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Cited by 543Genetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesEpigenetics and DNA MethylationAcute Myeloid Leukemia Research

Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age

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Busque, L, Mio, R, Mattioli, J, Brais, E, Blais, N, Lalonde, Y, Maragh, M, Gilliland, DG·1996·Blood
DOI 10.1182/blood.v88.1.59.59
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Abstract

Abstract 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.

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  • With aging, blood cells come from fewer and fewer stem cells.

    “during aging, blood cells are derived from fewer and fewer stem cells.”

    From Aging of hematopoietic stem cells (2018) · cites this paper as [79]

  • In some elderly individuals, HSCs acquire oncogenic mutations that allow them to outcompete their neighbors and clonally expand.

    “However, in some elderly individuals, HSCs acquire oncogenic mutations that allow them to outcompete their neighbors and clonally expand.”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Busque et al., 1996

  • As these HSCs clonally expand, they can account for a substantial fraction of steady state hematopoiesis, termed clonal hematopoiesis of indeterminate potential (CHIP).

    “As these HSCs clonally expand, they can account for a substantial fraction of steady state hematopoiesis, termed clonal hematopoiesis of indeterminate potential (CHIP) (Busque et al., 1996; Champion et al., 1997; Vas et al., 2012).”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Busque et al., 1996

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Research works printed but not linked: 1

  1. Busque L, Gilliland DG: The PGK-PCR based clonality assay (PPCA), in Harwood AJ (ed): Methods in Molecular Biology: Proto- cols for Gene Analysis, vol 31. Totowa, NJ, Humana Press 1994, p 237

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Authors
Busque, L., Mio, R., Mattioli, J., Brais, E., Blais, N., Lalonde, Y., Maragh, M., & Gilliland, D.
Affiliations
  • Hôpital Maisonneuve-Rosemont (CA)
  • Research Center, Hopital Maisonneuve-Rosemont, University of Montreal, Quebec, Canada.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
1996-07-01
Volume
88
Issue
1
Pages
59-65
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.v88.1.59.59
OpenAlex
W4242239767
Cited by
543
References
35
Citations by year
2026: 12 · 2025: 21 · 2024: 21 · 2023: 24 · 2022: 29 · 2021: 29 · 2020: 24 · 2019: 29 · 2018: 30 · 2017: 22 · 2016: 17 · 2015: 12 · 2014: 16 · 2013: 7 · 2012: 11
FWCI
9.33
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA47261)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
X chromosome inactivation, X-inactivation skewing, heterozygous females, stem cell depletion, clonal hematopoiesis, neonates, healthy women, blood cells, X-inactivation patterns
MeSH terms
Adult, Aged, Aged, 80 and over, Aging, Base Sequence, Clone Cells, Dosage Compensation, Genetic, Female, Heterozygote, Humans, Infant, Newborn, Methylation, Middle Aged, Models, Biological, Molecular Sequence Data, Phosphoglycerate Kinase, Transcription Factors, Polymerase Chain Reaction, Artifacts, Cell Lineage, RNA, Untranslated, RNA, Long Noncoding

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