In 1961 Mary Lyon, an English scientist, hypothesized that one of the two X chromosomes in females becomes genetically silent early in a female embryo's development. To understand how she arrived at this idea, which has come to be known as "the Lyon Hypothesis," we need to understand what was known about the sex chromosomes.
The Sex Chromosomes
Humans have twenty-three pairs of chromosomes, including one pair of sex chromosomes and twenty-two pairs of autosomes . The sex chromosomes are either X or Y chromosomes. Females have two X chromosomes, and males have an X and a Y chromosome.
In mammals, the sex of an individual is generally determined by whether the individual inherited an X or a Y chromosome from the father. The Y chromosome contains the SRY (Sex-determining Region Y) gene that directs male sexual development, but holds relatively few other genes. Many of the several dozen genes or gene families on the Y chromosome are necessary for the production of sperm. A handful are shared with the X chromosome, which is a medium-sized chromosome that is likely to contain more than one thousand genes.
Lyon knew that female mice that had only a single sex chromosome, the X chromosome, were normal. She also knew that mice carrying two different genes for coat color, one on each X chromosome, exhibited a mosaic, or blotchy, pattern of coat color. Some cells expressed one color gene, while others expressed the other, producing a mottled pattern.
Finally, she knew that when female cells are stained and looked at under a microscope a darkly staining region called a Barr body can be seen. She hypothesized that in female cells the Barr body is an inactive X chromosome. Thus, only one X chromosome would be active in any cell, resulting in a mottled pattern of X-linked gene expression. Furthermore, female cells lacking an X chromosome would be all right if the remaining X was the active one.
A good example of an animal that exhibits mosaicism is a tortoiseshell cat, which has patches of black and orange fur. There is a dominant gene on the X chromosome that makes the cat's fur orange. If a female cat has this geneon only one of its two chromosomes, then the pigment-producing cells in which this chromosome is active will generate orange fur, while those that have the gene on the inactive X chromosome will make black fur.
The choice of which X chromosome to inactivate occurs very early in development, when an embryo has less than one hundred cells. While this initial choice is generally random, the same inactivation pattern is then passed on to descendant cells through subsequent cell divisions, resulting in a patch of cells with one or the other X chromosome active, and therefore producing orange or black fur in the tortoiseshell cat.
Because the single X chromosomes in males is never inactivated, male cats do not have tortoiseshell coats. XXY male cats, however, which have an extra X chromosome, can have such coats.
X Chromosome Inactivation
How does a cell manage to silence one X chromosome in a cell but not the other even though the two chromosomes are almost identical? A clue to this puzzle came from the discovery of a gene named XIST (X inactive specific transcripts). This is a gene that is expressed only on the inactive X chromosome. It is transcribed into an RNA that does not code for protein, unlike most genes. Instead, the RNA associates with the X chromosome from which it is made, resulting in silencing of the chromosome.
We know many of the components of this silencing process, and they are proteins that have been implicated in the silencing of other genes or regions of chromosomes as well. They are predominantly factors that influence the structure of the chromatin, which is the complex of DNA and proteins that is found in chromosomes. For example, the chromatin structure can be changed by adding methyl groups to the DNA, or by adding acetyl or methyl groups to the histone proteins with which the DNA interacts.
Effect of X Inactivation on Human Disease
Females with a mutated gene on an X chromosome have two populations of cells. One group produces the intact protein, and the other produces a protein that is affected by the mutation. Like tortoiseshell cats, these females are mosaic. Health sometimes depends on what fraction of the cells in a tissue express the functional gene.
For reasons that are not yet well understood, some females exhibit non-random inactivation patterns. If the chromosome with the normal copy of a gene is inactivated in most of the cells in a female's body, and if the normal protein is vital for some function, the female is likely to develop a disease.
With some X-linked diseases, cells that contain a mutation on the active X chromosome proliferate less during development than cells that carry themutation on the inactive X chromosome. In such cases, the female primarily expresses the normal gene.
