Book Review

Females Are Mosaics: X Inactivation and Sex Differences in Disease

N Engl J Med 2008; 358:1644-1645April 10, 2008

Article

Females Are Mosaics: X Inactivation and Sex Differences in Disease
By Barbara R. Migeon. 271 pp., illustrated. New York, Oxford University Press, 2007. $59.95. ISBN: 978-0-19-518812-7

In Females Are Mosaics, Barbara Migeon makes a very strong case that women are superior to men in coping with disease and the environment. This is because they have two types of cells in all their organs, each with one of the two X chromosomes genetically active and the other essentially silent. This allows adaptability, since each of the two X chromosomes carries different mutations and polymorphisms that can alter women's susceptibility or resistance to detrimental genes, infectious agents, or other environmental dangers.

Much of the book is devoted to the reason for this state of mosaicism, which allows males and females to express equal quantities of proteins that are coded by genes on the X chromosome. Otherwise, females could have more of these proteins, a situation which in some settings could be incompatible with life. The formal term for the silencing of the two X chromosomes in the female is X inactivation, a phenomenon that was initially discovered in mice by Mary Lyon in 1961, and at about the same time by Elizabeth Russell. Lyon's original description was based on her observation of a mosaic pattern of coat color in female mice carrying a copy of a gene for a brown-colored coat on one of their X chromosomes and a normal (gray) allele on the other X chromosome. This led Lyon to postulate that one X chromosome in each cell was inactivated and that the process was random. She also showed that once an X was inactivated, the same X remained permanently inactive in all the cells that were derived from the cell in which inactivation occurred.

It was soon discovered that the details of this phenomenon differed in various vertebrate species — for example, marsupials always inactivate the paternally inherited X chromosome. Migeon makes a strong argument that this variation is caused by the timing of X inactivation in early embryogenesis in different species. Although the fundamental mechanism of X inactivation is thoroughly discussed and analyzed in the book, a number of questions remain to be resolved. For example, the mechanism by which all but one X chromosome are selected for inactivation is not totally clear, and much research is being done to try to resolve this important matter. We have learned several lessons about gene activity from the many studies that relate to the mechanism of X inactivation by way of a control region (inactivation center) on the X chromosome that contains a gene (X-inactivation–specific transcript, or XIST) that produces an RNA that causes inactivation along the length of the chromosome. The major lesson relates to the methylation of CpG (cytidine–phosphate–guanidine) islands, which turns off gene activity in all chromosomes. It is not entirely clear how the inactivating gene, XIST, causes this change in the X chromosome, but the result is the same as in the temporary or permanent inactivation of genes that are not needed in the cells of particular tissues. This process of methylation is also related to the mechanism of imprinting, in which the silencing of some genes depends on which parent they come from. Such imprinted genes exist throughout the human genome.

The most important portion of this book for the clinician is the third and last part, which consists of three chapters related to the medical consequences of X inactivation. The first of these chapters explains sex differences in susceptibility to X chromosome aneuploidy, such as in Turner's syndrome, Klinefelter's syndrome, and the triple X syndrome, as well as in deletions of different parts of the X chromosome and translocations of parts of the X chromosome to autosomes. This last problem is particularly important in that the X that is translocated to an autosome is always the active one, since the inactivation mechanism would also inactivate the autosome to which it is attached. This means that the same X is active in all cells of a woman who is carrying a translocation and that, therefore, any mutation in that X will express itself as if the woman were a man.

The next chapter in this section relates to the effect of mosaicism, which is particularly relevant in the carriers of some types of mutations of genes on the X chromosome. The specific mutation that a person carries may cause selection against the cells in which the X that carries the mutation is active, thus preventing any manifestation of the disease (e.g., X-linked severe combined immunodeficiency). In other situations, the mutation may give an advantage to the cell in which it is active and cause the disease to manifest itself in the carrier (e.g., adrenoleukodystrophy). The last chapter is about the effects of the interacting cell populations on the health of women and the effects of X inactivation on the normal female phenotype. There are two extensive appendixes with descriptions of relevant X-linked and other diseases, and descriptions of sex chromosome aneuploidy and other chromosomal abnormalities. Each chapter has a concise and helpful summary that contains Migeon's interesting speculations, many of which will probably prove to be correct.

I thoroughly enjoyed reading this book, but I do have a few criticisms that presumably will be addressed in necessary future editions — necessary because of the enormous amount of activity in the field, led by a number of researchers including Migeon. My main criticism is that the book requires better copyediting — there are numerous errors, mainly of oversight, although some are typographical. Examples include calling Klinefelter's syndrome XYY instead of XXY, and the statement that Figure 2-6 shows the nonsilenced genes outside the pseudoautosomal region instead of inside it, as well as a number of others that are a bit annoying but should be easy to correct. I also missed a discussion of patients with Turner's syndrome who may have 45,X/46,XY mosaicism, which increases the risk of gonadal tumors. Despite these minor problems, however, this important and enjoyable book should be read by physicians who care for women of all ages.

Kurt Hirschhorn, M.D.
Mount Sinai School of Medicine, New York, NY 10029
kurt.hirschhorn@mssm.edu