The Role of X Inactivation and Cellular Mosaicism in Women's Health and Sex-Specific Diseases

Abstract

Sex-specific manifestations of disease are most often attributed to differences in the reproductive apparatus or in life experiences. However, a good deal of sex differences in health issues have their origins in the genes on the sex chromosomes themselves and in X inactivation-the developmental program that equalizes their expression in males and females. Most females are mosaics, having a mixture of cells expressing either their mother's or father's X-linked genes. Often, cell mosaicism is advantageous, ameliorating the deleterious effects of X-linked mutations and contributing to physiological diversity. As a consequence, most X-linked mutations produce male-only diseases. Yet, in some cases the dynamic interactions between cells in mosaic females lead to female-specific disease manifestations.

Sexual dimorphism in cancer

“…Female tissues are mosaic for most X-linked genes, resulting from Xi in every cell. Although inactivation of one X chromosome over the other is generally random, preferential inactivation of one chromosome (skewed Xi) can protect women against the consequences of X-linked gene mutations 104 . On the contrary the absence of Xi can have detrimental effects: for instance loss of Xist has been reported in breast, ovarian and cervical cancer cell lines 105,106 and, only in female mutant mice, it caused deregulation of hematopoietic lineages and emergence of myeloid neoplasms associated with genome wide changes in gene expression 107 .…”

“…Sex hormones, especially estrogens, can play an important role in control of cellular senescence and aging-associated tissue deteriorations. Concomitantly, at the chromosomal level, it has been suggested that X-linked mutations are more likely to exert detrimental effects in male than female cells, which have the advantageous possibility of selective inactivation of the mutations-carrying X chromosome 104 .…”

The Acute Inflammatory Response in Trauma /Hemorrhage and Traumatic Brain Injury: Current State and Emerging Prospects

“…A clinical study provided evidence for differences in the early cytokine response between females and males after injury, with males having persistently elevated IL-6 cytokine expression over time as compared to similarly injured females [56]. An alternative hypothesis states that Xlinked genetic differences between males and females, independent of hormonal status, responsible for these gender-based differential outcomes after injury in humans [56,57,58]. These studies suggest a new avenue for T/HS research and interaction with the field of endocrinology.…”

X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases

“…Although relatively uncommon, there is also the possibility of metabolic interference when products from mutant cells interfere with the function of the normal cells. 50 The disorders discussed here result from severe elimination of gene function. It is likely that more subtle differences in the expression of these and other genes will produce more nuanced differences in how males and females manifest their mutations.…”