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X Chromosome Variation May Explain Differences Among Women, Between Sexes

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Duke Health News 919-660-1306

Durham, N.C. – The first comprehensive survey of gene
activity in the X chromosomes of women has revealed an
unexpected level of variation among individuals, according to
new work by researchers at the Duke University Institute for Genome Sciences
& Policy
(IGSP) and Pennsylvania State University.

The results may have important implications for
understanding the differences in traits among women and between
males and females, in terms of both health and disease, said
Huntington Willard, Ph.D., director of the IGSP and the study's
senior author. The findings also offer new insight into the
basis for well-established differences between the sexes, he
said.

Willard said that the extensive variation in gene activity
in the sex chromosomes means that, in essence, there is not one
human genome, but two -- male and female.

"We looked at the X chromosomes of 40 women and every one of
them had a unique pattern of gene expression," Willard said.
"All of that variation is completely unique to women. The X
chromosomes of males are all the same in this regard."

Willard and study co-author Laura Carrel, Ph.D., of Penn
State, reported their findings in the March 17, 2005, issue of
Nature. The
National Institutes of Health supported the research. In the
same issue of Nature, more than 250 researchers including
Willard and Carrel, reported the complete DNA sequence of the
human X chromosome.

In animals, sexual identity is governed by sex chromosomes.
In humans and other mammals, males have one X and one Y
chromosome, while females have a pair of X's.

Many genes on the male Y chromosomes have been lost over
evolutionary time, leaving the chromosome with fewer than 100
functional genes. In contrast, the X chromosome -- present in
at least one copy in both sexes -- encodes more than 1,000.

More than 45 years ago, researchers discovered that genes on
one copy of the female's X chromosome are switched off, a
modification known as X inactivation.

Originally, scientists had assumed that the inactivation
process resulted in complete silencing of the genes on the
second X chromosome, Willard said, in order to leave both sexes
with the same activity level, or dosage, of the genes encoded
by the X chromosome. Scientists had also implicitly assumed
that the X chromosomes in all women would be identical.

Earlier work of Willard and others shattered the first
assumption, when, in the late 1980s, the first evidence came to
light that some portion of the genes on the second X chromosome
in women remained active.

The new work extends that earlier finding to the full set of
X-linked genes and also further reveals that individual women
exhibit extensive differences among them with respect to X
inactivation, Willard said.

In their study, the researchers isolated cell lines from
each of 40 women. They then measured the activity level of each
of 471 genes to determine whether the second copy was turned on
or off.

Overall, about 15 percent of genes on the second X
chromosome escape inactivation to some degree, they found. The
proportion of genes that remain active differs dramatically
among regions of the X chromosome, they reported.

Furthermore, in some women but not others, an additional 10
percent of X-linked genes demonstrate variable patterns of
inactivation and different levels of activity in the "silenced"
X chromosomes, the team reported.

"The findings suggest a remarkable and previously
unsuspected degree of expression heterogeneity among females in
the population," Willard said. Further work is required to
explore potential consequences of that variation, he added.

However, the large number of genes that escape inactivation
and their concentration in certain portions of the X chromosome
has immediate implications for counseling the one in every 650
individuals born with X chromosome abnormalities, Willard said.
The expected severity of symptoms associated with the loss or
aberration of particular portions of the X chromosome will
depend on the number of active genes normally contained within
that segment, he explained.

The findings also highlight key differences between female
and male genomes, according to the researchers.

For one thing, women are known to consist of a mosaic of two
cell types that differ in which X chromosome is inactivated.
The Y chromosome also endows males with at least several dozen
expressed genes that females lack.

The incomplete nature of X inactivation, demonstrated in the
new study, means that at least 15 percent of the X-linked
genes, and their protein products, are present at
characteristically higher, and often variable, levels in
females compared to males.

Moreover, the findings show that a minimum of an additional
10 percent of genes are expressed at variable levels among
females, while all males express a single copy of such
genes.

"We now know that 25 percent of the X chromosome -- 200 to
300 genes –- can be uniquely expressed in one sex relative to
the other," Willard said. "In essence, therefore, there is not
one human genome, but two -- male and female.

"Such characteristic genomic differences should be
recognized as a potential factor to explain sex-specific traits
both in complex disease, as well as normal gender differences,"
he continued.

Notwithstanding the genomic and biological significance of
these sex-specific differences, many questions remain, Willard
said. For example, further study is required to determine if
the pattern of X inactivation differs across tissues or over
time and whether there are characteristic patterns of
inactivation in maternally versus paternally inherited X
chromosomes.

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