X-inactivation

X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome is inactivated in some female mammals. The inactive X chromosome is silenced by it being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome (see dosage compensation). The choice of which X chromosome will be inactivated is random in placental mammals such as humans, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism. Unlike the random X-inactivation in placental mammals, inactivation in marsupials applies exclusively to the paternally derived X chromosome. X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome is inactivated in some female mammals. The inactive X chromosome is silenced by it being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome (see dosage compensation). The choice of which X chromosome will be inactivated is random in placental mammals such as humans, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism. Unlike the random X-inactivation in placental mammals, inactivation in marsupials applies exclusively to the paternally derived X chromosome. In 1959 Susumu Ohno showed that the two X-chromosomes of mammals were different: one appeared similar to the autosomes; the other was condensed and heterochromatic. This finding suggested, independently to two groups of investigators, that one of the X-chromosomes underwent inactivation. In 1961, Mary Lyon proposed the random inactivation of one female X chromosome to explain the mottled phenotype of female mice heterozygous for coat color genes. The Lyon hypothesis also accounted for the findings that one copy of the X chromosome in female cells was highly condensed, and that mice with only one copy of the X chromosome developed as infertile females. This suggested to Ernest Beutler, studying heterozygous females for Glucose-6-phosphate dehydrogenase (G6PD) deficiency, that there were two red cell populations of erythrocytes in such heterozygotes: deficient cells and normal cells, depending on whether the inactivated X chromosome (in the nucleus of the red cell's precursor cell) contains the normal or defective G6PD allele. X-inactivation is part of the activation cycle of the X chromosome throughout the female life. The egg and the fertilized zygote initially use maternal transcripts, and the whole embryonic genome is silenced until zygotic genome activation. Thereafter, all mouse cells undergo an early, imprinted inactivation of the paternally-derived X chromosome in 4-8 cell stage embryos. The extraembryonic tissues (which give rise to the placenta and other tissues supporting the embryo) retain this early imprinted inactivation, and thus only the maternal X chromosome is active in these tissues. In the early blastocyst, this initial, imprinted X-inactivation is reversed in the cells of the inner cell mass (which give rise to the embryo), and in these cells both X chromosomes become active again. Each of these cells then independently and randomly inactivates one copy of the X chromosome. This inactivation event is irreversible during the lifetime of the individual, with the exception of the germline. In the female germline before meiotic entry, X-inactivation is reversed, so that after meiosis all haploid oocytes contain a single active X chromosome. The Xi marks the inactive, Xa the active X chromosome. XP denotes the paternal, and XM to denotes the maternal X chromosome. When the egg (carrying XM), is fertilized by a sperm (carrying a Y or an XP) a diploid zygote forms. From zygote, through adult stage, to the next generation of eggs, the X chromosome undergoes the following changes: