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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1274-1281
HEMATOPOIESIS
Assessment of mechanism of acquired skewed X inactivation by
analysis of twins
Mark A. Vickers,
Ewan McLeod,
Timothy D. Spector, and
Ian J. Wilson
From the Department of Haematology, Medicine and
Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, UK; the
Twin Research and Genetic Epidemiology Unit, St Thomas's Hospital,
London, UK; and the Department of Mathematical Sciences, Meston
Building, University of Aberdeen, Old Aberdeen, UK.
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.
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