Genetics: The X factor

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Nature 434, 266 - 267 (17 March 2005

Genetics: The X factor

The sequence of the 'feminine' X chromosome is a prime hunting ground for

geneticists interested in the evolution of the cognitive and cultural

sophistication that defines the human species. Check reports.

This January, Harvard University president Larry Summers incited a near riot by

suggesting that men might be better than women at science. The resulting

pandemonium has revealed few genuine insights into male and female mental

abilities — although it has shown that old prejudices linger on campus, and

beyond.

In contrast, biology presents a challenge to those who still believe women are

better off at home than in the hallowed halls of universities. As geneticists

search for the roots of humanity's unique mental abilities, they are beginning

to pay close attention to the 'feminine' X chromosome. Women have two copies of

this chromosome, whereas men have only one. And the complete sequence of the X

chromosome, published in Nature this week1 (see also News and Views, page 279),

confirms that an unusually large number of its genes code for proteins important

to brain function.

Why this should be the case is sparking debate among evolutionary biologists.

And some are even suggesting that the X chromosome will tell us why we are

different from our closest relatives — why we can write poetry and design

nuclear weapons, but chimpanzees can't. In a sense, they argue, the feminine

chromosome could hold the secrets of humanity. " We used to think that the X was

boring, " says Graves, an evolutionary geneticist at the Australian

National University in Canberra. " Now we're seeing just how wrong we were. "

Today's understanding of the X chromosome helps to explain a puzzling

observation from the late nineteenth century, when doctors combing through data

from the 1890 US Census noticed that more boys than girls were mentally

disabled2. We now know that this reflects a preponderance of genes for brain

function on the X chromosome. A woman uses only one of her two X chromosomes in

each cell, so if one of her X chromosomes has a defective gene, only some of her

cells will suffer. But men have only one X, so any defective brain genes from

that chromosome are invariably expressed.

All in the mind

Many different types of mental retardation have since been linked to defects in

genes on the X chromosome — far more than can be explained by their chance

distribution throughout the genome. According to one analysis, there are 221

known human genetic defects that can cause mental impairment, some 10% of which

reside on the X chromosome, even though it carries less than 4% of known human

genes3.

Detailed studies have also shown that the specific genes linked to mental

disabilities play crucial roles in normal brain function4. For instance, more

than a decade ago, an international team reported the discovery of the gene that

causes fragile X syndrome5, a disorder that leads to a range of problems

including mental disability. Scientists now know that the defective gene, called

FMR1, normally makes a protein that is involved in shuttling the genetic

messages that enable nerve cells to send signals through the brain6. Another

gene, known as MECP2, leads to a whole range of mental disorders when mutated;

its protein seems to be involved in the silencing of other genes required for

normal learning, memory and the growth of brain cells4.

It's still a giant step from understanding defects in single genes to proving

that the X chromosome allows us to write novels and solve calculus equations.

But there is some indirect evidence that genes on the X chromosomes are involved

in higher cognitive functions. One hint comes from a study of 4,000 sets of

British identical twins. Each female twin inherits two X chromosomes, one from

her mother and one from her father, but each individual twin randomly

inactivates one of her two X chromosomes. So identical twin sisters can express

different X-chromosome genes. In contrast, male identical twins inherit only one

X chromosome, from their mothers, and so must activate the same X-linked genes.

In the British study, researchers led by Ian Craig of King's College London

found that in some traits linked to intelligence, such as verbal skills and good

social behaviour, male twins were more alike than female twins7.

But why should the X chromosome have emerged as a hotspot for genes influencing

our cognitive abilities? Evolutionary geneticists believe that the two mammalian

sex chromosomes, X and Y, were once identical. As mammals began to diverge from

their reptilian ancestors, some 300 million years ago, the proto-X and proto-Y

chromosomes took on the role of determining an individual's sex. Both initially

started accumulating genes from elsewhere in the genome, but over time the two

chromosomes began to grow apart; the Y started to shrink and lost many of its

genes.

Solid foundation

Eventually, the sex chromosomes diverged to the point where they were no longer

able to exchange genetic material during the cell divisions that give rise to

sperm and eggs, as do the members of every other pair of chromosomes. This has

left the X chromosome as one of the most stable in the mammalian genome — which

paradoxically may have exposed its genes to more intense pressure to evolve.

The X chromosome gets a chance to shine, or to fail miserably, each time it

passes through the male line. Because a male carries only one copy, any new

mutations are revealed in all their glory. And because successful males have the

potential to sire very large numbers of children with multiple partners,

mutations on the X chromosome that are advantageous to both sexes can spread

rapidly through a population.

In our own species, where intelligence and social skills are thought to be

central to success, genes on the X chromosome seem to have evolved rapidly to

provide us with the necessary brain power. " If higher cognitive abilities were a

critical step in our own evolution, it makes sense that you might find those

functions on the X chromosome, " says Hunt Willard, a human geneticist and

director of the Institute for Genome Sciences and Policy at Duke University in

Durham, North Carolina.

Provocatively, researchers led by Horst Hameister at the University of Ulm in

Germany speculate that this process was driven by sexual selection3. Early in

human evolution, they suggest, females developed a preference for intelligent

males. According to their theory, the genes for super-intelligence and for the

preference of intelligent males were closely linked, and so were inherited

together. And because superior intelligence also aided survival, the process

wasn't kept in check by natural selection — unlike other sexually selected

characteristics such as the peacock's tail, which makes its bearers more

vulnerable to predators.

Many of the genes on the X chromosome associated with human brain function seem

to have distant relatives with different functions in other vertebrates, such as

chickens and fish8. So in boosting our cognitive abilities, the X chromosome

seems to have co-opted a diverse range of existing genes, rather than evolving a

new set of genetic sequences for the purpose. " These old genes are getting new

use, " says Hameister.

In some instances, geneticists have pinpointed genes on the X chromosome that

still seem to be in the process of adopting new roles in the brain. For

instance, a gene called JARID1C seems to be evolving from a similar gene called

JARID1D, which is found on the Y chromosome. If men inherit a damaged version of

the JARID1C gene on their single X chromosome, they develop mental disabilities.

The fact that the healthy Y chromosome version cannot compensate for its

defective cousin hints that JARID1C is becoming more crucial to the brain as it

evolves9.

Personality profiles

Geneticists are now gearing up to go after other X-linked genes that may help

explain what makes us human. In London, Craig's team plans to identify twins who

score high or low on certain 'people skills', such as sharing their toys and

volunteering help to others. The researchers will then use gene chips to scan

the twins' DNA, looking for particular genetic variations that correlate with

these traits. Once they find a region of DNA that seems to link to a particular

trait, the group will look at the detailed sequence of individual chromosomes to

try to pin down the exact gene involved. The X chromosome data, with its wealth

of information about human brain genes, is likely to feature prominently in this

endeavour.

Other researchers plan to continue the quest for genes involved in X-linked

brain disorders. Every two years, for instance, scientists meet as part of a

European consortium that catalogues genes involved in such conditions.

Researchers believe that the information so far gleaned about human brain

function from these studies barely scratches the surface.

If we want to understand the cognitive 'X factor' that separates us from the

rest of the animal kingdom, then it seems that the X chromosome is the place to

start looking. In the meantime, Summers and his acolytes can chew on this

thought: even if there's any truth in the idea that men are more suited to a

career in science than women, they just might owe this mental predisposition to

the 'girly' chromosome.

ERIKA CHECK

Check is Nature's Washington biomedical correspondent.

References

1. Ross, M. T. et al. Nature 434, 325–337 (2005).

2. , G. E. J. Psycho-Asthenics 2, 26–32 (1897).

3. Zechner, U. et al. Trends Genet. 17, 697–701 (2001).

4. Ropers, H. -H. & Hamel, B. C. J. Nature Rev. Genet. 6, 46–57 (2005).

5. Verkerk, A. J. et al. Cell 65, 905–914 (1991).

6. Oostra, B. A. & Chiurazzi, P. Clin. Genet. 60, 399–408 (2001).

7. Loat, C. S., Asbury, K., Galsworthy, M. J., Plomin, R. & Craig, I. W. Twin

Res. 7, 54–61 (2004).

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9. Jensen, L. R. et al. Am. J. Hum. Genet. 76, 227–236 (2005).