Twin study of genetic and aging effects on X chromosome inactivation

Kristiansen, Marianne; Knudsen, Gun Peggy; Bathum, Lise; Naumova, Anna K.; Sørensen, Thorkild I A; Brix, Thomas Heiberg; Svendsen, Anders Jørgen; Christensen, Kaare; Kyvik, Kirsten Ohm; Ørstavik, Karen Helene

doi:10.1038/sj.ejhg.5201398

Cited by 106 publications

(137 citation statements)

References 42 publications

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“…Age has been shown to have an effect on XCI skewing, but is only significant in females over 55 years of age. 34,35 The mothers in our study sample were aged from 28 to 55, and the age-related increase in degree of skewing is not therefore expected in the sample. This is also true of the patients and controls.…”

Section: Discussionmentioning

confidence: 85%

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

et al. 2006

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Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n ¼ 96) and their mothers (n ¼ 84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI Z80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother -daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype -phenotype correlations in Rett syndrome.

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Section: Discussionmentioning

confidence: 85%

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

et al. 2006

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“…[2][3][4]6,20 Furthermore, if only transcription based analysis were to be taken into account, the results obtained in this cohort of aging females and our recently published data obtained in neonates 13 document that the incidence of skewing triples from birth to older age. Further studies on age-dependent skewing may help understand the biology of the aging hematopoiesis, and the pathobiology of hematopoietic malignancies of the elderly.…”

Section: Support For the Acquired Skewing Phenomenonmentioning

confidence: 82%

Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies

Busque

Paquette

Provost

et al. 2009

Blood

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Nonrandom X-chromosome inactivation (XCI), also known as skewing, has been documented in the blood cells of a significant proportion of normal aging women by the use of methylation-based assays at the polymorphic human androgen receptor locus (HUMARA). Recent data obtained with a new transcription-based XCI determination method, termed suppressive polymerase chain reaction (PCR), has shed controversy over the validity of XCI ratio results obtained with HUMARA. To resolve this disparity, we analyzed XCI in polymorphonuclear leukocytes of a large cohort of women aged 43 to 100 years with the use of HUMARA (n ‫؍‬ 100), a TaqMan single nucleotide polymorphism (SNP) assay (n ‫؍‬ 90), and the suppressive polymerase chain reaction (PCR) assay (n ‫؍‬ 67). The 3 methods yielded similar skewing incidences (42%, 38%, and 40%, respectively), and highly concordant XCI ratios. This confirms that the skewing of XCI ratio seen in blood cells of aging women is a bona fide and robust biologic phenomenon. IntroductionGene dosage compensation between XX females and XY males occurs by the random inactivation of one of parental X chromosomes in the female embryo. 1 According to the Lyon hypothesis, 1 the fraction of cells with inactivation of each X chromosome should be equivalent. A deviation from the 1:1 X-chromosome inactivation (XCI) ratio is referred to as skewing. We have previously shown that skewing of XCI increases significantly in the blood cells of female subjects from the neonatal period to old age. 2 This observation has subsequently been confirmed by others 3-6 and has important implications for understanding the physiology of aging hematopoiesis and the pathogenesis of age-related hematopoietic malignancies. The concordance of skewing documented in elderly monozygotic versus dizygotic twins 7 supports a genetic component to the trait, and work by Abkowitz et al 8 in a feline model suggests an age-dependent hemizygous cell-selection process.A recent report 9 argued against the skewing phenomenon in blood cells of aging women. In this study, 9 the blood cells of 40 women older than 65 years of age were analyzed by both a methylation-based assay (ie, human androgen receptor locus [HUMARA]) and a novel real-time polymerase chain reaction (PCR) assay, termed suppressive PCR, in which allele-specific primers are used to identify coding single nucleotide polymorphisms (SNPs) in several X-linked genes, including the iduronate-2-sulphatase gene IDS. The use of HUMARA showed that 30% of women had skewed XCI in their blood cells, whereas the suppressive PCR assay did not show any significant skewing. 9 These observations led the authors to conclude that the skewed XCI patterns observed with HUMARA were not an accurate reflection of the proportion of cells bearing a particular X chromosome in the active state but rather reflected age-related dysregulation of methylation patterns. 9 Although this explanation is a plausible one for these data, it is at odds with previously published reports validating the HUMARA assay against trans...

