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."
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