Acquired skewing of Lyonization remains stable for a prolonged period in healthy blood donors

Dijk, Jeroen P. van; Heuver, Leonie H.H.; Stevens-Linders, Ellen; Jansen, Joop H.; Mensink, E. J. B. M.; Raymakers, Reinier; Witte, Théo de

doi:10.1038/sj.leu.2402379

Cited by 30 publications

(36 citation statements)

References 16 publications

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“…X-inactivation pattern analyzed in peripheral granulocytes, monocytes and T cells in 35 blood donors aged 20-75 years was not significantly different in repeated measures of samples drawn 18 months later. 30 The authors concluded that no fluctuation of X-inactivation pattern occurred in these blood cells in this time period. Similarly, no differences were found between most of the samples taken about two decades apart from 178 females aged 5-75 years.…”

Section: Discussionmentioning

confidence: 87%

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Mengel‐From

Thinggaard²,

Christiansen³

et al. 2011

Eur J Hum Genet

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In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55-60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73-100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more skewed DS (hazard ratio: 1.30; 95% CI: 1.04-1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52-0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS. European Journal of Human Genetics (2012) 20, 361-364; doi:10.1038/ejhg.2011.215; published online 7 December 2011Keywords: aging; sex; mortality INTRODUCTIONThe biological phenomenon of X-chromosome inactivation is observed in females across a variety of mammalian species. Females have two X chromosomes, of which either the maternal or the paternal X is inactivated in early embryonic life, at about the time of implantation. 1 Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. Early in life the two cell populations are normally distributed around a 50:50 ratio. 2,3 In some females, one of the two cell populations is more abundant than the other and the value of the larger proportion is called the degree of skewing (DS), with DSZ50. DS¼50 is therefore a complete random X inactivation and DS¼100 is a completely skewed X inactivation. X inactivation is believed to occur randomly for each cell and to be permanent for all descendants of the cell. For women younger than 55-60 years of age, DS does not increase significantly with age in populations 2,3 or within the same individual. 4 However, DS increases considerably with age in cross-sectional studies of populations older than 55-60 years and this age association continues to increase in populations at the most advanced ages. 2,3,5 Most X-inactivation studies have been performed on peripheral blood cells, but a higher frequency of skewed X inactivation in elderly women has also been found in buccal swab cells. 6,7 Most X-inactivation studies use an indirect assay targeted to a methylation site and polymorphic sequence named the HUMARA assay. The representativeness of this indirect method for studying X inactivation has been questioned. Recently, however, skewing of X inactivation in aging women was co...

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Section: Discussionmentioning

confidence: 87%

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Mengel‐From

Thinggaard²,

Christiansen³

et al. 2011

Eur J Hum Genet

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“…3 However, once engrafted, lyonization of the donor HSCs remained relatively stable with time. 14 The most important and unequivocal finding was the emergence after HSCT of G6PD deficiency in the blood cells of an apparently normal female donor who was in fact a heterozygote. Since most female HSCT donors are young and skewed lyonization is uncommon, heterozygotes are unlikely to show G6PD deficiency and hence be detectable by routine tests.…”

Section: Discussionmentioning

confidence: 99%

G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors

Pang

Lam

et al. 2007

Bone Marrow Transplant

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“…20 All samples were separated in polymorphic nucleated cells (granulocytes) and mononuclear cells using Ficoll 1.077 density gradient centrifugation. Granulocytes (polymorphic nucleated cells) appeared to be more than 95% pure by flow cytometric analysis based on lightscattering properties.…”

Section: Selection Of Granulocytes Monocytes and T Cells From Peripmentioning

confidence: 99%

“…Subsequent HUMARA analysis was performed as described earlier. 20 Digestion of 0.5 g of DNA was performed for at least 16 hours at 37°C in a reaction mixture of 25 l, containing 5 U DdeI (Life Technologies, Gaithersburg, MD) and with or without 25 U of concentrated HpaII (New England Biolabs, Hitchin, UK) in 1ϫ one-phor-all buffer PLUS (Amersham Pharmacia, Uppsala, Sweden). After digestion, 5 l of this mixture was used for PCR amplification of the HUMARA locus.…”

Section: Dna Isolation Digestion and Humara Pcrmentioning

confidence: 99%

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A Novel, Essential Control for Clonality Analysis with Human Androgen Receptor Gene Polymerase Chain Reaction

Dijk

Heuver

Reijden

et al. 2002

The American Journal of Pathology

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The most widely used technique for determining clonality based on X-chromosome inactivation is the human androgen receptor gene polymerase chain reaction (PCR). The reliability of this assay depends critically on the digestion of DNA before PCR with the methylation-sensitive restriction enzyme HpaII. We have developed a novel method for quantitatively monitoring the HpaII digestion in individual samples. Using real-time quantitative PCR we measured the efficiency of HpaII digestion by measuring the amplification of a gene that escapes X-chromosome inactivation (XE169) before and after digestion. This method was tested in blood samples from 30 individuals: 2 healthy donors and 28 patients with myelodysplastic syndrome. We found a lack of XE169 DNA reduction after digestion in the granulocytes of two myelodysplastic syndrome patients leading to a false polyclonal X-chromosome inactivation pattern. In all other samples a significant reduction of XE169 DNA was observed after HpaII digestion. The median reduction was 220-fold, ranging from a 9.0-fold to a 57,000-fold reduction. Also paraffin-embedded malignant tissue was investigated from two samples of patients with mantle cell lymphoma and two samples of patients with colon carcinoma. In three of these cases inefficient HpaII digestion led to inaccurate X-chromosome inactivation pattern ratios. We conclude that monitoring the efficiency of the HpaII digestion in a human androgen receptor gene PCR setting is both necessary and feasible.

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Acquired skewing of Lyonization remains stable for a prolonged period in healthy blood donors

Cited by 30 publications

References 16 publications

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors

A Novel, Essential Control for Clonality Analysis with Human Androgen Receptor Gene Polymerase Chain Reaction

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