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Baboon genome points to cholesterol genes in humans
  
By Ricki Lewis

Baboons on high-fat diets and a new twist on 'gene chip' technologies are helping researchers identify human genes linked to HDL, the "good" cholesterol. The strategy, which has yielded dozens of genes that may regulate HDL, can be used to investigate the genetics of complex human traits.


The strategy involves comparing genome maps of humans and baboons, and analyzing the activity of genes along a region linked to HDL. Of some 350 genes in the region, 53 showed differences in activity between baboons with different HDL levels. The researchers are whittling down this number by repeating the experiment with more baboons.

The researchers and the baboons hail from the Southwest Foundation for Biomedical Research, in San Antonio, Texas. Baboons have been used to study cardiovascular disease for decades, but genomic tools are making these animals even more valuable to researchers as stand-ins for people.

In the 1960s, a researcher at the Foundation, Henry McGill, began using the baboon as a model of heart disease. He found that baboon arteries and veins had fat streaks like those that appear in early stages of the disease atherosclerosis; soon he began to track LDL, HDL and other measures of cardiovascular health.

Over the years, the baboon colony expanded to include at any one time between 300 and 700 individuals, providing researchers with large numbers of related individuals and information about their medical histories and family pedigrees that could be used for genetic studies.

"We now have pedigrees for 1,000 baboons over six generations, although they are not still all alive," says Laura A. Cox, who led the new HDL study. The Foundation has DNA and liver samples going back to the first generation. Liver tissue, which is difficult to obtain, is crucial to understanding cholesterol's role in the body.

As McGill charted cholesterol levels in his baboons, he noticed that some animals had very high or low LDL or HDL. To study these traits in more detail, he mated the animals to produce offspring with high levels or low levels of LDL or HDL (or both).

"He bred parts of the population to create family structures where there are extremes," says Cox. "We obviously can't do that with people." High LDL and low HDL are risk factors for cardiovascular disease.

In 1998, a team led by Foundation researcher John L. VandeBerg, who is an author of the current study, identified a region of baboon chromosome 18 associated with HDL levels. The region covers about 20 million base pairs and corresponds to human chromosome 18. These regions in humans and baboons are strikingly similar in parts, making it possible to hunt for human cholesterol genes in baboons.

Another reason for the current study was that HDL levels change dramatically in some baboons when their diet shifts from the standard Purina monkey chow to a high-fat and high-cholesterol version.

To find HDL genes, the researchers monitored the activity of genes along the region of chromosome 18 in baboons whose diets were switched—and whose HDL levels changed. Because the rest of their genomes were presumably quite similar, genes whose activity differed between the siblings were candidates to influence cholesterol levels.


Between 300 and 700 baboons live in the corral.

They used a baboon family structure that, as Cox puts it, "stacks the deck" to help identify a gene or genes that controls fluctuations in HDL. Such families have one sibling that develops very high HDL and another very low HDL when given the fatty "challenge" diet.

The next step was to use a modified DNA microarray, or gene chip, to monitor the activity of many genes simultaneously. The new tool, called a "chromosomal region expression array", or CREA, records the activity of genes on a specific chromosomal region; gene chips, by contrast, typically monitor the activity of thousands of genes that reside throughout the genome.

To ensure that results for the baboon would be relevant to people, the new array consists of human DNA from the target region of chromosome 18. The array was used to analyze liver cells from a pair of baboon siblings before and after a seven-week stint on the fatty diet. This led to the 53 gene candidates that may regulate HDL.

"The more sibling pairs we can look at, the more power to discriminate which genes are viable candidates for controlling HDL," says Cox, who describes the new strategy in Genome Research. "We will find some differences, then determine which are random and which are associated with the trait." Then the researchers can sequence those gene candidates.

Using microarrays to hunt for genes known to reside in a particular part of the genome is faster than trying to identify a gene whose location is unknown. "With the traditional method, it is possible to spend years searching for a gene that influences common disease and come up empty handed," says VandeBerg.

The researchers are interested in other traits associated with increased risk of heart and blood vessel disease, but none may be as straightforward to analyze as HDL. A gene that controls LDL, for example, resides on a baboon chromosome that doesn't correspond particularly well to the human genome.

"That LDL gene is on baboon chromosome 4, which is human chromosome 6," says Cox. "When we compare human and baboon genomes, there are all kinds of rearrangements in that region."

But they say their technique may have broad applications. "Most interesting to us was that we saw a number of genes that change expression when the diet changes," says Cox. She anticipates the day when microarrays will reveal sweeping fluctuations in gene activity across the genome in response to changes in the environment.

On the practical front, these initial experiments may suggest new drug targets. "Since baboons and humans are so similar genetically and physiologically, it is likely that humans will exhibit similar mechanisms for regulating HDL levels," says VandeBerg.

"As a consequence," he continues, "when the identity of this gene and its mechanisms of action are known, it may be possible to develop new therapies for elevating HDL cholesterol in humans, thereby reducing the incidence of heart disease."

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Cox, L. A. et al. Identification of candidate genes regulating HDL cholesterol using a chromosomal region expression array. Genome Res 12, 1693-1702 (November 2002).
 

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