Skewed X-inactivation is common in the general female population
Shvetsova E., Sofronova A., Monajemi R., Gagalova K., Draisma HHM., White SJ., Santen GWE., Chuva de Sousa Lopes SM., Heijmans BT., van Meurs J., Jansen R., Franke L., Kiełbasa SM., den Dunnen JT., ‘t Hoen PAC., Heijmans BT., ’t Hoen PA., van Meurs J., Boomsma DI., Pool R., van Dongen J., Hottenga JJ., van Greevenbroek MM., Stehouwer CD., van der Kallen CJ., Schalkwijk CG., Wijmenga C., Zhernakova S., Tigchelaar EF., Slagboom PE., Beekman M., Deelen J., van Heemst D., Veldink JH., van den Berg LH., van Duijn CM., Hofman BA., Uitterlinden AG., Jhamai PM., Verbiest M., Suchiman HED., Verkerk M., van der Breggen R., van Rooij J., Lakenberg N., Mei H., Bot J., Zhernakova DV., van ’t Hof P., Deelen P., Nooren I., Moed M., Vermaat M., Luijk R., Jan Bonder M., van Iterson M., van Dijk F., van Galen M., Arindrarto W., Kiełbasa SM., Swertz MA., van Zwet EW., Isaacs A., Jansen R., Franke L., Francioli L., Menelaou A., Pulit S., van Dijk F., Palamara P., Elbers C., Neerincx P., Ye K., Guryev V., Kloosterman W., Deelen P., Abdellaoui A., van Leeuwen E., van Oven M., Vermaat M., Li M., Laros J., Karssen L., Kanterakis A., Amin N., Hottenga J., Lameijer E., Kattenberg M., Dijkstra M., Byelas H., van Setten J.
© 2018, The Author(s). 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.