X-chromosome biology and immune health in females

Introduction

Females have a higher risk for autoimmune disease and lower risk of mortality from infectious disease than males, reflecting a more robust immune response in females against both self-antigens (autoimmunity) and non-self-antigens (infections). Genes that escape the process of X-inactivation (XCI) are present in a higher dose in female cells and many play key roles in T-cell biology. XX-Health will reveal the role of escape genes in mediating sex differences in T-cell response.

X-Chromosome Inactivation

Different cells in a tissue can inactivate the maternal (Xm) or paternal X-chromosome (Xp) (mosaicism). In addition, different ratios of Xm and Xp may become silenced in cells of a given tissue, resulting in skewed X-inactivation (sXCI), rendering functional dissection of XCI very challenging.

Rare females (~1:300) inactivate the same parental X-chromosome in all cells (cXCI), removing the confounding effect of mosaicism and offering a powerful genetic system in which to dissect XCI in T-cell biology.

Methodology

We will develop a novel methodology, TriX-Seq, allowing high-resolution screening of sXCI and cXCI in a large (N~8,000) unselected cohort of females. Using T-cells isolated from identified cXCI females, we will:

1. Generate a unique multi-omic map of XCI during human T-cell differentiation at a resolution well beyond the state-of-the-art.
2. Directly test the function of alleles specifically expressed from the inactive X-chromosome (Xi) in T-cell biology.

With sXCI data in hand, we will also reveal the associations, if any, of sXCI with disease risk and use the unique availability of parental and grand-parental DNA to assess the genetic origin of cXCI.

Significance

Sex-bias in COVID-19 mortality has highlighted the importance of sex as a contributor to disease risk. The technical and conceptual advances delivered by XX-Health will make a seminal contribution to our understanding of this poorly understood component of human health.