Choosing the Active X: The Human Version of X Inactivation

Humans and rodents differ in how they carry out X inactivation (XI), the mammalian method to compensate for the different number of X chromosomes in males and females. Evolutionary changes in staging embryogenesis and in mutations within the XI center alter the process among mammals. The mouse model of XI is predicated on X counting and subsequently choosing the X to ‘inactivate’. However, new evidence suggests that humans initiate XI by protecting one X in both sexes from inactivation by XIST, the noncoding RNA that silences the inactive X. This opinion article explores the question of how the active X is protected from silencing by its own Xist locus, and the possibility of different solutions for mouse and human. Although all mammals use X inactivation as their means of X dosage compensation, the details of the process differ among them because of different staging of embryogenesis and mutations in the X inactivation center. An approximately 8-MB region of the short arm of human chromosome 19 is unique in the human genome because when triplicated in XX females, it leads to their preimplantation demise. This female-specific preimplantation loss contributes to the skewed sex ratio at birth, 1.05–1.06 male:1 female. Triplication of this region in 69, XXX or 69, XXY human embryos leads to two active X chromosomes. Within this region are several epigenetic factors, capable of repressing XIST. Therefore, an early step in X inactivation in human cells seems to protect the single active X by repressing its XIST locus. Later, any X chromosome with a nonrepressed XIST locus will be inactivated by XIST upregulation, and spreading of XIST transcripts along the chromosome – no matter the number of X chromosomes, or sex of the embryo.