A normal individual has a set of DNA consisting of 23 pairs of chromosomes in their genetic make-up which hold all the genes necessary to synthesise proteins and therefore control the characteristics (phenotype) of the individual. Two copies of each chromosome are contained in the nucleus of every cell of the body, with the exception of red blood cells, which do not contain a nucleus. These pairs are called homologues (or homologous chromosomes) and are genetically similar.
Among these chromosomes, one pair determines the sex of the individual. These sex chromosomes are called the X and the Y. In normal sexual development, an individual who possesses two X chromosomes has a female chromosome constitution, so develops into a phenotypic woman. An X and a Y sex chromosome is the chromosome constitution for a male so gives rise to a phenotypic man.
Since a man possesses both types of sex chromosome, he can produce two types of gamete, one type carrying the X chromosome, and the other the Y chromosome. Therefore, in humans, males are the heterogametic sex (i.e. they possess both sex chromosomes) as it is the man's gamete that determines the sex of a couple's offspring. The mother can only pass an X sex chromosome onto her children so the chance that the egg is fertilised with a sperm containing an X or a Y chromosome determines whether the child will be a female or a male.
In order for an organism to generate gametes for reproduction, somatic cells (cells in the germ line with the full chromosome number (23 pairs - 46 in total) which are involved in gamete production) must first replicate the chromosomes and organelles inside the cells and then divide twice to give four haploid cells (cells that contain half the chromosome number - 23 chromosomes, one from each homologous pair)) so that the full diploid number (46 chromosomes- 23 pairs) can be restored at fertilisation.
The process of meiosis is vital in ensuring that each gamete is genetically different, so that offspring show variation. In order to ensure that each sex cell contains different chromosomes, the DNA undergoes two types of recombination while it is replicating. Firstly, there is random alignment of the chromosomes in the cell. [TOOLE&TOOLE AS]This is where before cell division, the pairs of chromosomes line up together along the centre of the cell but arrange themselves randomly so that any one of each pair may end up any one daughter chromosome. In this way, each daughter cell will have a different set of chromosomes, depending on how they were lined up in the parent cell. [RANDOM ALIGNMENT OF CHROMOSOMES]
Another way in which gametes are made genetically different is through chromosomal crossover. When the homologous chromosomes are paired up and are in the prophase stage the chromosomes have replicated but not yet separated and are joined together by centromeres- one sister chromatid from each homologue on the inside can exchange genetic information by crossing over at a chiasma (the point at which they cross) and swapping DNA at homologous (matching) regions. When the sister chromatids finally separate, after the duplication of the centromere, this results in four genetically different chromosomes which are then separated into four gametes. This process happens in all pairs of autosomal. In females, because they have two X sex chromosomes, these are homologous to one another all the way down the DNA so can cross over at any point. However, in the male sex chromosomes, only two small parts of the Y chromosomes are homologous to the X chromosomes. These regions are called the pseudoautosomal regions [HUMAN GEN. R LEWIS] (also known as the PAR region 1 and 2) and are 63 genes long altogether. Only these small corresponding parts of the X and the Y chromosomes can undergo pairing and genetic recombination in the male germline [X CHROMOSOME DOSAGE COMPENSATION p736]. It is vital that the crossover between an X and a Y chromosome is accurate because any genetic recombination beyond the pseudoautosomal region may result in the relocation of genes on the X to the Y and vice versa. Any genes that lie on the boundary between the pseudoautosomal regions and the non-homologous region of the male sex chromosomes are at risk of relocation.
