Αρχική > βιολογία > Seeing X Chromosomes in a New Light

Seeing X Chromosomes in a New Light

Launch media viewer

In a female mouse’s brain, a left-to-right pattern in the silencing of the X chromosome. These patterns may influence how individual brains function. Hao Wu and Jeremy Nathans/Cell Press

By CARL ZIMMERJAN, The New York Times, 20.1.2014

The term “X chromosome” has an air of mystery to it, and rightly so. It got its name in 1891 from a baffled biologist named Hermann Henking. To investigate the nature of chromosomes, Henking examined cells under a simple microscope. All the chromosomes in the cells came in pairs.

All except one.

Henking labeled this outlier chromosome the “X element.” No one knows for sure what he meant by the letter. Maybe he saw it as an extra chromosome. Or perhaps he thought it was an ex-chromosome. Maybe he used X the way mathematicians do, to refer to something unknown.

Today, scientists know the X chromosome much better. It’s part of the system that determines whether we become male or female. If an egg inherits an X chromosome from both parents, it becomes female. If it gets an X from its mother and a Y from its father, it becomes male.

But the X chromosome remains mysterious. For one thing, females shut down an X chromosome in every cell, leaving only one active. That’s a drastic step to take, given that the X chromosome has more than 1,000 genes.

Launch media viewer

Cells silence X chromosomes in different patterns, sometimes skewing entire organs toward one parent. Clockwise from top left, a mouse’s cornea, skin, cartilage and inner ear. Dr. Jeremy Nathans hopes his colored maps serve as an atlas for the effects of X-chromosome inactivation on women. Hao Wu and Jeremy Nathans/Cell Press

In some cells, the father’s goes dormant, and in others, the mother’s does. While scientists have known about this so-called X-chromosome inactivation for more than five decades, they still know little about the rules it follows, or even how it evolved.

In the journal Neuron, a team of scientists has unveiled an unprecedented view of X-chromosome inactivation in the body. They found a remarkable complexity to the pattern in which the chromosomes were switched on and off.

At the same time, each copy of the X chromosome contains versions of genes not found on its partner. So having two X chromosomes gives females more genetic diversity than males, with their single X chromosome. Because of that, females have a genetic complexity that scientists are only starting to understand.

“Females simply have access to realms of biology that males do not have,” said Huntington F. Willard, the director of Duke University’s Institute for Genome Sciences & Policy, who was not involved in the research.

But while the additional genes provided by their second X chromosome may in some cases provide females with a genetic advantage, X chromosomes also have a dark side. Their peculiar biology can lead to genetic disorders in males and, new research suggests, create a special risk of cancer in females. Understanding X-chromosome inactivation can also shed light on the use of stem cells in therapies.

A Japanese biologist, Susumu Ohno, first recognized X-chromosome inactivation in the late 1950s. In every female cell that he and his colleagues studied, they found that one of the two X chromosomes had shriveled into a dormant clump. Scientists would later find that almost no proteins were being produced from the clump, indicating that it had been shut down.

The British geneticist Mary F. Lyon realized that she could learn more about X-chromosome inactivation by breeding mice, because some color genes sit on the X. In 1961 she reported that female mice sported patches of hair with their mother’s color and others with their father’s.

Getting a deeper look at how females shut down their X chromosomes has remained a challenge in the decades since Dr. Lyon’s discovery. In recent years, Dr. Jeremy Nathans, a Howard Hughes Medical Institute investigator at Johns Hopkins University, and colleagues have developed a way to make X chromosomes from different parents light up. They inserted a set of genes into the X chromosomes of mice. The genes produced a green fluorescent protein, but only if their X chromosome was active and they were exposed to a particular chemical trigger.

Dr. Nathans and his colleagues engineered other mice to produce a red protein from active X chromosomes in response to a different chemical. The researchers bred the altered mice to produce female pups. The pups inherited a green X from one parent and a red one from the other.

The scientists then added both of their color-triggering chemicals to the mouse cells. The cells lit up in a dazzling mosaic of reds and greens. One cell might shut down the mother’s X, while its neighbor shut down the father’s.

In recent years, scientists have increasingly appreciated that our cells can vary genetically — a phenomenon called mosaicism. And X-chromosome inactivation, Dr. Nathans’s pictures show, creates a genetic diversity that’s particularly dramatic. Two cells side by side may be using different versions of many different genes. “But there is also much larger-scale diversity,” Dr. Nathans said.

