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.

Original languageEnglish
Pages (from-to)455-465
Number of pages11
JournalEuropean Journal of Human Genetics
Volume27
Issue number3
DOIs
Publication statusPublished - Mar 2019

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X Chromosome Inactivation
X Chromosome
Population
Genes
Alleles
Genome
Netherlands
Theoretical Models
Nucleotides
Parents
Mothers
RNA

Cite this

@article{a52ef3cdefa14e0e8fd62b815add60f4,
title = "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.",
author = "Ekaterina Shvetsova and Alina Sofronova and Ramin Monajemi and Kristina Gagalova and Draisma, {Harmen H M} and White, {Stefan J} and Santen, {Gijs W E} and {Chuva de Sousa Lopes}, {Susana M} and Heijmans, {Bastiaan T} and {van Meurs}, Joyce and Rick Jansen and Lude Franke and Kiełbasa, {Szymon M} and {den Dunnen}, {Johan T} and {'t Hoen}, {Peter A C} and D.I. Boomsma and R. Pool and {van Dongen}, J. and J.J. Hottenga and Gonneke Willemsen and {BIOS Consortium}",
year = "2019",
month = "3",
doi = "10.1038/s41431-018-0291-3",
language = "English",
volume = "27",
pages = "455--465",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",
number = "3",

}

Skewed X-inactivation is common in the general female population. / Boomsma, D.I.; Pool, R.; van Dongen, J.; Hottenga, J.J.; Willemsen, Gonneke; BIOS Consortium.

In: European Journal of Human Genetics, Vol. 27, No. 3, 03.2019, p. 455-465.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Skewed X-inactivation is common in the general female population

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 - Boomsma, D.I.

AU - Pool, R.

AU - van Dongen, J.

AU - Hottenga, J.J.

AU - Willemsen, Gonneke

AU - BIOS Consortium

PY - 2019/3

Y1 - 2019/3

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.

U2 - 10.1038/s41431-018-0291-3

DO - 10.1038/s41431-018-0291-3

M3 - Article

VL - 27

SP - 455

EP - 465

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 3

ER -