One gene that has its locus just [DETAIL] below the pseudoautosomal region on the Y chromosome is the Sex-determining Region of the Y (SRY) gene. [NEWS&VIEWS THE MAKING OF MALE MICE] After years of debate, it has been proven that this gene is vital in initiating male sex differentiation. In 1959 the Y chromosome was first considered to be the factor that determines maleness in humans and in mice. Further research showed that only a very small part of the Y chromosome is necessary for the development of male genitalia. [CELIA'S NOTES] At first, in 1987, Page et al. suspected that a gene called ZFY (for zinc finger protein on the Y) which is found on the Y chromosome controlled male sex differentiation. However, this hypothesis fell through when several problems were discovered. Firstly, they thought that ZFY was consistent throughout the Y chromosomes of all mammals but later discovered that the gene was absent from marsupials [SIGNIFICANCE?]. Also, the gene is expressed at the wrong time during sex differentiation to be having a major affect on testis development. [NEWS&VIEWS THE MAKING OF MALE MICE] However, since it is expressed in embryonic mouse developing ovaries with defective testis determining genes, compared to SRY, which is not expressed, SRY seemed to be a better candidate for a testis-determining gene [SIGNIFICANCE?]. [CELIA'S] Many characteristics of SRY make it a more suitable candidate for the factor that controls testis determination than ZFY. It is found in the normal Y chromosomes of all mammals, including marsupials. It is expressed at the right time for testis determination. Around 80% of all sex reversed XX males carry SRY, indicating that it is a factor that influences male genital development. In 1990, it was proven that the SRY gene was crucial for the initiation of male sex determination and not the whole Y chromosome by experimenting on mice. Yoopman et al. transferred an SRY gene into the DNA of 11 female XX mice. This resulted in three of these mice becoming sex-reversed males- they developed male testes, showing that the act of implementing SRY had led to these mice switching sex. However, it was questioned why this only happened to three of the 11 female mice, and why the eight other mice failed to express the gene. The most likely reason was that the SRY gene may have been inserted into an inappropriate place on the genome. [WINK&NUDGE] SRY is a member of a family of 20 genes which are transcription factors. These transcription factor proteins are called SOX proteins, which stands for SRY-related HMG box protein. These genes are transcribed into RNA and the translated into proteins, which bind to promoter (the beginnings) of genes and bend the DNA to force the double helix apart so that the genes in the DNA can be expressed into RNA.
[HUMAN GENETICS 8TH p109] For a long time, it was considered that female sexual characteristics were a ‘default' option in sex determination, with a sex determining gene intervening to differentiate an embryo into a male. However, now, sex determination is described as a fate that falls upon an embryo with two unspecialised gonads at around five to six weeks after conception (in humans), depending on the sex determining genes expressed. A normal XY embryo holds the SRY gene on the Y chromosome, which is a transcription factor, meaning that it can control the actions of genes below it on the hierarchy, therefore, when it is expressed it can stimulate male sex development. Sustentacular cells (a type of support cell), which can be found in the testis, respond to signals sent from SRY to secrete a hormone called Anti-Müllerian hormone (AMH). The role of AMH is to destroy any potential female structures, for example, the uterus and upper vagina. Meanwhile, internal male structures, such as the seminal vessels and ejaculatory ducts, start to develop from what are known as the [MEDICAL GENETICS] Wolffian ducts. The development of these structures is initiated by the secretion of testosterone from another type of cell in the testis called interstitial cells. The masculinisation of external structures, such as the urethra, prostate gland, penis and scrotum is initiated by dihydrotestosterone (DHT), which is made from excess testosterone.
[MEDICAL GENETICS] A normal female chromosome constitution lacks the Y chromosome and therefore lacks SRY. Two X chromosomes means that a female has a ‘double dose' of all the genes found on the X chromosome. A double dosage of a gene on the X called DAX1, (standing for dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1), leads to the development of the unspecialised gonads into ovaries. Since SRY is absent, AMH is not produced, therefore the Müllerian ducts develop into the uterus, Fallopian tube and proximal vagina. In the case of external genitalia, the default pathway is that of the female genitalia, so with the absence of DHT, the clitoris, labia and distal vagina are produced.
Genetic abnormalities can occur by altering the base sequence in an individual's DNA, resulting in a change in the amino acid sequence of a protein which may inhibit or change its function. This can happen through substitution of a base in the DNA for a different one, leading to the wrong protein being synthesised, which may be non-functional, or the insertion or elimination of one or more bases, causing the whole gene to be read differently and therefore, the wrong protein, or no protein at all to be produced. Most cases of disrupted sex determination caused by mutation are consequences of mutations in three vital genes for sex determination, that code for transcription factors. These genes are SRY, SOX 9 and NR5A1.
[MUTATION ANALYSIS (ilMED)] Sex reversal can occur at varying levels of severity and it is assumed that the level of severity depends upon at which stage of development that the gonads are disturbed. The earlier in sex development that a mutation or disruption occurs, the more complete the sex reversal. This is because the higher up in a cascade of controlling genes (transcription factors) a mutation occurs, the more processes it will inhibit because in a cascade of transcription factors, each gene relies on the one above to be activated to ensure that it is activated itself. The most complete sex reversals usually happen as a result of a mutation or relocation of the SRY gene. This is because SRY is considered to be high up in the ‘genetic hierarchy' for gonadal differentiation.
