Different species have developed strikingly different strategies to deal with disparities in the dose of X chromosome between males and females: in XX female mammals, one of the two X chromosomes is randomly inactivated; XX hermaphrodite nematodes halve the expression from each X chromosome; and male Drosophila
double expression from their single X chromosome in somatic cells [2
]. These dosage compensation mechanisms serve to balance the differences between the number of copies of X-linked genes in somatic tissues of the two sexes.
"Although we now know that these species use different approaches to achieve dosage compensation, this amounts mainly to playing differently with a limited panoply of chromatin-based modifications," says Philip Avner from the Pasteur Institute in Paris, France. X inactivation in mammals requires expression of the Xist
gene, which produces a large, non-coding RNA that coats the inactive X chromosome [3
]. The inactive X is characterized by DNA methylation, histone hypoacetylation, late replication and enrichment in the variant histone macroH2A. The hypertranscription of the Drosophila
X chromosome in somatic cells is dependent on the 'male specific lethal'
) loci, which encode a histone-modifying MSL complex that acetylates histone H4 on lysine 16 (H4 K16) [4
"Much less attention has been paid to the question of X/autosome dosage," says Avner. "X inactivation would be expected to lead to halved quantities of X-linked gene products compared to autosomal gene products. Haploinsufficiency
for the entire X would a priori
be expected to be catastrophic to the organism and lead to lethality during early embryonic development." Haploinsufficiency was the issue that Gupta and colleagues set out to address. "There was a lack of evidence for a germline dosage compensation machinery," notes Gupta, citing studies showing that in Drosophila
the X chromosomes are not coated with MSL complexes or hyperacetylated on H4 K16 in male germ cells [5
] (see the box for more on the rationale for the work). "Also, Parisi et al
] showed that a subset of ribosomal protein encoding genes are equally expressed in both testis and ovaries and we had seen that X;AA and XX;AA tumors showed very similar gene expression profiles," adds Gupta. "I've been thinking about this problem since I was a graduate student in the late 80s," recalls Brian Oliver who heads the research group at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, USA. "Until microarrays appeared, we didn't really see a good way to do a convincing experiment."