Dosage Compensation Effect

Dosage compensation is a mechanism by which the activity of X-linked genes is made equal in the two sexes of the type XX and XY, in which one sex has two X-chromosomes and the other only one. In placental mammals, marsupials, and some monotremes, compensation is achieved by the inactivation of one X-chromosome in somatic cells of females (1). During embryonic development of the mouse, both X-chromosomes are active, and differentiation between the active form Xa and the inactive form Xi occurs in the primitive ectoderm. Once inactivation has been initiated at this stage, the same X-chromosome remains inactive in the descendants of each cell after mitosis throughout the life of the mouse. Reactivation of chromosome Xi in females occurs at the time of meiosis, so that both X-chromosomes are active in oocytes. In male germ cells, the single X-chromosome becomes inactive at the late spermatogonial stage.

 The chromatin of chromosome Xi is in the condensed state, and its DNA replication begins later than in Xa or in autosomes. The cytosine bases of CpG Islands near the 5′ promoter regions of genes are heavily methylated on chromosome Xi, but not on Xa (2). Differential hypersensitivity to digestion by deoxyribonuclease indicates altered binding of proteins to the DNA and different packaging of nucleosomes in the two X-chromosomes (3).

During studies of translocations between the X- and autosome chromosomes in mice, it was observed that only one of the two X-chromosomes undergoes inactivation which spreads from the inactive segment into the attached autosomal material. It appears as if an inactivation center existed on the X-chromosome, which becomes blocked on one X-chromosome (which becomes Xa) only at the time inactivation is initiated. The location of the inactivation center has been accurately mapped in human and mouse from studies of chromosomal translocations and deletions. A gene, called XIST in humans and Xist in the mouse, maps in the region of the inactivation center and is expressed by Xi but not by Xa (4). In the male, Xist is expressed only in the testis, suggesting a role in inactivation of the single X-chromosome in male germ cells. No protein product of Xist or XIST has yet been identified.

In Drosophila melanogaster, where X-chromosome is not inactivated, both X-chromosomes are transcribed in females. Compensation occurs by up-regulation and a doubled rate of transcription of the single X-chromosome in males. As a result, the level of transcription of the genes carried by the X-chromosome is the same in both sexes. The increase in the rate of transcription in males is caused by binding of transcription factors, called msl-1, msl-2, and msl-3, to enhancer elements on the X-chromosome. These transcription factors appear to act at the level of the chromatin structure and have been extensively studied in the polytene salivary gland chromosomes, where they bind codependently to the same set of sites along the male X-chromosome. Molecular characterization of the protein coded by msl-2 has to a great extent solved the question of how msl-mediated dosage compensation is restricted to males. Cloning and molecular analyses of the msl genes have substantiated the proposal that the MSL proteins function as a multimeric complex to mediate dosage compensation (5), (6.(

In the nematode Caenorhabditis elegans, equalization of transcription seems to occur by down-regulation in XX animals.

References

1. S. M. Gartler and A. D. Riggs (1983) Ann. Rev. Genet. 17, 155–190. 

2. A. D. Riggs (1990) Phil. Trans. R. Soc. London B326, 285–297. 

3. G. P. Pfeifer and A. D. Riggs (1991) Genes Dev. 5, 1102–1111. 

4. M. F. Lyon (1991) Trends Genet. 7, 69–70. 

5. S. Zhou et al. (1995) EMBO. J. 14, 2884–2895. 

6. G. J. Bashaw and B. S. Baker (1996) Curr. Opin. Genet. Dev. 6, 496–501.