In some brains, for example, a mother’s X chromosome was seen dominating the left side, while the father’s dominated the right. Entire organs can be skewed toward one parent. Dr. Nathans and his colleagues found that in some mice, one eye was dominated by the father and the other by the mother. The diversity even extended to the entire mouse. In some animals, almost all the X chromosomes from one parent were shut; in others, the opposite was true.

Launch media viewer

To learn more about how females shut down their X chromosomes, researchers developed a way to make X chromosomes from different parents light up as green or red in mice. A mouse’s left and right retinas. Hao Wu and Jeremy Nathans/Cell Press

“It’s incredibly important,” said Dr. Willard, the Duke geneticist. “This is the most stunning display of what Mary Lyon said 50 years ago.”

Dr. Nathans hopes his colored maps can serve as an atlas for the effects of X-chromosome inactivation on women’s bodies. Because each X chromosome carries different variants of the same genes, father-dominated tissues may behave differently from mother-dominated ones.

How one cell ends up silencing its mother’s or father’s X chromosome is still not entirely clear. Scientists are just starting to decipher some of the key steps in the process. “The knowledge of this is exploding,” said Dr. Jeannie T. Lee, a Howard Hughes Medical Institute investigator at Harvard Medical School.

Scientists don’t know how a cell chooses one chromosome or another to silence. But they’ve identified a number of the molecules that do the silencing. The leader of this molecular team is known as Xist.

Ever since it was discovered in the 1990s, scientists have debated how Xist managed to shut down an entire chromosome. Some researchers suggested that one Xist molecule landed on one spot on the X chromosome and then others attached to it, spreading along its length. But recent studies by Dr. Lee and colleagues show that Xist molecules envelop the X chromosome like a swarm of bees. “It’s going to all the genes all at once,” she said.

Once Xist latches on, it lures other types of molecules. Together they enshroud the X chromosome. When a cell divides, new copies of the molecules silence the same chromosome in its descendants.

Why women’s cells should bother with such an elaborate dance has also intrigued scientists. While scientists have proposed a number of explanations ever since X-chromosome inactivation was discovered, Gabriel A.B. Marais, an evolutionary biologist at the University of Lyons in France, said that none fit the current evidence very well. “The situation is very confusing,” he confessed.

It’s possible, for example, that males have to increase the production of proteins from their X chromosome because they have only one copy of its genes. But this creates a quandary for females, because they may overdose themselves. They shut down one of the hyperactive X chromosomes to regain a balance of their own.

Females might have evolved to choose randomly between their parents’ chromosomes because it gave them more genetic versatility. Sometimes a gene on one X chromosome is defective. Cells that use the healthy copy of the X chromosome can compensate. Males, by contrast, are far more prone to genetic disorders linked to the X chromosome, such as color blindness. With only one X chromosome in their cells, they have no backup.

Dr. Nathans speculates that using chromosomes from both parents is especially useful in the nervous system. It could create more ways to process information. “Diversity in the brain is the name of the game,” he said.

But the X chromosome may also pose a risk to women. Dr. Lee and her colleagues have found that when they shut down Xist in female mice, the animals were more likely to develop cancer. She suspects that when a cell stops making Xist, its inactivated X chromosome wakes up. The extra proteins it makes can drive a cell to grow uncontrollably.

“That has bearing on stem cell therapy,” she added. When stem cells are reared in the lab, they sometimes stop making Xist as well. Dr. Lee is concerned that female stem cells may rouse sleeping X chromosomes, with devastating consequences.

Before stem cells can be safely used in medical treatments, we may finally need to solve the mystery that Henking originally labeled with an X.

A version of this article appears in print on January 21, 2014, on page D1 of the New York edition with the headline: Seeing X in a New Light. Order Reprints|Today’s Paper|Subscribe

 

What is the X chromosome?

 

The X chromosome is one of the two sex chromosomes in humans (the other is the Y chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The X chromosome spans about 155 million DNA building blocks (base pairs) and represents approximately 5 percent of the total DNA in cells.

Each person normally has one pair of sex chromosomes in each cell. Females have two X chromosomes, while males have one X and one Y chromosome. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in cells other than egg cells. This phenomenon is called X-inactivation or Lyonization. X-inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell. Because X-inactivation is random, in normal females the X chromosome inherited from the mother is active in some cells, and the X chromosome inherited from the father is active in other cells.