During male meiosis, when forming gametes, [IAN D YOUNG p177] illegitimate crossing-over can occur, whereby the region of the Y that crosses over with the X goes beyond the PAR boundary, to include the region containing the SRY gene. This relocation results in a Y chromosome that is now missing SRY, and an X chromosome that is SRY-positive. This is called translocation.[Me] These are then separated into different gametes. If, by chance, during fertilisation, one of these gametes fertilises an ovum, the resulting child may experience sex reversal. If the sperm with an SRY-positive X chromosome fertilises an ovum, every cell in the child's body will contain an X chromosome with SRY, so has the ability to express this gene. [IAN D YOUNG] In normal sex development, though some genes for male sex development are found on the autosomes, and are therefore present in the female chromosome constitution as well as in males, they are silenced in females due to the lack of SRY, so cannot be expressed. [reference may finish here] Now that SRY is present, due to translocation, the indifferent gonads are led along the pathway to produce the male reproductive tract, and the Wolffian ducts to develop into _________________________________________________________. Also, testosterone ___________________________________________________________. The individual is now classed as an XX male. Many genes coding for male fertility and spermatogenesis [ßREFERENCE!] (sperm production) are found on the Y chromosome. Therefore, it is inevitable that, due to the absence of the Y chromosome, these XX males are infertile. Consequentially of the sex reversal, a sufferer has a male appearance and small testes. This type of translocation to give rise to an XX male occurs rarely, at less than one case in every 25000 births. However, this varies by location, for example in areas where high levels of consanguinity are found - usually in communities that are separated from the general population, such as in the Yupik Inuit of Alaska, which promotes the prevalence of congenital adrenal hyperplasia and consequential sex reversal.
[MECHANISMS OF DISEASE: TRANSCRIPTION FACTORS…] The reciprocal of this type of sex reversal is an individual with an XY genotype, the Y chromosome being SRY-negative due to the translocation of it onto an X chromosome during illegitimate cross-over, as we have seen before. This type of sex-reversal gives rise to an XY female, and is called ‘Swyers Syndrome' or XY gondadal dysgenesis. [Mum notes] An individual who suffers from this condition has completely female exterior and external genitalia, but is infertile [SPRINGERLINK] due to gonadal dysgenesis, which is often referred to as ‘streak gonads'. Streak gonads are characterised by the loss of primordial germ cells (cells that give rise to gametes) in the developing gonads. [www.ncbi.nlm.nih.gov/entraz/dispomim.cgi?id=400044] This loss leads to disfunctioning gonads that are mainly composed of fibrous tissue. [SPRINGERLINK] Since the XY genotypic individual lacks SRY AMH is not produced, so Müllerian ducts can develop. Also, testosterone is not produced, so the Wolffian ducts do not develop into external male structures. The lack of testosterone means that DHT is not formed, so the development of external masculine characteristics is not initiated. An individual suffering from Swyer Syndrome will usually be diagnosed with the genetic condition at puberty because it is unnoticeable due until sufferers do not develop secondary sexual characteristics at puberty, and have amenorrhea (failure to menstruate).
As well as the complete displacement of the SRY gene, mutations in single genes that have an important role in sex determination can lead to varying severities of sex reversal, and ambiguous genitalia. [SECTION ON MUTATION IN SRY!!!]
Gene Mutations and Sex Reversal
SOX 9 is a gene found on an autosome - chromosome 17, so two copies are present in males and females. It codes for a protein which is a member of the SOX family of transcription factors. The gene is high in the developmental pathway for sex development so any mutation in it will have relatively severe consequences. [MECHAISMS OF DISEASE] The only known case of a deletion of SOX 9 occurred in an XX female. Since, as in any normal XX female, this individual lacks SRY, the SOX 9 gene cannot be activated, so stays silent. Therefore, the deletion of the gene does not affect the individual's sex. However, the individual did [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114290] suffer from campomelic dysplasia - a skeletal disorder characterised by the bowing of long bones, along with other bone defects. Mutations called ‘loss of function' (L.O.F.) mutations can also induce sex reversal by occurring in genes important in sex determination such as SOX 9. Genes can lose function due to a variety of different mutations. [A2 text book : mutations! All genetic mutations are based on changes in the DNA code. The genetic code which controls phenotype is made] These have a very similar affect on sex differentiation as the deletion of SOX 9 because the only difference between these two types of abnormality is that the deletion of SOX 9 leads to the absence of the gene, whereas in L.O.F. mutations, the SOX 9 is still present, but is inactive. Therefore, L.O.F. mutations in SOX 9 give rise to XY females with campomelic dysplasia.[MECHANISMS OF DISEASE] Though this type of abnormality has not yet been found in an XY individual, scientists assume that a SOX 9 deletion would lead to sex reversal, and therefore, an XY female. This is because the SOX 9 gene has a very important role in male sex development, so its deletion will inhibit male differentiation. It is safe to say that XY females with sex reversal due to SOX 9 deletion will also result in campomelic dysplasia because [IAN D YOUNG p179] SOX 9 has other roles along with controlling male sex determination, such as regulating the expression of a collagen gene (COL2A1) in the cartilage, which codes for the production of collagen, a structural protein that provides strength to bones. If collagen production is reduced, i.e. through the deletion of SOX 9, bones are weakened and bow easily.
