X Chromosome Inactivation
X chromosome inactivation, also called the Lyon hypothesis, is a phenomenon that occurs in every female mammal that has the double X chromosome configuration. Based on her own work on mice with mottled coats, Mary F. Lyon of the Medical Research Council's Mammalian Genetics Unit in Harwell, England, proposed in 1960 the idea of X inactivation. To ensure that the sexes work with similar doses of X genes, which scientists believe is critical for embryonic development, female mammals evolved the ability to inactivate one of their sex chromosomes. Early in embryonic life, one of the X chromosomes in every cell randomly shuts itself down. Researchers have uncovered evidence that DNA sequences usually dismissed as junk DNA without any function actually may help determine what genes on the X chromosome are suppressed. Some of the X chromosome genes, however, resist inactivation. Huntington F. Willard of Case Western Reserve University School of Medicine in Cleveland and his colleagues recently analyzed the activity of more than 200 genes mapped to the X chromosome, about 10 percent of the chromosome's estimated total. In Proceedings of the National Academy of Sciences, Willard's team reported that an unexpectedly large number of X chromosome genes, 34 of 224, are not inactivated. Of the 34 escapees, 31 are located on the short arm of the chromosome. In addition, most of these don't have a partner on the Y chromosome.
"Strict dosage compensation of all genes on the chromosome isn't necessary," stated coauthor Laura Carrel. The mechanism of how this inactivation occurs remains controversial. Somehow, the inactivated gene stays tightly coiled so that it becomes unavailable for replication. This inactivated chromosome appears in female cells as a small dark staining spot called a Barr body. In oocytes, the inactivation is reversed so that the females full DNA complement can be replicated.
As one chromosome is inherited from the father and one from the mother, this inactivation means that females are actually mosaics of both parents. This has definite consequences for genetic health, in that females are chimeric for the gene products of the X chromosome. Some mutations that cause genetic disease only occur on the X chromosome. The defective blood clotting disease Hemophilia is one such disease. Males only have one copy of the X chromosome, which they have inherited from their mother. If the mutation occurs on their X chromosome then they will express the disease because they do not have another copy of the gene that is not defective. On the other hand, females may or may not express the disease clinically, depending on how many of their cells contain the active chromosome with the defective gene. Thus, one sees gradations in the severity of symptoms with females, from none at all, to prolonged but non-fatal clotting times. They would be carriers, and could pass the disease on to their children.
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