X-Inactivation

If you've ever had a basic biology class then you know female humans have the sex chromosomes, XX, whereas males have XY. You inherit one X from your mother and either an X or a Y from your father and that determines your sex. However, females would have double the X-linked genes that males would have had. Therefore, a process called X chromosome inactivation (XCI) compensates for this dosage of X-linked genes in females. In humans, this process is random meaning that the maternal or paternal X can be silenced. Three articles were published this year in the same journal about this phenomenon. I just want to focus on one that I found the most interesting.

The first one was an overview of XCI and reactivation in X-linked diseases. Maternal and paternal X chromosomes have the same probability of inactivation, but the authors state that one particular X chromosome can be preferentially inactivated in most cells arising to a skewed or unbalanced XCI. It has been proposed that XCI skewing is heritable with possibly multiple X-linked genes driving this process. Some of these genes can escape XCI and have been suggested to play a role in Turner and Klinefelter syndromes. Turner syndrome occurs in females partially or completly missing an X chromosome (XO), whereas Klinefelter syndrome results in two X chromosomes in males (XXY). In addition, females who are carriers and heterozygous for X-linked dominant disorders can be phenotypically okay because the active X chromosome has the normal allele. Conversely, a skewed XCI can lead to an X-linked recessive trait transforming into a dominant trait if the normal allele has been silenced in the majority of cells. Another interesting finding is that some inactivated genes in the mouse model escape inactivation in humans and expression of these escapee genes is tissue dependent. Therefore, discrepancies were found between phenotypes of patients and the mouse model. Studies on humans have only recently been introduced and some of the results are interesting. It appears that human cells are more sensitive to environmental factors in culture conditions. Apparently, this could be attributed to humans having a more complex XIC process but this requires deeper exploration through research (1).

References:

1) Vacca M, Ragione F D, Scalabri F, D'Esposito M. X inactivation and reactivation in X-linked diseases. Seminars in Cell & Developmental Biology 56 (2016) 78-87.

For more on this topic:

2) Migeon B R. An overview of X inactivation based on species differences. Seminars in Cell & Developmental Biology 56 (2016) 111-116.

3) Goodrich L, Panning B, Leung K N. Activators and repressors: A balancing act for x-inactivation. Seminars in Cell & Developmental Biology 56 (2016) 3-8.