[IAN D YOUNG] Sex reversal can also result from L.O.F. mutations in other genes in the sex determining gene hierarchy, for example, in Steroidogenic Factor 1 (SF1). SF1 is a regulatory gene that controls the synthesis of steroids, such as testosterone, in the adrenal glands and developing testes. A L.O.F. mutation in this gene would lead to the inability to produce testosterone, therefore _______________________ would not develop, leading to an XY female with adrenal failure.
[46,XX SEX REVERSAL] As well as XX male individuals developing due to the translocation of Y chromosome material including SRY, testes determination can come about as a result of mosaicism, whereby a proportion of cells in the individual display the Y chromosome. This can be shown as 46,XX/46,XY. Depending on the ratio of XX cells to XY cells, these individuals can display both male and female sexual characteristics: ovaries develop as a result of XX cells and testes, due to the presence of the Y chromosome.
In the complete absence of the Y chromosome of any Y related genes, chance mutations on the autosomes can induce sex reversal in 46,XX individuals. Usually, this involves the activation of genes which are silenced until in the presence of a functioning SRY gene. The only way this can happen without SRY is through mutation - a ‘gain of function' (G.O.F.) mutation.
Disorders of sex development bring about many consequences. These can be personal to the suffering individual, but can also have secondary impacts on relatives of the sufferer, as well as, in some cases, impact on society.
[MANAGEMENT IN CULTURES] Along with the health risks and conditions that sex reversal brings, they can also bring about social and psychological issues. Individuals whose conditions result in ambiguous genitalia often experience psychological gender issues. Up until around 20 years ago, all 46,XY individuals with ambiguous genitalia underwent surgical intervention to make them phenotypically female because it was thought that this, plus the reinforcement of a female lifestyle was sufficient to produce a stable female. Also, the operation to convert these individuals to females is easier, compared to conversion to male genitalia, which often results in a small penis. However, many patients were returning later in life to ask for gender reassignment.
Now it has been proven that gender identity is not set in genes or chosen by nature but is very much influenced by one's upbringing. Therefore, much consideration is put into choosing an optimum gender for someone. Firstly, Doctors must decide on which operation or/ gender would pose less risk on the child physically. For example, the risk of osteoporosis is increased if gonads are removed and the operation is not followed by hormone therapy.
The best option for reducing the psycho-social impacts on the child is always considered. For example, the choice of optimum gender may be influenced by how accepting the parents will be of the outcome. In some cultures, mostly in less well developed countries, boys are more favourable over girls because parents often rely on their children to look after them in old age, so need to be economically independent. For women, this would involve marriage, which is next to impossible if the individual is infertile, which may be the case in sex reversed individuals. Also, in many developing countries, males have a social advantage- they have a better chance of employment and would inherit the father's wealth, whereas a daughter may only inherit half or less. Also, the child with a disorder of sex development (DSD) may pose social disadvantages on the family as a whole, so this may be an influential factor in gender reassignment decisions. Most Western/ developed countries have a different approach to deciding on gender. The main focus is usually on the ability for the child to enjoy sexual pleasure and be able to sexually please a partner in the future. Another psycho-social risk that is considered while choosing an optimum gender is the risk of social embarrassment, discrimination and isolation of the child. For example, in many African communities, hermaphrodites are thought to be resultant from witchcraft and are socially excluded. In India, there is a well known community of hermaphrodites, who are referred to as ‘hijra'. It is rumoured and believed that these people kidnap babies with DSDs to increase their population. Investigation has shown that most of this population are not actual sex-reversed individuals, but consist of transvestites and people with other gender identity issues, as well as kidnapped and castrated boys. This community is deeply feared, and some parents whose children have DSDs consider giving them up to the hijra as a viable option.
