Genetic and environmental determinants of age-acquired skewed X-inactivation and escape from X-inactivation

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In humans, females carry two copies of the X chromosome and males one X and one Y chromosome. To maintain a consistent level of gene expression between the sexes, in every cell females silence or 'inactivate' one of their two X chromosomes. Most females randomly silence one X in each cell so that at a tissue level each X is silenced 50% of the time. Functionally, this means that cells in the same body are utilizing different DNA depending on which chromosome X is silenced in a given cell. However, as women age, one of the two X's starts to predominate; 35% of women over 60 have the same X chromosome silenced in >90% of their cells (termed 'skewed X-inactivation'), and the proportion of women with preferential silencing of the same chromosome X increases with age. It is not known why this age-associated preferential silencing happens, however it is associated with biomarkers of cancer and is seen in individuals with autoimmune diseases such as systemic lupus and thyroid disease. Intriguingly, twin-studies have shown that age-associated preferential silencing is heritable, suggesting an individual's genetics interact with the ageing process to promote cells silencing one X or the other. In this study we will investigate the genetic basis of age-associated chromosome X preferential silencing in order to determine what genetic factors drive this process and whether the same genetic factors are implicated in risk of cancer and autoimmune disease. As the UK population ages, it is a public health priority to identify factors that contribute to healthy ageing and develop biomarkers that monitor healthy ageing and predict future disease. We will explore the relationship between preferential silencing and ageing phenotypes such as frailty and disease incidence to determine if preferential silencing can act as a biomarker of healthy ageing in women. Some genes on the silenced (or 'inactive') X chromosome are still turned on - they escape inactivation. Genes on the silenced X have a critical role in female biology; women with only one X chromosome (and therefore absolutely no expression of genes from a second chromosome) have Turners syndrome, which includes dysfunction of various organ systems. Genes expressed from the silenced X have a higher dosage in females than males which is thought to underlie differences in disease prevalence between men and women. For example, several of the genes known to escape X-inactivation are tumor-suppressor genes and the extra dosage from the silenced X chromosome has a protective effect - overall women develop less cancer than men. Conversely, several genes implicated in the female-biased auto-immune diseases Systemic Lupus Erythematosus and Rheumatoid Arthritis are expressed from the silenced X chromosome. In this case, it is thought that women may produce too much of these genes which pre-disposes them to developing disease. Understanding how genes on the silenced X are controlled, and how this varies in different contexts, is critical to understanding how these genes contribute to disease. For example, tissue-limited escape would indicate which tissue is important for mediating a gene's effect on disease. It is currently estimated that 12-20% of genes on the silenced X can be turned on and that their strength of escape varies across individuals. In this study we will perform deep sequencing of the genes on chromosome X to determine which genes escape, how the strength of escape varies across unrelated individuals, between identical twins (thereby removing variability due to genetics), and across tissues. We will focus on autoimmune disease relevant tissues as these have been linked to escape, as well as looking in existing multi-tissue datasets of blood, fat and skin. Finally, we will investigate how escape varies with age both cross-sectionally in the autoimmune tissues and longitudinally over 10 years in a whole blood dataset.