Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Abstract

In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55-60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73-100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more skewed DS (hazard ratio: 1.30; 95% CI: 1.04-1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52-0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS. European Journal of Human Genetics (2012) 20, 361-364; doi:10.1038/ejhg.2011.215; published online 7 December 2011Keywords: aging; sex; mortality INTRODUCTIONThe biological phenomenon of X-chromosome inactivation is observed in females across a variety of mammalian species. Females have two X chromosomes, of which either the maternal or the paternal X is inactivated in early embryonic life, at about the time of implantation. 1 Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. Early in life the two cell populations are normally distributed around a 50:50 ratio. 2,3 In some females, one of the two cell populations is more abundant than the other and the value of the larger proportion is called the degree of skewing (DS), with DSZ50. DS¼50 is therefore a complete random X inactivation and DS¼100 is a completely skewed X inactivation. X inactivation is believed to occur randomly for each cell and to be permanent for all descendants of the cell. For women younger than 55-60 years of age, DS does not increase significantly with age in populations 2,3 or within the same individual. 4 However, DS increases considerably with age in cross-sectional studies of populations older than 55-60 years and this age association continues to increase in populations at the most advanced ages. 2,3,5 Most X-inactivation studies have been performed on peripheral blood cells, but a higher frequency of skewed X inactivation in elderly women has also been found in buccal swab cells. 6,7 Most X-inactivation studies use an indirect assay targeted to a methylation site and polymorphic sequence named the HUMARA assay. The representativeness of this indirect method for studying X inactivation has been questioned. Recently, however, skewing of X inactivation in aging women was co...

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