Abstract
Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.
Highlights
Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes
XIST is uniquely expressed from the Xi3,28,31, so the relative expression of parental alleles within the XIST transcript are representative of XCI skewing levels in a bulk sample
We ran a series of benchmarking analyses to compare the non-PARASE calls to the XISTASE-based XCI skew calls (Supplementary Note 1, Supplementary Figs. 2–4) and demonstrated that the XISTASE is the appropriate method to use in our analyses
Summary
Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner. Asymmetric selection of the X chromosome to inactivate causes the predominance of one parental Xi in a population of cells, unbalancing the X-linked transcriptional and allelic dosages toward one parental X chromosome This phenomenon, known as skewed XCI (or nonrandom XCI), occurs when at least 80% of cells within a tissue inactivate the same parental X chromosome. In heterozygous females with skewed XCI, the X-linked transcriptional and allelic dosages of silenced genes are unbalanced and may be functionally homozygous.
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