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An X chromosome gene regulates hematopoietic stem cell kinetics
J L Abkowitz1, M Taboada, G H Shelton
1Division of Hematology, University of Washington, 1959 Northeast Pacific Street, Box 357710, Seattle, WA 98195-7710, USA. janabk@u.washington.edu
Summary
Aging women and female cats show skewed X chromosome gene expression in blood cells. This phenomenon, termed hemizygous selection, results from a gene advantage for certain stem cells, not disease.
Area of Science:
- Genetics
- Hematology
- Gerontology
Background:
- Females are genetic mosaics for X chromosome-linked genes due to random X chromosome inactivation, typically resulting in a 1:1 ratio of parental phenotypes in blood cells.
- A significant percentage of women over 60 exhibit skewed X chromosome inactivation ratios (>3:1), previously attributed to stem cell depletion or myelodysplasia.
Purpose of the Study:
- To investigate the underlying mechanism of skewed X chromosome inactivation observed with aging in females.
- To determine if this phenomenon has pathological consequences or represents a normal aging process.
Main Methods:
- Longitudinal studies were conducted on female Safari cats to observe X chromosome inactivation patterns over time.
- Analysis focused on identifying the mechanism responsible for excessive X chromosome skewing in aging individuals.
Main Results:
- Similar skewed X chromosome inactivation patterns were observed in aging female Safari cats, mirroring human findings.
- The study identified 'hemizygous selection' as the cause of age-related X chromosome skewing, a non-pathological mechanism.
- Evidence suggests a competitive advantage for hematopoietic stem cells (HSCs) with a particular X chromosome phenotype.
Conclusions:
- Age-related X chromosome skewing in females is driven by hemizygous selection, not stem cell exhaustion or neoplastic processes.
- An X chromosome gene or genes appear to regulate hematopoietic stem cell replication, differentiation, and/or survival, conferring a selective advantage.
- This finding has implications for understanding aging and potential therapeutic strategies in elderly patients undergoing chemotherapy or transplantation.