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Differences in X chromosome silencing can greatly affect the same organ on different sides of the body. Shown are the left and right retinas from a single mouse. Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. (Credit: Hao Wu, courtesy of Neuron)

genes

Red and green show which X chromosome is turned on

Researchers have figured out how to color code the two X chromosomes in female mice to reveal which is working and which has been switched off.

Knowing which X chromosome is active in particular cells or tissues can be significant, especially if one carries a normal copy of a particular gene and the other a defective copy.

Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. (Credit: Hao Wu, courtesy of Neuron)
Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. (Credit: Hao Wu, courtesy of Neuron)

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“X chromosome inactivation is a fascinating aspect of mammalian biology,” says Jeremy Nathans, professor of molecular biology and genetics at Johns Hopkins University.

By genetically tagging different X chromosomes with genes that make them glow either red or green, researchers can peer into different tissue types to analyze their genetic diversity at the cellular level.

The technique is likely to be valuable for studies of many diseases and disabling conditions. X-linked genetic variations such as hemophilia or color blindness are relatively common, in part because the human X chromosome carries so many genes: approximately 1,000, or close to 4 percent of the total.

“This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at the role that this process plays in brain development,” Nathans says.

One chromosome at a time

Females carry two X chromosomes in the nucleus of every cell, one contributed by the mother’s egg and the other by the father’s sperm. Males, on the other hand, have one X and one Y.

Scientists have long known that only one of a female’s X chromosomes works in any particular cell, with its genes pumping out proteins that govern that cell’s contribution to various inherited traits. Meanwhile, that cell’s other X remains dormant.

A new study, published in the journal Neuron, shows that which X is active—the mother’s or the father’s—can vary widely at every level: within tissues, on the left or right sides of a tissue like the brain, among different tissue types, between paired organs (like the eyes), and among individuals.

A good model to think of, is a calico cat: all are female, and they have mottled coat colors because cells in different areas have inactivated different X chromosomes.

The cats “have two different versions of a gene for coat color, which is located on the X chromosome,” Nathans says. “Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells.

“X chromosome inactivation actually occurs in all cells in female mammals, including humans, and it affects most of the genes on the X chromosome,” he says. “Although this phenomenon has been known for over 50 years, it couldn’t be clearly visualized in internal organs and tissues until now.”

Turn one X off

Early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell somehow makes a “decision” to inactivate one of the two X chromosomes, Nathans says. The choice appears to be random within each individual cell, but once it is made, the descendants of that cell maintain the initial decision.

Researchers created female mice carrying two copies of the gene for green fluorescent protein—one on each of the two X chromosomes—and mated them with  males whose single X chromosome carried the gene for a red fluorescent protein. Their female offspring had cells that glowed red or green depending on which X chromosome was silenced.

The team engineered the mice so that not all of their cells were color-coded, since that would make it hard to distinguish one cell type from another. Instead, a single cell type in each mouse, such as heart muscle cells, was color-coded.

The patterns are determined by the way each tissue develops, Nathans says. Some tissues are created from a very small number of “founder cells” in the early embryo; others are created from a large number. Statistically, the larger the group of founder cells, the greater the chances are of having a nearly equivalent number of red and green cells.

Although the ratio in the founding group is roughly preserved as the tissue grows, the distribution of the cells is determined by how much movement occurs. For example, in a tissue like blood, where the cells move a lot, the red and green cells are all mixed up.

In skin, where the cells don’t move much, each patch of skin consists of descendants of a single cell, which share the same inactive X chromosome—and the same color—creating a patchwork of red and green. Before Nathans’ team developed its technique, these patterns were not easily visualized.

The National Cancer Institute, the Human Frontier Science Program, the Howard Hughes Medical Institute and Johns Hopkins’ Brain Science Institute funded the work.

Source: Johns Hopkins University

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