Some genes on the X chromosome escape X-inactivation. Many of these genes are located at the ends of each arm of the X chromosome in areas known as the pseudoautosomal regions. Although many genes are unique to the X chromosome, genes in the pseudoautosomal regions are present on both sex chromosomes. As a result, men and women each have two functional copies of these genes. Many genes in the pseudoautosomal regions are essential for normal development.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The X chromosome likely contains 800 to 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

Genes on the X chromosome are among the estimated 20,000 to 25,000 total genes in the human genome.

How are changes in the X chromosome related to health conditions?

Many genetic conditions are related to changes in particular genes on the X chromosome. This list ofdisorders associated with genes on the X chromosome provides links to additional information.

Changes in the structure or number of copies of a chromosome can also cause problems with health and development. The following chromosomal conditions are associated with such changes in the X chromosome.

intestinal pseudo-obstruction

Intestinal pseudo-obstruction, a condition characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis), can be caused by genetic changes within the X chromosome.

Some individuals with intestinal pseudo-obstruction have mutations, duplications, or deletions of genetic material in the X chromosome that affect the FLNA gene. Researchers believe that these genetic changes may impair the function of the filamin A protein, causing abnormalities in the cytoskeleton of nerve cells (neurons) in the gastrointestinal tract. These abnormalities result in impaired peristalsis, which causes abdominal pain and the other gastrointestinal symptoms of intestinal pseudo-obstruction.

Deletions or duplications of genetic material that affect the FLNA gene can also include adjacent genes on the X chromosome. Changes in adjacent genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals.

Klinefelter syndrome

Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male’s cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone (a hormone that directs male sexual development). A shortage of testosterone can lead to delayed or incomplete puberty, genital abnormalities, breast enlargement (gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility). Children with Klinefelter syndrome may also have learning disabilities, delayed speech and language development, and a shy and unassuming personality.

Typically, people with Klinefelter syndrome have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). Less commonly, affected individuals may have two or three extra X chromosomes (48,XXXY or 49,XXXXY). As the number of extra sex chromosomes increases, so does the risk of learning problems, intellectual disability, birth defects, and other health issues.

Some people with features of Klinefelter syndrome have the extra X chromosome in only some of their cells; in these individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). Individuals with mosaic Klinefelter syndrome may have milder signs and symptoms, depending on how many cells have an additional X chromosome.

microphthalmia with linear skin defects syndrome

A deletion of genetic material in a region of the X chromosome called Xp22 causes microphthalmia with linear skin defects syndrome. This region includes a gene called HCCS, which carries instructions for producing an enzyme called holocytochrome c-type synthase. This enzyme helps produce a molecule called cytochrome c. Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate (ATP), the cell’s main energy source. It also plays a role in the self-destruction of cells (apoptosis).

A deletion of genetic material that includes the HCCS gene prevents the production of the holocytochrome c-type synthase enzyme. In females (who have two X chromosomes), some cells produce a normal amount of the enzyme and other cells produce none. The resulting overall reduction in the amount of this enzyme leads to the signs and symptoms of microphthalmia with linear skin defects syndrome.

In males (who have only one X chromosome), a deletion that includes the HCCS gene results in a total loss of the holocytochrome c-type synthase enzyme. A lack of this enzyme appears to be lethal very early in development, so almost no males are born with microphthalmia with linear skin defects syndrome. A few affected individuals with male appearance but who have two X chromosomes have been identified.

A reduced amount of the holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without the holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye and skin abnormalities characteristic of microphthalmia with linear skin defects syndrome.

triple X syndrome

Triple X syndrome (also called 47,XXX or trisomy X) results from an extra copy of the X chromosome in each of a female’s cells. Females with triple X syndrome have three X chromosomes, for a total of 47 chromosomes per cell. An extra copy of the X chromosome is associated with tall stature, learning problems, and other features in some girls and women.

Some females with triple X syndrome have an extra X chromosome in only some of their cells. This phenomenon is called 46,XX/47,XXX mosaicism.

Females with more than one extra copy of the X chromosome (48,XXXX or 49,XXXXX) have been identified, but these chromosomal changes are rare. As the number of extra sex chromosomes increases, so does the risk of learning problems, intellectual disability, birth defects, and other health issues.

