Galaxy Of Genetic Differences
Between Men & Women
Latest Research Into X Chromosome
Brings Startling Discoveries

By Robert Lee Hotz
The Scotsman - UK
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 "female" sex chromosome that all men and women have in common. In a study published this week in the journal Nature, scientists said they had found an unexpectedly large genetic variation in the way parts of womenís two X chromosomes are distributed among them. The findings were published in conjunction with the first comprehensive decoding of the chromosome.
Females can differ from each other almost as much as they do from males in the way many genes at the heart of sexual identity behave, researchers say. "Literally every one of the females we looked at had a different genetic story," says 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 chromosomes may be activated differently in women than in men, says the other author of the paper, Laura Carrel, molecular biologist at the Pennsylvania State University College of Medicine.
The newly discovered genetic variation between women might help account for differing gender reactions to prescription drugs and the heightened vulnerability of women to some diseases, experts say.
"The important question becomes how men and women actually vary and how much variability there is in females," Carrel says. "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 per cent of their entire genetic inheritance, greater than the hereditary gap between humankind and its closest relative, the chimpanzee. "In essence," Willard says, "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 parcelled in 23 pairs of rod-like structures called chromosomes, which are 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 per cent 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 per cent of them in all female cells were still active, or "expressed". In some women, up to an additional 10 per cent 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 says. "This is a huge number."
Researchers were surprised that they found so many unexpected differences in the behaviour 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.
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, Cambridge.
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 say, there are 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 colour blindness, haemophilia and Duchenne muscular dystrophy. Nearly 10 per cent of the genes may belong to a group known to be more active in testicular cancers, melanomas and other cancers, the team reports.
"The biggest surprise for us was just how many of these [cancer-related] genes there are on the X," Ross says.
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 also reside on chromosome 1 and chromosome 4 of chickens.
That supports the theory that the human sex chromosomes evolved from a regular pair of chromosomes from a common ancestor of chickens and humans - about 300 million years ago.



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