posted March 17, 2005 05:33 PM         

Women Are Very Much Not Alike, Gene Study Finds

X chromosome diversity among females suggests that in effect 'there is not one human genome, but two -- male and female,' researcher says.

Scientists have found genetic evidence for what some men have long suspected: It is dangerous to make assumptions about women.

The key is the X chromosome, the feminine sex chromosome that all men and women have in common.

In a study published today in the journal Nature, scientists said they had found an unexpectedly large genetic variation on the X chromosome among women. The findings were published in conjunction with the first comprehensive decoding of the chromosome, which appeared in the same journal.

Females can differ from each other almost as much as they do from males in the behavior of many genes at the heart of sexual identity, researchers said.

"Literally every one of the females we looked at had a different genetic story," said Duke University genetics expert Huntington Willard, who co-wrote the study. "It is not just a little bit of variation."

The analysis also found that the obsessively debated differences between men and women were, at least on the genetic level, even greater than previously thought.

As many as 300 of the genes on the X chromosome may be activated differently among women than among men, said molecular biologist Laura Carrel at Pennsylvania State University College of Medicine, the other author of the paper.

The newly discovered genetic variation among women might help account for differing gender reactions to prescription drugs and the heightened vulnerability of women to some diseases, experts said.

"The important question becomes how men and women actually vary and how much variability there is in females," Carrel said. "We now might have new candidate genes that could explain differences between men and women."

All told, men and women may differ by as much as 2% of their entire genetic inheritance, greater than the hereditary gap between humankind and its closest relative — the chimpanzee.

"In essence," Willard said, "there is not one human genome, but two — male and female."

Scientists estimate that there may be as many as 30,000 genes in the chemical DNA blueprint for human growth and development known as the human genome.

The genes are parceled out in 23 pairs of rod-like structures called chromosomes contained in every cell of the body.

The most distinctive of the chromosomes are the mismatched pair of X and Y chromosomes that guide sexual development.

Until now, researchers considered the shuffle of sex chromosomes at conception a simple matter of genetic roulette.

The chromosomes that dictate sexual development are mixed and matched in predictable combinations: A female inherits one X chromosome from each parent; a male inherits an X chromosome from his mother and a Y chromosome from his father.

To avoid any toxic effect from double sets of X genes, female cells randomly choose one copy of the X chromosome and silence it — or so scientists had believed.

The new analysis found that the second X chromosome was not a silent partner. As many as 25% of its genes are active, serving as blueprints to make necessary proteins.

To investigate this variation, Carrel and Willard isolated cells from 40 women and measured the activity of hundreds of genes to see whether those on the second X chromosome were active or silent.

Although those extra genes were supposed to be turned off, they found that about 15% of them in all female cells were still active, or in the terminology of genetics, "expressed." In some women, up to an additional 10% of those X-linked genes showed varying patterns of activity.

"This is 200 to 300 genes that are expressed up to twice as much as in a male or some other females," Willard said. "This is a huge number."

Researchers were surprised that they found so many unexpected differences in the behavior of the one sex chromosome that men and women share.

Though there is dramatic variation in the activation of genes on the X chromosomes that women inherit, there is none among those in men, the researchers reported.

Researchers have yet to understand the effect of so many different patterns of gene activation among women or determine what controls them, but all the evidence suggests that they are not random.

"What had looked like a simple yes or no has turned into a thousand shades of gray," said molecular biologist David Page, an expert on sex evolution at the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Illuminating this complex palette was the work of an international team of 250 scientists led by geneticist Mark Ross at the Wellcome Trust Sanger Institute in Hinxton, England. The team produced the first complete sequence of the X chromosome about two years after the decoding of the male Y chromosome.

The researchers found that the X chromosome, though relatively poor in genes, is rich in influence, deceptively subtle, and occasionally deadly to males.

The international team identified 1,098 functional genes along the X chromosome, more than 14 times as many as scientists had located on the tiny Y chromosome.

Even so, the researchers said, there were fewer genes to be found on the X chromosome than on any of the other 22 chromosomes sequenced so far.

Most of the X genes are slightly smaller than average. But one is the largest known gene in the human genome, a segment of DNA linked to diseases such as muscular dystrophy that is more than 2.2 million characters long.

The X chromosome contains a larger share of genes linked to disease than any other chromosome.

It is implicated in 300 hereditary disorders, including color blindness, hemophilia and Duchenne muscular dystrophy. Nearly 10% of the genes may belong to a group known to be more active in testicular cancers, melanomas and other cancers, the team reported.

"The biggest surprise for us was just how many of these [cancer-related] genes there are on the X," Ross said. "There are very few of these elsewhere on the genome."

The complete gene sequence provided some clues to the origins of the human sex chromosomes.

The researchers found that most of the genes on the X chromosome reside on chromosome 1 and chromosome 4 of chickens.

posted March 17, 2005 05:39 PM         

WEDNESDAY, March 16 (HealthDay News) -- Something is stirring in the supposedly inactive female chromosome that plays a major role in genetic differences between men and women, researchers report.

One pair of chromosomes out of the 23 found in human cells determines sex. Women have two full-sized X chromosomes, while men have one X and a smaller Y, which holds the genes for masculine traits. To even things up, one of the two X chromosomes is inactivated in women, according to standard genetics textbooks.

Those textbooks may now need to be revised, according to a report in the March 17 issue of Nature. Studies have detected activity by some of the genes on the supposedly inert X chromosome, researchers conclude.

"Our study shows that the inactive X in women is not at silent as we thought," said co-researcher Laura Carrel, an assistant professor of biochemistry and molecular biology at Pennsylvania State University College of Medicine.

It's too early in the game to say exactly which genes are active and what this all might mean medically, Carrel said, but the finding does hold interesting possibilities.

"The effects of these genes from the inactive X chromosome could explain some of the differences between men and women that aren't attributable to sex hormones," she said.

Carrel has been studying skin cells from a number of women, using laboratory systems she developed to compare the activity of 94 genes in both the active and inactive X chromosomes. She found that "25 of the genes we looked at were expressed in the inactivated X chromosome," with "an intriguing level of variability" in their activity from woman to woman.

"The surprising aspect was the discovery of the extreme variability seen between different women," said study co-author Huntington L. Willard, head of the Institute for Genome Sciences and Policy at Duke University, where most of the work was done. Carrel recently left Duke to start her own laboratory at Penn State.

"We expected that all men were alike [genetically], within reason, and all women were alike, within reason," Willard said. "Now we have this subset of genes on the X chromosome that were expressed at different levels -- not only different numbers of genes, but also different levels of expression."

While this is work that remains in the realm of basic science, "the potential big payoff is in trying to understand diseases that are found to occur in different frequencies in men and women," Willard said. "Also, understanding the habits of behavior in neurocognition, which are different in men and women. It has been thought to be due to hormonal or sexual differences. This work could suggest a basis for the difference that lies in the human genome."

Carrel said she is continuing and extending this research. One new aspect of her lab's work will be to study possible differences in the proteins whose production is governed by gene activity. "We want to find out whether there is a difference at the protein level, and whether there is possible applicability to disease," she said.

posted March 18, 2005 05:11 AM         

Glad to hear you read and enjoy them too, even if you dont post on all of them.

Fascinating stuff coming to light!

BTW, I think you rock too.