Turner syndrome

Turner syndrome results when one normal X chromosome is present in a female’s cells and the other sex chromosome is missing or structurally altered. The missing genetic material affects development before and after birth, leading to short stature, ovarian malfunction, and the other features of Turner syndrome.

About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in an individual’s body has only one copy of the X chromosome instead of the usual two sex chromosomes. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent.

Some women with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Some cells have the usual two sex chromosomes (either two X chromosomes or one X chromosome and one Y chromosome), and other cells have only one copy of the X chromosome. Women with Turner syndrome caused by X chromosome mosaicism (45,X/46,XX or 45,X/46,XY) are said to have mosaic Turner syndrome.

Researchers have not determined which genes on the X chromosome are responsible for most of the features of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. The SHOX gene is located in the pseudoautosomal regions of the sex chromosomes. Missing one copy of this gene likely causes short stature and skeletal abnormalities in women with Turner syndrome.

46,XX testicular disorder of sex development

In most individuals with 46,XX testicular disorder of sex development, the condition results from an abnormal exchange of genetic material between chromosomes (translocation). This exchange occurs as a random event during the formation of sperm cells in the affected person’s father. The translocation affects the gene responsible for development of a fetus into a male (the SRY gene). TheSRY gene, which is normally found on the Y chromosome, is misplaced in this disorder, almost always onto an X chromosome. A fetus with an X chromosome that carries the SRY gene will develop as a male despite not having a Y chromosome.

48,XXYY syndrome

48,XXYY syndrome is caused by the presence of an extra X chromosome and an extra Y chromosome in a male’s cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone in adolescent and adult males. Extra copies of genes from the pseudoautosomal regions of the extra X and Y chromosome contribute to the signs and symptoms of 48,XXYY syndrome; however, the specific genes have not been identified.

other chromosomal conditions

Chromosomal conditions involving the sex chromosomes often affect sex determination (whether a person has the sexual characteristics of a male or a female), sexual development, and the ability to have children (fertility). The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in the chromosomes.

Is there a standard way to diagram the X chromosome?

Geneticists use diagrams called ideograms as a standard representation for chromosomes. Ideograms show a chromosome’s relative size and its banding pattern. A banding pattern is the characteristic pattern of dark and light bands that appears when a chromosome is stained with a chemical solution and then viewed under a microscope. These bands are used to describe the location of genes on each chromosome.

Ideogram of the X chromosome

See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about the X chromosome?

You may find the following resources about the X chromosome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

Where can I find general information about chromosomes?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

 

What glossary definitions help with understanding the X chromosome?

adenosine triphosphate ; adolescent ; aneuploidy ; apoptosis ; ATP ; cell ; chromosome ; cytoskeleton ;deletion ; digestive ; DNA ; egg ; embryonic ; enzyme ; fertility ; fetus ; gastrointestinal ; gene ;gene dosage ; gynecomastia ; hormone ; infertility ; inflammation ; lyonization ; mitochondria ; molecule ;monosomy ; mosaic ; mosaicism ; necrosis ; neurological ; obstruction ; ovarian ;oxidative phosphorylation ; phosphorylation ; protein ; puberty ; sex chromosomes ; sex determination ;short stature ; sperm ; stature ; syndrome ; testes ; testosterone ; translocation ; trisomy ; X-inactivation

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (25 links)

 

http://ghr.nlm.nih.gov/chromosome/X

 

 

  1. Δεν υπάρχουν σχόλια.
  1. No trackbacks yet.

Σχολιάστε

Εισάγετε τα παρακάτω στοιχεία ή επιλέξτε ένα εικονίδιο για να συνδεθείτε:

Λογότυπο WordPress.com

Σχολιάζετε χρησιμοποιώντας τον λογαριασμό WordPress.com. Αποσύνδεση /  Αλλαγή )

Φωτογραφία Google

Σχολιάζετε χρησιμοποιώντας τον λογαριασμό Google. Αποσύνδεση /  Αλλαγή )

Φωτογραφία Twitter

Σχολιάζετε χρησιμοποιώντας τον λογαριασμό Twitter. Αποσύνδεση /  Αλλαγή )

Φωτογραφία Facebook

Σχολιάζετε χρησιμοποιώντας τον λογαριασμό Facebook. Αποσύνδεση /  Αλλαγή )

Σύνδεση με %s

Αρέσει σε %d bloggers: