|MadSci Network: Genetics|
Dear Chris, The reason that you have not heard of cases of both X chromosomes being active in a female mammal is that it is incompatible with viability. We know this through a set of interesting observations and genetic experiments. First, consider the general problem of alterations in gene dosage. The only full trisomy that is compatible with viability in humans is trisomy 21 (Down syndrome). The phenotypes caused by this trisomy are not the result of increased dosage of a single gene, but result from the additive effects of alterations in gene dosage of many genes. Chromosome 21 is quite a bit smaller than the X chromosome and has fewer genes. We can look at the status of the human genome project to see the number of predicted genes on both chromosomes. Go to: http:// www.ncbi.nlm.nih.gov/genome/guide/human/ Click on chromosome 21 to see that there are 285 genes annotated to chromosome 21; click on the X to see that there are 1095 genes annotated to the X chromosome. So there are more than three times the number of genes on the X chromosome as on chromosome 21. The dosage difference in trisomy 21 is a 50% increase in the dosage of 285 genes. The dosage difference from males to females is a 100% increase in the dosage of 1095 genes. From another perspective, males suffer a monosomy of the X chromosome; there are no human monosomies that are compatible with viability. All this is a way of showing you that some form of dosage compensation system is essential for any organism that has a chromosomal sex determination system. Mammals use X inactivation in females; all X chromosomes except one are inactivated, so normal XX females have one inactive X chromosome in each cell. Abnormal XXX females have two inactive X chromosomes in each cell. X inactivation is initiated in an "X inactivation center," a specific region of the mammalian X chromosome. Once inactivation starts at this site, it spreads to the rest of the chromosome. Interestingly, the inactivation process does not "know" that X chromosome genes are being inactivated. We know this because there is a class of chromosome rearrangements called translocations, in which two different chromosomes are broken and rejoined to make a pair of new chromosomes. If one of these chromosomes is an X chromosome, one new chromosome will have the X inactivation center and part of another chromosome, while the other chromosome will have that part of the X chromosome lacking the X inactivation center and part of the other chromosome. The first new chromosome of this translocated pair will inactivate its X chromosome genes but also the autosomal genes on the same chromosome. The second new chromosome will fail to inactivate some X chromosome genes. Depending on the position of the chromosome breaks, the genic imbalance and the effects on viability will be more or less severe. In Drosophila (fruit flies) a different system of dosage compensation is used. Both X chromosomes are active in females; the X chromosome in males is twice as active as either X chromosome in females. There are sex-specific lethal mutations in Drosophila that kill males only. These lethal mutations affect genes required for the hypertranscription of the X chromosome in males. The male X chromosome is therefore transcribed at the level of a single female X chromosome, a level incompatible with adult viability (although dying larvae can be studied). We would expect that there could be sex-specific lethals in mammals. Mutations interfering with X inactivation should be lethal to females. I do not know of such mutations, but our ability to search for mutations of this kind in mammals is limited. Finally, there are some cells in females that have both X chromosomes active. Pre-oogonial cells reactivate the X chromosome, so that both X chromosomes are active during oogenesis. I can speculate that this does not create a genic imbalance in these cells because 1) not all the genes on the X chromosome are active in these cells (or any cell type, for that matter) , and 2) the X chromosome genes that are active have their levels of expression adjusted to produce the correct level of gene product by cell-type-specific transcription factors. You also speculate that activating the X would cause feminization, since XXY males are feminized. I can see why you might think this, but the underlying biology of mammalian sexual differentiation suggests that this would not be the case. Briefly, the "ground state" or "default" setting for mammalian sexual differentiation is female. Early mammalian embryos are identical in both sexes. There is a presumptive gonad and rudiments of both male- and female-specific structures. If an embryo contains a Y chromosome (or more accurately, a specific gene on the Y chromosome) in the cells of the presumptive gonad, androgen is made during development, the female structures do not develop and the male ones do. If there is no androgen (or if the cells cannot respond to androgen because of a mutation in the androgen receptor), the male structures do not develop and the female ones do. Mutations that completely eliminate the function of the androgen receptor result in the most feminized mammals possible. For a description of the human syndrome, please see: http:// www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300068 The androgen receptor gene is X-linked, so these individuals are identified as chromosomal males at puberty, because they do not menstruate and are sterile (germ cell sex determination is not affected). Since they have only one X chromosome, there is no Barr body, yet these individuals are extremely feminized: "The phenotype is often voluptuously feminine: Netter et al. (1958) reported this disorder in a famous photographic model, Marshall and Harder (1958) reported affected monozygotic twins who worked as airline stewardesses, and Polaillon (1891) described prostitution in an affected person." This argument is meant to lead you to the conclusion that we should view the phenotype of XXY males as incompletely masculinized rather than as feminized. You may also find it useful to consider that a Barr body, being an inactive X chromosome, cannot have a genetic effect in principle because it is genetically inactive. Actually, a few genes on the X chromosome escape inactivation, but it is not clear to me that these have anything to do with the phenotype of XXY males. There is a great deal of literature on your question. Try a PubMed search on "X inactivation," using "Limits" to restrict your results to "Reviews." I would recommend: Trends Genet. 2003 May;19(5):243-7 Annual Rev Genet. 2002;36:233-78. Curr Opin Genet Dev. 2002 Apr;12(2):219-24. Nat Rev Genet. 2001 Jan;2(1):59-67. Please also see the MGI Glossary: http:// www.informatics.jax.org/mgihome/other/glossary.shtml Thank you for an interesting question. Yours, Paul Szauter Mouse Genome Informatics
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