Females Are Mosaics: X Inactivation and Sex Differences in Disease
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Women can be described as genetic mosaics because they have two distinctly different types of cells throughout their bodies. Unlike males, who have one X chromosome, females have two X chromosomes in every cell. Much has been written about the Y chromosome and its role in inducing maleness. This is the only book about the X chromosome as a key to female development and the role of X-related factors in the etiology of sex differences in human disease. This new edition reflects research advances from the six years since the widely praised first edition. New advances include knowledge of species differences in mammalian X inactivation processes and silencing of the inactive X chromosome.
developmental stage. We are all familiar with the role of cell selection in malignant processes such as leukemia, where unfortunately the cancer cells—having acquired mutations leading to a growth advantage—proliferate faster than the normal cells and eventually replace them. Fortunately, mutations expressed during normal embryonic development most often have a neutral or detrimental effect on viability so that if there is any proliferative advantage, the normal cells usually have it. Selection
section. We are acquiring knowledge of the process by which CpG islands become methylated on the inactive X, yet remain unmethylated on the active X. Conceivably the islands on the transcriptionally active chromosome are protected from methylation by the presence of the protein complexes involved in transcription. As for the islands on the inactive X, clearly they are methylated only after the chromatin becomes transcriptionally inactive, and there is some evidence that trimethylation of histone
loss of a relatively large number of cells because many cells present in early stages of development are not needed in subsequent ones. The loss of as much as half the blastocyst is well tolerated and does not compromise survival of the embryo. Certainly, twins and even quadruplets originate from a single fertilized ovum, attesting to the surplus of cells in the early embryo. The existence of females with X deletions shows the protective advantage that X inactivation provides for such embryos.
proliferate normally. As you see, the phenotype associated with HPRT deficiency in heterozygous females is determined independently in each tissue, based on the severity of the mutation and the availability of intercellular communication. As a consequence, mutant cells may receive essential products in one tissue and be eliminated in another tissue. An even more impressive demonstration of cell selection is the elimination of abnormal cells in heterozygotes for X-linked immunodeficiencies such as
to determine the proportion of each cell type in the heterozygote (the ratio of cells with active maternal X to cells with active paternal X). Any expressed variation can be used as an assay. One needs a marker—either a variant protein such as G6PD A (discussed in chapter 5) or a common DNA sequence variant (polymorphism)—to distinguish one allele from another. If the allelic difference is in the expressed (exonic) portion of a gene, then which parental allele(s) is being transcribed in that