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Skewing During Adult Life is Not Random and Results from X-linked Polymorphism

Oz Pomp, Denise Fong Mei Leong, Pamela Ying-Yuan Mok, Jerry Chan and Alan Colman

During early human development, females randomly inactivate one of the two X chromosomes in a process called X chromosome inactivation. Since this process is usually random, most women are a balanced 50:50 mosaic of cells. While this is the situation in young females, mosaicism is usually lost in the elderly, particularly in the blood, a process referred to as skewing. We have previously shown, using primary cell populations, that skewing is highly predictable in vitro and results from hemizygous selection whereby a competitive advantage is conferred to all cells that express genes from one X chromosome. Here we examine the mechanism behind skewing in vitro and conclude that the major factor is X-linked polymorphism. Similar observations are made in vivo where we find that most adult female mice skew in a predictable pattern towards a dominant X. These findings have important implications for in vitro studies and offer a platform to gain insights into the dynamics of skewing in the hematopoietic system.