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“…22; 67% in centenarians, ref. 23). Although a recent report suggested that buccal epithelial cells were also subjected to increased skewing with time (24), the incidence of skewing in hematopoietic versus nonhematopoietic tissues of aging individuals is generally poorly correlated (correlation ratio 0.19-0.74) (25)(26)(27) except in some cases of extreme skewing, suggesting a more stable incidence of skewing in nonhematopoietic tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Variant alleles of the X chromosome controlling element (Xce) were subsequently found to bias XCI in mice and cause skewing in heterozygous mice, suggesting that primary skewing was genetically controlled, at least in this species (31). In humans, no Xce-like element has been identified to date, though a few isolated reports have favored a genetic influence on primary skewing: (a) a rare mutation in the X (inactive)-specific transcript (XIST) minimal promoter was found to favor primary skewing (32,33); (b) an alteration in X chromosome inactivation center (XIC) was suggested to be responsible for the skewing of XCI observed in 3 related females (34); (c) twin studies reported a good concordance of XCI patterns between monozygous twins (35)(36)(37); and (d) other studies have documented the heritability of the skewing trait (38)(39)(40). Most of these studies either reported rare genetic events or were conducted in blood cells of adult females (likely affected by age-associated skewing).…”

Section: Introductionmentioning

confidence: 99%

No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

Bolduc¹,

Chagnon²,

Provost³

et al. 2008

J. Clin. Invest.

104

122

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Skewing of X chromosome inactivation (XCI) can occur in normal females and increases in tissues with age. The mechanisms underlying skewing in normal females, however, remain controversial. To better understand the phenomenon of XCI in nondisease states, we evaluated XCI patterns in epithelial and hematopoietic cells of over 500 healthy female mother-neonate pairs. The incidence of skewing observed in mothers was twice that observed in neonates, and in both cohorts, the incidence of XCI was lower in epithelial cells than hematopoietic cells. These results suggest that XCI incidence varies by tissue type and that age-dependent mechanisms can influence skewing in both epithelial and hematopoietic cells. In both cohorts, a correlation was identified in the direction of skewing in epithelial and hematopoietic cells, suggesting common underlying skewing mechanisms across tissues. However, there was no correlation between the XCI patterns of mothers and their respective neonates, and skewed mothers gave birth to skewed neonates at the same frequency as nonskewed mothers. Taken together, our data suggest that in humans, the XCI pattern observed at birth does not reflect a single heritable genetic locus, but rather corresponds to a complex trait determined, at least in part, by selection biases occurring after XCI. IntroductionIn mammals, dosage compensation of X-linked genes in females is achieved by the transcriptional silencing of 1 of the 2 X chromosomes during early development, a process known as X chromosome inactivation (XCI) (1). Once XCI has occurred, the heterochromatin-enriched inactive X chromosome is stably transmitted to each daughter cell through subsequent mitoses. In human and mouse embryos, either of the 2 X chromosomes (paternal or maternal) can be inactivated. As a consequence, females from both species present a mosaic pattern of 2 cell lines, one expressing maternal X-linked genes and the other expressing paternal X-linked genes. The XCI ratio (or XCI pattern) corresponds to the relative proportion of each cell line. This ratio can be determined by the analysis of expression (2), transcription (3), or differential methylation (4) of polymorphic X-linked genes, such as the human androgen receptor (HUMARA) gene (5). Significant deviation from the theoretical 1:1 ratio between the 2 parental alleles is called skewing. As it was first suggested by pioneers of X-inactivation analysis, including Fialkow (6) and Vogelstein (7), in most studies, skewing and extreme skewing are arbitrarily defined as greater than or equal to 75% and greater than or equal to 90% of cells expressing the same X chromosome, respectively.Skewed patterns of XCI were initially found in female carriers of specific X-linked mutations (8, 9) where skewing resulted from

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Twin study of genetic and aging effects on X chromosome inactivation

Cited by 106 publications

References 42 publications

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies

No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

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