Assessment of mechanism of acquired skewed X inactivation by analysis of twins

Mark Adrian Vickers, Ewen McLeod, I. J. Wilson, T. D. Spector

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Skewed X-chromosome inactivation in peripheral blood granulocytes becomes more frequent with increasing age, affecting up to half of those over 75 years old. To investigate the mechanisms underlying this phenomenon, X-inactivation profiles in 33 monozygotic and 22 dizygotic elderly twin pairs were studied, Differential methylation-sensitive restriction enzyme cutting at a hypervariable locus in the human androgen receptor gene (HUMARA) was studied on purified granulocytes using T cells as controls. A large genetic effect on skewed granulocytic X inactivation was shown (P < .05); heritability was estimated to be 0.68, A minor part (SD .0151 relative allele frequency [ie, larger/smaller] units) of the observed variance is due to experimental error. A further contributor to acquired skewing is stochastic asymmetric stem cell division, which was modeled and shown as unlikely to account for a substantial part of variance. Two monozygotic twin pairs had X-inactivation ratios skewed markedly in opposite directions, evidence for a further stochastic mechanism, suggestive of a single overrepresented clone. In conclusion, all 3 suggested mechanisms contribute to acquired X inactivation but the dominant mechanism is genetic selection. The observed proportion of putatively clonal hematopoiesis is similar to the lifetime incidence of hematopoietic stem cell malignancy consistent with the concept that clonal hematopoiesis precedes stem cell malignancy. (Blood, 2001; 97:1274-1281) (C) 2001 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)1274-1281
Number of pages7
JournalBlood
Volume97
Issue number5
DOIs
Publication statusPublished - Mar 2001

Keywords

  • PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA
  • LINKED DNA POLYMORPHISMS
  • HEMATOPOIETIC STEM-CELLS
  • CHROMOSOME INACTIVATION
  • CLONAL ANALYSIS
  • HUMAN-TUMORS
  • BONE-MARROW
  • MYELOPROLIFERATIVE DISORDERS
  • NORMAL WOMEN
  • CORD-BLOOD

Cite this

Assessment of mechanism of acquired skewed X inactivation by analysis of twins. / Vickers, Mark Adrian; McLeod, Ewen; Wilson, I. J.; Spector, T. D.

In: Blood, Vol. 97, No. 5, 03.2001, p. 1274-1281.

Research output: Contribution to journalArticle

Vickers, Mark Adrian ; McLeod, Ewen ; Wilson, I. J. ; Spector, T. D. / Assessment of mechanism of acquired skewed X inactivation by analysis of twins. In: Blood. 2001 ; Vol. 97, No. 5. pp. 1274-1281.
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AB - Skewed X-chromosome inactivation in peripheral blood granulocytes becomes more frequent with increasing age, affecting up to half of those over 75 years old. To investigate the mechanisms underlying this phenomenon, X-inactivation profiles in 33 monozygotic and 22 dizygotic elderly twin pairs were studied, Differential methylation-sensitive restriction enzyme cutting at a hypervariable locus in the human androgen receptor gene (HUMARA) was studied on purified granulocytes using T cells as controls. A large genetic effect on skewed granulocytic X inactivation was shown (P < .05); heritability was estimated to be 0.68, A minor part (SD .0151 relative allele frequency [ie, larger/smaller] units) of the observed variance is due to experimental error. A further contributor to acquired skewing is stochastic asymmetric stem cell division, which was modeled and shown as unlikely to account for a substantial part of variance. Two monozygotic twin pairs had X-inactivation ratios skewed markedly in opposite directions, evidence for a further stochastic mechanism, suggestive of a single overrepresented clone. In conclusion, all 3 suggested mechanisms contribute to acquired X inactivation but the dominant mechanism is genetic selection. The observed proportion of putatively clonal hematopoiesis is similar to the lifetime incidence of hematopoietic stem cell malignancy consistent with the concept that clonal hematopoiesis precedes stem cell malignancy. (Blood, 2001; 97:1274-1281) (C) 2001 by The American Society of Hematology.

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