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The Sex Chromosomes, Mosaic Expression, X Chromosome Inactivation, Effect Of X Inactivation On Human Disease

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.

Chromosomal Mosaicism.

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.

Mitochondrial Mosaicism.

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.

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.

Internet Resource

Online Mendelian Inheritance in Man. Johns Hopkins University, and National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/omim>.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 3