Unlike females, males with an X-linked mutation will usually show signs of the disease, because they have no second functional copy. (Females will usually show symptoms if they inherit a mutated copy of the gene from each parent.) Males therefore inherit X-linked diseases, such as Duchenne muscular dystrophy, hemophilia, or colorblindness, much more commonly than females. Some X-linked disorders are almost never found in males, which may seem paradoxical until we consider that the absence of a functional gene can be so harmful that most males who inherit the disease die before being born.
Such is the case with Rett syndrome, an X-linked, dominant neurological disorder. This disorder is due to a mutation in a gene called MECP2. The disorder is primarily found in females, whose mosaicism gives them partial protection from its effects. Only a handful of males with Rett syndrome are known.
Other Types of Mosaicism
Since humans consist of more than ten trillion cells, it is not surprising that mutations occur in the genes in some of these cells, rendering the individual a mosaic. In some cases such changes have limited impact and are found in only a few cells. In other cases they may lead to cancer or disease.
We are all likely to have some cells in our body that have acquired mutations, and therefore everyone may be considered a mosaic at some level. Mosaicism can create differences among a person's cells. It can also result in differences between "identical" twins.
Most females are mosaics, due to X chromosome inactivation, though their mosaicism does not necessarily involve any disease gene. Chromosomal and mitochondrial mosaicism are also observed frequently.
Every time a cell divides, the genetic material assembled in chromosomes needs to be divided too. If the chromosomes do not separate evenly, then cells are formed with missing or extra chromosomes. Such cells are called aneuploid. If this occurs early in embryonic development, a significant proportion of cells in an individual will be abnormal.
Chromosomal mosaicism may also result from the "rescue" of a fertilization that resulted from an aneuploid sperm or egg. If a fertilized egg contains three copies of a particular chromosome, a condition called trisomy, instead of the normal two, one of the extra copies can be "lost" if the chromosomes divide unevenly, restoring the normal chromosome number to the daughter cell.
Typically, in fetuses surviving the first trimester of pregnancy, the abnormal cells are found in placental but not in fetal tissues. Cells with three copies of a chromosome may be able to survive better in placental tissues, or there may be stronger selection against the growth of such cells in fetal tissues.
Trisomy is occasionally associated with pregnancy complications, such as poor fetal growth, but it may be common in placental tissues, and mosaicism confined to the placenta has been suggested to occur in up to 5 percent of births. Trisomic cells can also be found in the fetus itself, although this occurs much more rarely. Sometimes the abnormal cells will be present in only one type of tissue, such as the skin or lungs. Such variability has made it difficult to determine how often such chromosome mosaicism occurs and how it affects the health of an individual.
The mitochondria are organelles in the cytoplasm that release energy stored in molecules for cells to use. They contain their own small chromosome. The mitochondrial chromosome contains 16,569 base pairs, compared with the nuclear chromosomes, which, together, contain three billion base pairs.
Two features make mitochondria prone to mosaicism. First, their DNA is mutated more frequently than the nuclear DNA, in part because of the more dangerous cellular environment facing mitochondria and in part because mitochondria are not equipped to repair mutations as effectively as the nucleus.
Second, each mitochondrion contains numerous copies of its genome, and there are thousands of mitochondria in each cell. Thus individuals can have mutations in some of their mitochondrial genomes that are not found in their other mitochondria. This can lead to variable expression of diseases associated with mitochondrial mutations. Deletions of part of the mitochondrial genome appear to accumulate in different tissues with age and have been suggested to be a critical factor in normal human aging.
see also Chromosome, Eukaryotic; DNA Repair; Gene Expression: Overview of Control; Mitochondrial Diseases; Mitochondrial Genome; Muscular Dystrophy; Nondisjunction; X Chromosome.
Carolyn J. Brown
Avner, Philip, and Edith Heard. "X-Chromosome Inactivation: Counting, Choice and Initiation." Nature Reviews: Genetics 2 (2001): 59-67.
Lyon, Mary F. "Gene Action in the X-Chromosome of the Mouse (Mus musculus L. )."Nature 190 (1961): 372-373.