The X chromosome occupies an exceptional place in the mammalian genome . Together with the Y chromosome, the X chromosome differentiates the sexes. Males have one X chromosome and a Y chromosome and females have two X chromosomes. Because of this fundamental genetic difference, diseases caused by genes located on the X chromosome affect males and females differently and thus present unusual inheritance patterns. Furthermore, equal dosage of expression from genes on the X chromosome is restored between males and females by a special process called X inactivation, in which genes on one of the female X chromosomes are shut down.
Role of the X Chromosome in Sex Differentiation
The so-called sex chromosomes differentiate the sexes: females are XX and males XY, which is the basis for the development of a fetus into a girl or a boy (Figure 1). All other chromosomes (called autosomes) are present in two copies in both males and females. It is the presence of a Y chromosome that determines the male sex of a baby, because the Y carries a gene that induces undifferentiated gonads to turn into testes in the fetus. The number of X chromosomes does not change the sex of a baby. Indeed, people with a single X chromosome and no Y chromosome are females with Turner syndrome, a rare genetic disorder characterized by short stature and infertility. Conversely, people who have two X chromosomes and a Y chromosome are males with Klinefelter's syndrome, which includes tall stature and infertility.
Sex Chromosome Evolution
Present-day sex chromosomes look very different from each other: The X chromosome comprises about 5 percent of the human genome, and contains about 2,000 genes, while the Y chromosome is quite small and contains only about 50 genes (Figure 1). This striking difference in size and gene content between the sex chromosomes makes it hard to believe that they are actually ancient partners in a pair of chromosomes that originally were very similar. Once sex became determined by a genetic signal from the Y, the sex chromosomes largely stopped recombining in germ cells . Degeneration of Y genes ensued, together with accumulation of genes that are advantageous to males on the Y chromosome, such as genes involved in testicular function and in male fertility. Similar genes appear to have accumulated on the X chromosome, so that the X chromosome also plays an important role in sperm production. The X chromosome may also have a prominent role in brain function and intelligence. A strong argument in favor of this intriguing but still controversial theory is that mental disability is more common in males.
The X Chromosome and Diseases
Some diseases affect males but not females in a family. Such diseases, called X-linked recessives, are often caused by mutations in genes located on the X chromosome, called X-linked genes. An X-linked disease is transmitted from the mother, not from the father, to an affected male, and an affected male will transmit a copy of the mutant gene to all his daughters. A famous example of an X-linked disease is hemophilia A. The blood of hemophiliac males fails to coagulate properly, leading to thinning of the blood and unstoppable bleeding after injury. This disease was recognized in the royal family of Queen Victoria, where examination of the huge pedigree readily confirmed recessive X-linked inheritance. Only males were affected, having inherited an X chromosome with a copy of a mutated gene from their healthy mothers, who were carriers of the disease. The mutated gene in hemophilia A was identified as factor VIII, a gene that encodes a protein essential for proper clotting of the blood. Males with a mutated gene cannot compensate since they have only one X chromosome, whereas female carriers have one normal gene that can compensate for the diseased gene. This typical recessive X-linked inheritance has been described for a variety of genes.
Dominant X-linked mutations, in which female carriers with just one mutated copy of the gene are affected, are rare. One example of such a disease is vitamin D-resistant rickets, in which people develop skeletal deformities. Generally, the disease is less severe in females than in males, because of X inactivation (see below). A famous X-linked disorder with inheritance that cannot be classified as either recessive or dominant is fragile X mental retardation. The fragile X chromosome bears its name because it displays a site susceptible to chromosome breakage. The mutated gene at the site contains a triplet repeat expansion, in which a series of three consecutive bases are copied multiple times. This causes the gene to be turned off by secondary changes in its structure. Affected males have severe mental retardation and female carriers can also be affected.
X inactivation consists of the silencing of genes on one of the X chromo somes in the female fetus. This silencing, which results in the absence of protein products from the inactivated genes, restores equal X-linked gene expression between the sexes. So, in the end, females have only one active X chromosome, like males (Figure 1). In the case of individuals with an abnormal number of X chromosomes, such as three X chromosomes, only one X will remain active.
One may wonder then why females do not express deleterious recessive X-linked mutations like males. This is because X inactivation is random, and a female is a mosaic of cells with either her paternal X active or her maternal X active (Figure 1). Thanks to this randomness, female carriers usually have plenty of cells with the normal gene remaining functional. Sometimes, there is even cell selection in carrier females, leading to skewed X inactivation in favor of the normal gene remaining functional. One intriguing feature of X inactivation is that it does not affect all X-linked genes. About 20 percent of genes "escape" X inactivation in humans. With a higher expression level in females than in males, such genes could perhaps play a role in female-specific functions. In males, some of these unusual genes have retained a functionally similar gene on the Y, as remnants of the ancient partnership of the sex chromosomes.
X inactivation was discovered in 1961 by Mary Lyon, a British scientist who studied mice. Thus, another name for this phenomenon is "Lyonization." The physiologic or normal regulation of expression of many genes is at the level of the individual gene. In contrast, X inactivation regulates a whole chromosome that comprises a huge number of genes. Special mechanisms of regulation evolved to initiate X inactivation through the action of a master gene on the X. Once one of the two X chromosomes (maternal or paternal) is randomly chosen to become inactivated in a given fetal cell, it will be faithfully maintained in this state in the progeny of the cell. The stability of the inactivation is mediated by a series of complex molecular changes called epigenetic modifications. X inactivation is lost in only one type of cells, the female germ cells, where both X chromosomes are functional for transmission to the next generation. Thus, X inactivation involves special mechanisms of initiation, maintenance, and reactivation. Much work still needs to be done to fully understand the fascinating roles of the X chromosome and its regulation.
see also Chromosomal Aberrations; Fragile X Syndrome; Hemophilia; Inheritance Patterns; Intelligence; Meiosis; Mosaicism; Sex Determination; Y Chromosome.
Christine M. Disteche
Miller, Orlando J., and Eeva Therman. Human Chromosomes. New York: Springer-Verlag, 2001.
Nussbaum, Robert L., Rod R. McInnes, and Huntington F. Willard. Thompson & Thompson Genetics in Medicine. Philadelphia, PA: Saunders, 2001.
Wang, Jeremy P., et al. "An Abundance of X-linked Genes Expressed in Spermatogonia." Nature Genetics 27, no. 4 (2001): 422-426.