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Nonrandom X-inactivation patterns in normal females: lyonization ratios
vary with age
L Busque, R Mio, J Mattioli, E Brais, N Blais, Y Lalonde, M Maragh and DG Gilliland
Research Center, Hopital Maisonneuve-Rosemont, University of Montreal,
Quebec, Canada.
The utility of X-inactivation based clonality assays for evaluation of
human neoplasia is well-documented. However, excessive Lyonization is a
potential limitation of these assays, because it mimics clonal derivation
of cells. The incidence of excessive Lyonization in healthy females is
controversial, with reported incidence varying from 4% to 33%. Several
explanations have been offered for the observed variation, including
different criteria for excessive Lyonization, diversity of X- linked
clonality assays, small population sizes and more recently, tissue
specificity of X-inactivation patterns. However, it is also possible that
stem cell depletion, clonal hematopoiesis, or selection pressures on blood
cells results in an increased incidence of excessive skewing. If any of the
latter is true, then the incidence of excessive skewing should increase
with age in blood cells. To test this hypothesis, we determined
X-inactivation ratios at the human androgen receptor locus of 295 normal
females from three age groups: (1) neonates, (2) females 28 to 32 years old
and, (3) females aged > or = 60 years. The incidence of skewing (allele
ratios > or = 3:1) was 8.6% (14 of 162) in neonates (P = .104 v 28 to
32); 16.4% (11/67) in 28 to 32 y.o. (P = .0064 v > or = 60), and 37.9%
(25 of 66) in women > or = 60 y.o. (P < .0001 v neonates). When a
more stringent criterion for skewing was used (allele ratios > or =
10:1), the incidence was 1.9% (3 of 162) in neonates (P = .362 v 28 to 32),
4.5% (3 of 67) in 28 to 32 y.o. (P = .0022 v > or = 60), and 22.7% (15
of 66) in > or = 60 y.o. group (P < .0001 v neonates). Results have
been confirmed at the phosphoglycerate kinase locus for 48 heterozygous
females. The incidence of excessive skewing increases with age. In
neonates, the incidence is low and may correspond to true excessive
Lyonization. Acquired skewing occurs with aging in normal females and is
present in 38% of females over the age of 60. Further studies are needed to
determine whether acquired skewing is a consequence of stem cell depletion,
true clonal hematopoiesis, growth advantage conferred by parental-specific
X-chromosomes, or other causes. These data provide an explanation for
variation in reported incidence of excessive skewing in normal females.
Furthermore, these findings suggest that any study of clonality using
X-inactivation based assays should incorporate age- matched controls for
Lyonization.
Volume 88,
Issue 1,
pp. 59-65,
07/01/1996
Copyright © 1996 by The American Society of Hematology
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