AN X-CHROMOSOME GENE REGULATES HEMATOPOIETIC STEM-CELL KINETICS

Females are natural mosaics for X chromo some-linked genes, As X chrom osome inactivation occurs randomly, the ratio of parental phenotypes a mong blood cells is approximately 1:1. Recently, however, ratios of gr eater than 3:1 have beers observed in 38-56% of women over age 60, Thi s could result from a depletion of hematopoietic stem cells (HSCs) wit h aging (and the maintenance of hematopoiesis by a few residual clones ) or from myelodysplasia (the dominance of a neoplastic clone), Each p ossibility has major implications for chemotherapy and for transplanta tion in elderly patients, We report similar findings in longitudinal s tudies of female Safari cats and demonstrate that the excessive skewin g that develops with aging results from a third mechanism that has no pathologic consequence, hemizygous selection, We show that there is a competitive advantage for all HSCs with a specific X chromosome phenot ype and, thus, demonstrate that an X chromosome gene (or genes) regula tes HSC replication, differentiation, and/or survival.