The human genome typically contains two sex chromosomes, and males usually have an X and a Y chromosome while most women have two X chromosomes. In women, one of the X chromosomes usually doesn't express genes; it is inactivated. But the same X chromosome is not inactivated in every cell, and although the X chromosomes carry the same set of genes, the patterns of expression among those genes can vary between them. Scientists have now shown that in a cell, inactive X chromosome can influence the expression of genes on the other X chromosome. The study authors suggested that inactive X chromosomes may, therefore, have an unappreciated role in health and disease. The findings have been reported in Cell Genomics.
Although one X chromosome is 'inactivated,' there are still some genes being expressed from that inactive chromosome. Previous work has suggested that as many as one quarter of the genes on inactive X chromosomes are actually active. Even so, the inactive X chromosome has been thought of as a silent partner. This study has suggested that it's much more than that.
In this work, the researchers obtained samples of blood and skin cells from people who carry atypical combinations of sex chromosomes, such as X0, in which only one X chromosome is present, to XXXXY. When multiple X chromosomes are present, all are inactivated but one X. The researchers also assessed gene expression in individuals who carry extra copies of a chromosome other than X.
Gene expression was assessed in these individuals, and the researchers determined how much each chromosome was contributing to overall gene expression. When people carried extra copies of a chromosome other than X, such as two copies of Y, or an extra copy of chromosome 21, the expression of active genes was simply doubled.
But something else happened when more than one X chromosome was present. The investigators found that each additional inactive X chromosome could raise the expression of one gene by 20 percent and another by 70 percent, while in other genes, expression actually decreased with the presence of an extra inactive X. Genes that should only be expressed by the active X were influenced by the gene on the supposedly inactive X.
The activity of X chromosomes seems to depend on inactive X chromosomes, and inactive X genes can modulate active X genes by increasing or decreasing their activity. There were two types of cells assayed in this study, and 38 percent of active X genes were impacted by inactive X chromosomes, either because those genes were also expressed by the 'inactive' X, because the inactive X influences their expression, or both.
Some people who have these combinations also have health issues. Males who carry XXY have Klinefelter syndrome, which causes muscle weakness and infertility. Turner syndrome occurs in X0 women, who may have hearing difficulties, heart defects, and other symptoms.
The researchers are hopeful that this study will shed new light on sex differences.
"Everybody on the planet carries one active X chromosome, so that first X chromosome really does not contribute, we think, to differences between males and females," said lead study author and Howard Hughes Medical Institute investigator Professor David Page of the Massachusetts Institute of Technology.
"If we transition from saying that females are XX and males are XY, to saying that females are Xi [have an inactive X] and males are Y, that really focuses the question," added Page, who is also a Whitehead Institute Member.
Sources: Whitehead Institute, Cell Genomics
