H. Sharat Chandra

PhD., University of California, Berkeley,USA

Almost from the time it was first described (Lyon,1961), mammalian X-chromosome inactivation has been looked upon as a means of dosage compensation, to balance the activity of X-linked genes between males (AAXY) and females(AAXX). The question of how the two sexes managed to avoid the consequences of X-chromosome monosomy was left unaddressed until Ohno (1967) proposed a two-step evolutionary process involving, first, enhancement of the rate of transcription of the single X chromosome in the male such that the product levels of X-linked genes and those of the two sets of autosomal genes are similar. But in the XX female such enhancement would be expected to push the levels of X-linked gene products to potentially harmful tetrasomic levels. Ohno therefore reasoned that the function of X inactivation is to bring down X-linked gene activity to a disomic level. For over 40 years Ohno's hypothesis has been a widely used framework for thinking about the evolution of X inactivation, dosage compensation and heteromorphic sex chromosomes in mammals.

Two studies of gene activity employing micro-array methods appeared to support this hypothesis, but in a recent study of human male and female cells by the methods of RNA-seq and proteomics, Xionget al. (2010) observed that the X:AA expression ratio is ~0.5 rather than ~1, suggesting that there is no doubling of activity of X-linked genes to reach a balance between X chromosomes and autosomesas proposed by Ohno. Two other studies have confirmed the observations of Xiong et al. If, as these results indicate, the rates of transcription and product levels of X-linked genes need not be equal to those of autosomal genes, why is it necessary to inactivate an X and induce functional monosomyof this large chromosome as part of normal female development? In other words, we go back to the question posed earlier: what is the evolutionary function of X inactivation?

There exists a large body of theoretical work on the roles imprinting, sex-specific selection,conflict between parental genomes, and sexual antagonism are thought to have played in the evolution of X inactivation. In the hope that X-chromosome gene content, and differences between genes subject to inactivation and those that are not, might provide useful clues,I am looking at present into these aspects of Xchromosome organization.

Selected publications:

1.Dosage compensation from the view point of natural selection.In 'Sex Chromosomes and Sex-determining Genes'. Eds. KC Reed and JAMarshall Graves. Harwood Academic,Switzerland (1993). Chandra HS, Nanjundiah V

2.X chromosomes and dosage compensation.Nature, 319: 18 (1986). Chandra HS Is human X-chromosome inactivation a sex determining device? Proceedings of the National Academy of Sciences USA, 82: 6947-6949 (1985). Chandra HS

3.Is human X-chromosome inactivation a sex determining device? Proceedings of the National Academy of Sciences, USA, 82: 6947-6949 (1985) Chandra HS

X-chromosome painting: The two X chromosomes in the cells of a woman light up following hybridization with X-specific DNA probes