Skewed X-inactivation is common in the general female population

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes ( SSR4 , REPS2 , and SEPT6 ), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

“…Current results suggest that, in heterozygous carrier females, X‐inactivation status in blood and skin fibroblasts does not predict the clinical outcome. This is very much in line with results obtained for other X‐linked disease genes and also with recent findings suggesting that skewed X‐inactivation is common in the general female population (Shvetsova et al, ). Still, the variable clinical manifestations of heterozygous carrier females with a de novo variant ranging from very mildly to severely affected may be partially explained by the X‐inactivation status within specific affected cells and tissues.…”

Clinical and molecular genetic characterization of two female patients harboring the Xq27.3q28 deletion with different ratios of X chromosome inactivation

“…Next, we focused on the molecular mechanism of skewed XCI of the normal X chromosome of patient 1. Studies of X inactivation patterns in general population demonstrated that only very small proportions (8% and 10%) of unaffected females show significantly skewed inactivation (<25:75/>75:25; Amos-Landgraf et al, 2006;Nesterova et al, 2003;Shvetsova et al, 2019). However, patients harboring Xq27.3q28 deletion, including the presented patient 1 of the current study, show relatively high ratios of skewed XCI of the normal allele (5/12).…”

Gut microbiota on gender bias in autism spectrum disorder

“…Men are the only ones who inherit Y-chromosome-linked genes, but both men and women can inherit X-chromosome-linked genes (Zhang et al 2017). X-chromosome inactivation is responsible for sex chromosome dosage compensation in females (XX) (Shvetsova et al 2019) that is the reason why males have worse symptoms than females. Males are more susceptible and have worse symptoms than females in ASD.…”