated X chromosome remains within a cell as a Barr body.

Humans, as well as some other organisms, can have a rare chromosomal arrangement that is contrary to their phenotypic sex; for example, XX males or XY females (see androgen insensitivity syndrome). Additionally, an abnormal number of sex chromosomes (aneuploidy) may be present, such as Turner's syndrome, in which a single X chromosome is present, and Klinefelter's syndrome, in which two X chromosomes and a Y chromosome are present, XYY syndrome and XXYY syndrome.[6] Other less common chromosomal arrangements include: triple X syndrome, 48, XXXX, and 49, XXXXX.

In most mammals, sex is determined by presence of the Y chromosome. "Female" is the default sex, due to the absence of the Y chromosome.[7] In the 1930s, Alfred Jost determined that the presence of testosterone was required for Wolffian duct development in the male rabbit.[8]

SRY is a sex-determining gene on the Y chromosome in the therians (placental mammals and marsupials).[9] Non-human mammals use several genes on the Y chromosome. Not all male-specific genes are located on the Y chromosome. Platypus, a monotreme, use five pairs of different XY chromosomes with six groups of male-linked genes, AMH being the master switch.[10] Other species (including most Drosophila species) use the presence of two X chromosomes to determine femaleness: one X chromosome gives putative maleness, but the presence of Y chromosome genes is required for normal male development.

Birds and many insects have a similar system of sex determination (ZW sex-determination system), in which it is the females that are heterogametic (ZW), while males are homogametic (ZZ).[11]

Many insects of the order Hymenoptera instead have a haplo-diploid system, where the males are haploid (having just one chromosome of each type) while the females are diploid (with chromosomes appearing in pairs). Some other insects have the X0 sex-determination system, where just one chromosome type appears in pairs for the female but alone in the males, while all other chromosomes appear in pairs in both sexes.[12]

PBB Protein SRY image

In an interview for the Rediscovering Biology website,[13] researcher Eric Vilain described how the paradigm changed since the discovery of the SRY gene:

For a long time we thought that SRY would activate a cascade of male genes. It turns out that the sex determination pathway is probably more complicated and SRY may in fact inhibit some anti-male genes.

The idea is instead of having a simplistic mechanism by which you have pro-male genes going all the way to make a male, in fact there is a solid balance between pro-male genes and anti-male genes and if there is a little too much of anti-male genes, there may be a female born and if there is a little too much of pro-male genes then there will be a male born.

We [are] entering this new era in molecular biology of sex determination where it's a more subtle dosage of genes, some pro-males, some pro-females, some anti-males, some anti-females that all interplay with each other rather than a simple linear pathway of genes going one after the other, which makes it very fascinating but very complicated to study.

In mammals, including humans, the SRY gene is responsible with triggering the development of non-differentiated gonads into testes, rather than ovaries. However, there are cases in which testes can develop in the absence of an SRY gene (see sex reversal). In these cases, the SOX9 gene, involved in the development of testes, can induce their development without the aid of SRY. In the absence of SRY and SOX9, no testes can develop and the path is clear for the development of ovaries. Even so, the absence of the SRY gene or the silencing of the SOX9 gene are not enough to trigger sexual differentiation of a fetus in the female direction. A recent finding suggests that ovary development and maintenance is an active process,[14] regulated by the expression of a "pro-female" gene, FOXL2. In an interview[15] for the TimesOnline edition, study co-author Robin Lovell-Badge explained the significance of the discovery:

We take it for granted that we maintain the sex we are born with, including whether we have testes or ovaries. But this work shows that the activity of a single gene, FOXL2, is all that prevents adult ovary cells turning into cells found in testes.

Looking into the genetic determinants of human sex can have wide-ranging consequences. Scientists have been studying different sex determination systems in fruit flies and animal models to attempt an understanding of how the genetics of sexual differentiation can influence biological processes like reproduction, ageing[16] and disease.

In humans and many other species of animals, the father determines the sex of the child. In the XY sex-determination system, the female-provided ovum contributes an X chromosome and the male-provided sperm contributes either an X chromosome or a Y chromosome, resulting in female (XX) or male (XY) offspring, respectively.

Hormone levels in the male parent affect the sex ratio of sperm in humans.[17] Maternal influences also impact which sperm are more likely to achieve conception.

Human ova, like those of other mammals, are covered with a thick translucent layer called the zona pellucida, which the sperm must penetrate to fertilize the egg. Once viewed simply as an impediment to fertilization, recent research indicates the zona pellucida may instead function as a sophisticated biological security system that chemically controls the entry of the sperm into the egg and protects the fertilized egg from additional sperm.[18]

Recent research indicates that human ova may produce a chemical which appears to attract sperm and influence their swimming motion. However, not all sperm are positively impacted; some appear to remain uninfluenced and some actually move away from the egg.[19]

Maternal influences may also be possible that affect sex determination in such a way as to produce fraternal twins equally weighted between one male and one female.[20]

The time at which insemination occurs during the estrus cycle has been found to affect the sex ratio of the offspring of humans, cattle, hamsters, and other mammals.[17] Hormonal and pH conditions within the female reproductive tract vary with time, and this affects the sex ratio of the sperm that reach the egg.[17]

Sex-specific mortality of embryos also occurs.[17]

Aristotle believed incorrectly that the sex of an infant is determined by how much heat a man's sperm had during insemination. He wrote:

...the semen of the male differs from the corresponding secretion of the female in that it contains a principle within itself of such a kind as to set up movements also in the embryo and to concoct thoroughly the ultimate nourishment, whereas the secretion of the female contains material alone. If, then, the male element prevails it draws the female element into itself, but if it is prevailed over it changes into the opposite or is destroyed.

Aristotle claimed in error that the male principle was the driver behind sex determination,[21] such that if the male principle was insufficiently expressed during reproduction, the fetus would develop as a female.

Nettie Stevens and Edmund Beecher Wilson are credited with independently discovering, in 1905, the chromosomal XY sex-determination system, i.e. the fact that males have XY sex chromosomes and females have XX sex chromosomes.[22][23][24]

The first clues to the existence of a factor that determines the development of testis in mammals came from experiments carried out by Alfred Jost,[25] who castrated embryonic rabbits in utero and noticed that they all developed as female.

In 1959, C. E. Ford and his team, in the wake of Jost's experiments, discovered[26] that the Y chromosome was needed for a fetus to develop as male when they examined patients with Turner's syndrome, who grew up as phenotypic females, and found them to be X0 (hemizygous for X and no Y). At the same time, Jacob & Strong described a case of a patient with Klinefelter syndrome (XXY),[27] which implicated the presence of a Y chromosome in development of maleness.[28]

All these observations lead to a consensus that a dominant gene that determines testis development (TDF) must exist on the human Y chromosome.[28] The search for this testis-determining factor (TDF) led a team of scientists[29] in 1990 to discover a region of the Y chromosome that is necessary for the male sex determination, which was named SRY (sex-determining region of the Y chromosome).[28]