TY - JOUR
T1 - Skewed X-inactivation is common in the general female population
AU - BIOS Consortium
AU - GoNL consortium
AU - Shvetsova, Ekaterina
AU - Sofronova, Alina
AU - Monajemi, Ramin
AU - Gagalova, Kristina
AU - Draisma, Harmen H.M.
AU - White, Stefan J.
AU - Santen, Gijs W.E.
AU - Chuva de Sousa Lopes, Susana M.
AU - Heijmans, Bastiaan T.
AU - van Meurs, Joyce
AU - Jansen, Rick
AU - Franke, Lude
AU - Kiełbasa, Szymon M.
AU - den Dunnen, Johan T.
AU - ‘t Hoen, Peter A.C.
AU - Heijmans, Bastiaan T.
AU - ’t Hoen, Peter Ac
AU - van Meurs, Joyce
AU - Boomsma, Dorret I.
AU - Pool, René
AU - van Dongen, Jenny
AU - Hottenga, Jouke J.
AU - van Greevenbroek, Marleen Mj
AU - Stehouwer, Coen Da
AU - van der Kallen, Carla Jh
AU - Schalkwijk, Casper G.
AU - Wijmenga, Cisca
AU - Zhernakova, Sasha
AU - Tigchelaar, Ettje F.
AU - Slagboom, P. Eline
AU - Beekman, Marian
AU - Deelen, Joris
AU - van Heemst, Diana
AU - Veldink, Jan H.
AU - van den Berg, Leonard H.
AU - van Duijn, Cornelia M.
AU - Hofman, Bert A.
AU - Uitterlinden, André G.
AU - Jhamai, P. Mila
AU - Verbiest, Michael
AU - Suchiman, H. Eka D.
AU - Verkerk, Marijn
AU - van der Breggen, Ruud
AU - van Rooij, Jeroen
AU - Lakenberg, Nico
AU - Mei, Hailiang
AU - Bot, Jan
AU - van Dijk, Freerk
AU - van Dijk, F.
AU - Hehir-Kwa, Jy
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058459928&partnerID=8YFLogxK
U2 - 10.1038/s41431-018-0291-3
DO - 10.1038/s41431-018-0291-3
M3 - Article
C2 - 30552425
AN - SCOPUS:85058459928
SN - 1018-4813
VL - 27
SP - 455
EP - 465
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -