Article] Just how normal is normal?

Just how normal is normal?
18 November 2003 16:00 GMT
by Helen Dell

Studying the variation between so-called normal lab animals could help
explain how seemingly minor differences between people can produce major
differences in how they respond to their environment, suggests systems
biologist Joe Nadeau.
"There is an enormous amount of genetic variation among humans," said
Nadeau, chairman of the Department of Genetics at Case Western Reserve
University in Cleveland, Ohio, speaking at the autumn meeting of the
British Genetics Society in London.

"We focus on disease genes and think about the genetic heterogeneity in
disease, and we treat everybody else as 'normal'," he said, "as though
there is one homogenous mass of people who are healthy."

But things are undoubtedly more complex than that; for example,
individuals might have a disease gene, but also carry a protective gene,
and so they appear healthy. "We aren't a collection of 30,000 genes that
act independently of each other; they work together in elaborate ways
that we don't understand very well," he said.

Traditionally, researchers have studied gene mutations with severe
effects to try to work out the networks underlying a disease - for
instance by knocking the gene out in a transgenic mouse. "That's like
trying to figure how your computer works by ripping out one part at a
time and asking how does this computer work when this part is missing,"
said Nadeau.

His approach is to study more subtle changes, by using 'normal' genetic
variation. "We can use the genetic variation between strains of
laboratory mice to get at the biology and genetics of complex systems,"
he said.

To show the utility of the approach, he and his team are studying the
well-characterized folate and homocysteine metabolism system. Folate
deficiency and elevated homocysteine are interdependent risk factors for
neural tube defects in embryo development, vascular disease, cancers
such as colon cancer, and neurodegenerative disorders.

The basic biochemistry of the system is already well known, making it
ideal to study as a proof-of-concept, says Nadeau. "At least, there's
some starting ground to nucleate the bigger study," he said. "But even
though biochemists said everything is known, everything is understood,
they still couldn't explain why anomalies in this pathway are associated
or perhaps even causally related to common diseases."

Nadeau's team began by looking at folate homeostasis in two different
strains of mice - A/J and B6. Both are standard inbred laboratory
strains; they are healthy and considered essentially normal.

The mice were fed a standard diet for seven days, then a
folate-deficient diet for seven days, and then returned to the standard
diet. The researchers measured circulating folate and homocysteine
levels in these test mice and compared them with folate and homocystein
levels in mice fed a standard diet throughout

Removing folate from the diet of the A/J mice initially decreased
internal folate levels, while homocysteine levels remained unchanged.
Gradually, homocysteine levels also dropped and, once the folate was
added back to the diet, both levels gradually returned to roughly the
starting point.

In the B6 mice, however, removing folate in the diet initially caused a
decrease in circulating homocysteine levels, while folate levels
remained about the same. Circulating folate gradually dropped and, with
the return of folate to the diet, both homocysteine and folate begin to
increase. But neither folate nor homocysteine levels reached the
starting point in the experiment period.

Gene expression patterns vary between the strains too. When folate is
removed from the diet, the A/J mice show a few genes that are different
at time zero, which then return to base level. When the folate is added
back, a lot of genes expression patterns change, and then they return to
the base line. In the B6 mice, however, there seem to be accumulating
changes during the study, with the expression patterns of many more
genes being affected than in the A/J mice.

The two strains seem to be following different pathways to achieve
folate homeostasis, concludes Nadeau. They start off in different
directions, and only the A/J mice manage to reset their levels within
the experiment period. For the B6 mice, there are two possible outcomes:
B6 mice either follow a longer and more roundabout way to get back to
the start, or they never get back.

"If it does get back, the longer more circuitous route might make them
susceptible to secondary perturbations that might not bother [A/J
mice]," he said. "Or if it doesn't get back, then maybe it's sitting in
a place where there is a problem, maybe those mice will deteriorate and
get sick."

Nadeau plans to extend the time period of his experiments to distinguish
between the possibilities, and also to see how the mouse strains differ
in their responses to repeated perturbations.

The results could have interesting implications for how genetic
variations interact with environmental insults to cause disease in some
people but not others, says Margit Burmeister, associate research
professor of psychiatry at the University of Michigan, who studies human
and mouse behavioral genetics.

"It's a nice example of gene-environment interaction, where you won't
see a difference between the basic folate levels or basic homocysteine
levels, but the difference shows up when you perturb it," she said. "I
think this is exactly where complex genetics is heading."

>From BioMedNet
http://gateways.bmn.com/news/story?day=031119&story=1

--
Kind Regards,
Robert Karl Stonjek.