Individuals with DSDs can have an impact on society at a national level, for example in the health service. In developing countries, it is often not economically/ affordable for a patient to be reassigned to one or another sex through surgery. This is because the already limited funding put towards health care must be spent on public health priorities to provide clean water, immunisation and treatment for acute medical conditions such as accidents, malnutrition and infectious diseases, so rare medical conditions have a very low priority. Also, doctors in developing countries are not always able to keep up to date with rapidly developing medical discoveries/ technologies so may only recognise and be able to treat very common conditions. This results in DSD individuals seeking other methods of treatment, such as herbal medicines, and are often left undiagnosed. In other cases, DSD patients seek no medical advice at all because of embarrassment of shame. Also, in many communities, there is a stigma that comes with discussing sexual issues publically, so no medical advice is sought.
Not only does the patient suffer from personal psycho-social consequences, but often, parents are also severely affected. It is commonly for many parents to go through stages of guilt, depression and anxiety after having given birth to a child with a DSD. In developing countries where the male sex is favoured, any disorders that a child may have are often blamed on the mother. In some extreme cases, husbands have been known to demand an annulment as a result of bearing a child with a DSD.
DSDs have raised controversial issues on a national level in some countries, due to the debate as to whether a third sex should be legally established for those who cannot, or choose not to assign themselves to a male or female gender. This idea has been accepted more kindly in some cultures than in others. The Samoan culture allows some males to class themselves as fa'afafine, which is a sex with female characteristics, whereas most other societies strongly oppose the idea.
If an individual takes on roles/ careers during his or her life wich are gender specific, these situations often spark problems. One situation in which someone's uncertain gender stimulates debate is in competitive sport. Problems arise when individuals with ambiguous gender compete in a sport where then may have a competitive advantage. For example, a DSD may cause an individual with a female genotype to have raised levels of testosterone, which will make then stronger or more physically capable than a normal female competitor. If an individual like this then competes in a female category, it is debatable as to whether he/ she can be awarded prizes. A recent example of this type of speculation is Caster Semenya. Caster Semenya was 18 years old when she won the gold medal in the womens 800m at the Berlin Olympics. After the race, she was asked to take a gender test due to raised questions about her masculine physique.
Gender testing was first introduced in the 1966 European Track and Field Championships, before being introduced into the Olympic in 2968 for the Mexico City games, to catch competitors for gender-fraud. Gender testing involves http://www.slate.com/id/2225810/ [HISTORY OF TESTING]. http://timesofindia.indiatimes.com/The-sad-story-of-Santhi-Soundarajan/articleshow/1109135.cms àAthletes who fail a gender test are allowed to compete after any necessary surgery and/ or hormone therapy. Caster Semenya was subject to consultation by a variety of medical experts including an endocrinologist (specialises in disorders of the endocrine system, which includes hormones), a gynaecologist, an internal medical expert, a gender expert and a psychologist, who looked for certain conditions. They were suspicious that she may have congenital adrenal hyperplasia, which would _____[WHY WOULD THIS MAKE HER MALEISH?]____. They also looked for polycystic ovaries -- a disorder of the endocrine system which often results in infertility, amenorrhea, and excess secretion of androgens. The excess testosterone may give the individual a physical advantage over a normal woman___________. Also, if Semenya was found to have tumours that secreted androgens, this would also increase the level of testosterone in her blood, which may give her a competitive advantage over her rivals. The results of Caster Semenya's gender test were never revealed, due to confidentiality, but negotiations were made to allow her to keep her medal and prize money. She is due to run in more official races this year.
Though Caster Semenya's sex-test results would hopefully solve the mystery as to whether there is any medical readon behind her distinct/ definite maleness, it is still subject to debate as ato whether she should be allowed to compete. The answer to this question seens to be very much down to personal opinion. One side of the argument is that if Semenya has a DSD, or increased androgen levels as a consequence of another disorder, this came about by chance through natural mutation and she is just lucky to be at an advantage compared to her rivals. Also, taking her passion away from her by banning her from racing may cause more harm than good to her, psychologically. http://timesofindia.indiatimes.com/The-sad-story-of-Santhi-Soundarajan/articleshow/1109135.cms --> For example, Santhi Soundarajan competed and won the silver medal in the 2006 Asian games, but had her award stripped of her in January 2007 after failing a gender verification test. She also lost the potential to compete further in official games. Unfortunately, she fell into depression and she attempted suicide in September 2007. It was thought that the sudden loss of her passion was partly to blame for this. Therefore it may be risky to take too much immediate and often rash action in conjunction with these situations.