@ottercup interesting, but anyway, those XY people, who aren't part of the alleged "six sexes" discussion anyway, as you know and would still be genetically male according to their sex chromosomes. They have a defect in their androgen receptor gene so have androgen insensitivity in some cells, so their biology didn't develop as it should have.
Yet they still have testes, and no internal female organs, so confused if their SRY gene works normally because isn't this the part in the Y chromosome that initiates the male sex determination of of foetal development. I'm confused because TDF (testis-development factor) is encoded by SRY, these XY males with androgen insensitivity, in some cases with complete androgen insensitivity these ones phenotypically female on the outside (Not all of them have the outer appearance/phenotype of female, there are different levels, some have normal male phenotype, some have mild condition, yes some have female outer appearance the ones with complete androgen insensitivity syndrome. en.m.wikipedia.org/wiki/Androgen_insensitivity_syndrome
en.m.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome
"AIS is differentiated according to the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) when the external genitalia is that of a normal female, mild androgen insensitivity syndrome (MAIS) when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome (PAIS) when the external genitalia is partially, but not fully masculinized"
"Clinical phenotypes in these individuals range from a normal male habitus (body shape) with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus (body shape), despite the presence of a Y-chromosome")
Anyway, so the confusion I have is, SRY gene or TDF? ( and I have trouble understanding/separating the two) "SRY gene effects normally take place 6–8 weeks after foetus formation and inhibits the female anatomical structural growth in males. It also works towards developing the dominant male characteristics." So no it can't be working properly, or maybe 'some of it' is/isnt. ?? Or maybe it's talking about internal female anatomical structural growth. But the vagina? Ah wait I found that Sertoli cells of the testes secret anti-Müllerian hormone - AMH is activated by SOX9 in the Sertoli cells of the male fetus.[4] Its expression inhibits the development of the female reproductive tract, or Müllerian ducts (paramesonephric ducts), in the male embryo, thereby arresting the development of fallopian tubes, uterus, and upper vagina"
So, this is why they have a shallow vagina not an upper one (and sometimes not really one at all) I seem once describe d as a dimple !?
Oh wait
"Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y chromosome.[79] The gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads.[79] By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome’s SRY gene.[53][54] This process does not require the presence of androgen, nor a functional androgen receptor.[53][54]
Until around the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the Müllerian ducts and the Wolffian ducts.[79] Sertoli cells within the testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause their degeneration.[79] Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia (uterus, cervix, fallopian tubes, and upper vaginal barrel).[79] Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default.[80] In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles.[79] If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate.[81]
male genitalia do not develop properly.[82][83][84][85][86] As is the case with the internal male genitalia, a functional androgen receptor is needed for dihydrotestosterone to regulate the transcription of target genes involved in development.[73]
Pathogenesis of AIS
Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex.[3] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.[3] Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. This predictive ability is primarily retrospective in origin; the different functional domains of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR.[3] For example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation.[3][80] Unfortunately, even when the affected functional domain is known, predicting the phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult.
Some mutations can adversely impact more than one functional domain. For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact.[80] A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein.[3] The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.[3]
Other, more complex relationships have been observed as a consequence of mutated AR; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system.[9][23][87][88][89] The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain.[87][89] This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth.[3] The pathogenesis of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology. The trinucleotide repeat expansion of the polyglutamine tract of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to proteolyze and disperse properly.[90] These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus.[90] Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with SBMA
AR mutations
As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow.[2] Inheritance is typically maternal and follows an X-linked recessive pattern;[1][39] individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. About 30% of the time, the AR mutation is a spontaneous result, and is not inherited.[10] Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself.[40] In one study,[41] three of eight de novo mutations occurred in the postzygotic stage, leading to the estimate that up to one-third of de novo mutations result in somatic mosaicism.[1] Not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of genetic males,[42][43][44][45] and is thought to adversely affect only a small number of individuals when other genetic factors are present.[46]
Other causes
Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation,[2] as well as between 27[6][47] and 72%[48] of individuals with PAIS.
In one patient, the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein.[49] In another patient, CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the normal androgen receptor to the basal transcription machinery of the cell.[50] A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor may have been deficient in this patient.[50] The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a normal AR gene.[1] "
Correlation of genotype and phenotype
Individuals with partial AIS, unlike those with the complete or mild forms, present at birth with ambiguous genitalia, and the decision to raise the child as male or female is often not obvious.[1][40][61] Unfortunately, little information regarding phenotype can be gleaned from precise knowledge of the AR mutation itself; the same AR mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family.[1][39][52][62][63][64][65][66][67][68] Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts,[69] sensitivity to and variations in the intrauterine endocrine milieu,[52] the effect of coregulatory proteins active in Sertoli cells,[21][70] somatic mosaicism,[1] expression of the 5RD2 gene in genital skin fibroblasts,[62] reduced AR transcription and translation from factors other than mutations in the AR coding region,[71] an unidentified coactivator protein,[50] enzyme deficiencies such as 21-hydroxylase deficiency,[4] or other genetic variations such as a mutant steroidogenic factor-1 protein.[49] The degree of variation, however, does not appear to be constant across all AR mutations, and is much more extreme in some.[1][4][46][52] Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity"
If we getting this deep might as well post this but pay close attention. This all starts from something going wrong with a sperm cell, causing the SRY gene to transfer from the Y chromosome to the X chromosome which it's not supposed to which causes lots of problems for the hypothetical offspring who inherit these defective genes.
"Embryos are gonadally identical, regardless of genetic sex, until a certain point in development when the testis-determining factor causes male sex organs to develop. Therefore, SRY plays an important role in sex determination. A typical male karyotype is XY. Individuals who inherit a normal Y chromosome and multiple X chromosomes are still male (such as in Klinefelter syndrome, which has an XXY karyotype). Atypical genetic recombination during crossover when a sperm cell is developing can result in karyotypes that do not match their phenotypic expression.
Most of the time, when a developing sperm cell undergoes crossover during its meiosis, the SRY gene stays on the Y chromosome. If it is transferred to the X chromosome, however, the resulting Y chromosome will not have an SRY gene and can no longer initiate testis development. Offspring which inherit this Y chromosome will have Swyer syndrome, characterized by an XY karyotype and a female phenotype. The X chromosome that results from this crossover event now has a SRY gene, and therefore the ability to initiate testis development. Offspring who inherit this X chromosome will have a condition called XX male syndrome, characterized by an XX karyotype, and a male phenotype. While most XX males develop testis, it is possible for them to experience incomplete differentiation resulting in the formation of both testicular and ovarian tissues in the same individual. XX male syndrome results in infertility, most likely caused by the inactivation (either random or non-random) of the X chromosome containing the SRY in some cells.[16]
While the presence or absence of SRY has generally determined whether or not testis development occurs, it has been suggested that there are other factors that affect the functionality of SRY.[17] Therefore, there are individuals who have the SRY gene, but still develop as females, either because the gene itself is defective or mutated, or because one of the contributing factors is defective.[18] This can happen in individuals exhibiting a XY, XXY, or XX SRY-positive karyotype."
en.m.wikipedia.org/wiki/Testis-determining_factor
Lots of things can happen with genetics. Mutations, defects, missing genes, extra genes. Some could affect transgender individuals we don't know, it hasn't been found yet. If trans people say research is transphobic and don't participate, it will never be found. There are still two sexes. That's how the human population reproduces.
People with down syndrome or other genetic conditions are still human beings and wonderful, like my cousin, not a different species.