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Introduction Sex determination (male/female) at the biological level is determined by the presence or absence of the Y chromosome, originally this factor was designated "testis determining factor" but we now (since 1990) know this to be the SRY gene product. It was discovered by studying a human XY female. It turned out that she had a deletion in the Y chromosome that did not allow testis development. Mapping of the deletion allowed isolation and characterization of the TDF gene. The presence in females of 2 X chromosome raises the separate issue of gene dosage and in the case of mammals this is regulated by inactivating one of the X chromosomes (see X inactivation notes).
Background Mammalian sex determination is regulated by chromosomes. Females have two X chromosomes. (XX) Males have a single X and a small Y. (XY) The X and Y chromosome are morphologically and functionally different from each other. Evolutionary studies have shown that the Y was once the homologous pair for X. It is only in the last 5 years that we have some idea about how these two types of chromosomes may be regulated and genes of inportance located upon them. In females the main scientific problem was that of gene dosage, only one copy of X chromosome is needed to be active. In males the main scientific problem was what on the Y chromosome determined "maleness", and how did it do it.   Y-Chromosome The Y chromosome is male determining. Evolutionary studies have shown that the Y was once the homologous pair for X. It has been progressively degraded consisting mainly of degraded copies of X linked genes and large regions of repeated sequences. Somatic cell phenotype is regulated by testicular hormones. Therefore testis determination is the inital step in sex determination. Some factor on the Y chromosome must initiate the formation of testis, the "testis determining factor" (TDF). The breakthrough was the discovery of the SRY gene which turned out to be the TDF. This gene was discovered by 2 groups separately in 1990. Berta et al., (1990) Nature 348 448-45 Jager et al., (1990) Nature 348 452- 53 It was found by studying a human XY female. It turned out that she had a deletion in the Y chromosome that did not allow testis development. Mapping of the deletion allowed isolation and characterization of the TDF gene. Activation of the SRY gene leads to the development of male testis. SRY is only expressed: when testes begin to form in gonadal tissue does not require the presence of germ cells •SRY encodes a zinc-finger transcription factor. That is it is a protein that binds to specific sites of DNA and regulates the transcription of other genes. It is still not fully known what genes SRY regulates.   X- Chromosome Contains about 5% of the haploid genome. Genes encode house-keeping and specialized functions. Completely conserved in gene content between species. It does not encode sex determination or differentiation. In females one of the X-chromosomes is inactivated in each and every cell. [known since 1961] This inactivation occurs during embryogenesis. X Inactivation appears to be random in somatic cells. (mosaic pattern) The process starts at the "X inactivation centre" and spreads along the chromosome. The mechanism of inactivation was unknown. X-Chromosome Inactivation The breakthrough was the discovery of the X inactive specific transcript (XIST). Brown et. al., (1991) Nature 349, 372-373. This gene is located within the "X inactivation centre" and only expressed by the inactive X chromosome. unlike other genes that encode protein XIST contained no "open reading frames" (ie no codons to encode amino acids). XIST is transcribed but not translated. XIST appears to act as RNA. Current thinking is that it binds to the X Chromosome and is involved in it's translocation to the nuclear periphery. It now appears that XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that maintains inactivity.
Lecture Notes Please note that these notes only relate to the Anat 3311 Course. This section is not completely available, as I have been unable to transfer all my Lecture notes and research material in time for the deadline. This will be available in later versions. Early Development Lecture Simple pictures illustrating the early events of fertilization. Spinal Cord Development Figures and text relating to early events of spinal cord formation. Sex Determination Text relating to the molecular events of sex determination in the embryo. Polarity Concepts A short comparison of establishing positional information in embryos. Antennapedia The fly mutation that opened the field of Hox Genes and the conservation of pattern formation control mechanisms between species in embryonic development.
External WWW Search This current page has additional windows that allow searching of OMIM Morbid Map and OMIM Gene Map and access to other External WWW Search pages (Medical dictionaries, glossaries, chemicals and drugs). In the DNA Notes there is a window to search the Human Genome by keyword and also to search for a specific species classification. In the DNA Notes there is also a page with 3 search windows for Nucleotide Sequence, Protein Sequence and Biomolecule 3D Structure from NCBI. In the Chemical Notes there is a window to search a Material Safety Data Sheet database for a specific chemical and its associated hazard.
About Notes These lecture notes from the Embryology Program compiled and written by Dr Mark Hill. This updated section of notes is still being developed Mar99 and is not yet complete. Note that reference lists are only relevant to the date that the original search was carried out.	Links Serial Sections Homepage Human Homepage Pig Homepage
m.hill@unsw.edu.au Date Last Modified: 19/3/99 This site maintained by Dr M. Hill