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Heart gene yields insights into evolution, disease risk

07.09.2004


Analyzing the frequency among human populations of a variant in a gene that influences vulnerability to heart disease, biologists have found evidence that the gene has been influenced by the pressure of natural selection. What’s more, this evolutionary pressure has influenced heart disease risk.



An analysis of data on the genetic variation among 2,400 British middle-aged men indicated that the men would have suffered 43 percent more heart attacks had the positive selection for the gene variant not occurred.

The researchers, led by Duke University Professor of Biology Gregory Wray, published their findings in the September 7, 2004, issue of the journal "Current Biology." Lead author of the paper was graduate student Matthew Rockman of Duke. Other co-authors were, Dagan Loisel of Duke, Matthew Hahn of the University of California at Davis and Nicole Soranzo and David Goldstein of University College London.


The researchers said their findings offer an intellectual model for a broader evolutionary study of genetics. This broader study would aim to bridge the gap between medical scientists’ detailed molecular understanding of the genetic mutation underlying a disease and the evolutionary biologists’ insights into how natural selection acted on the gene to propagate that mutation in the population.

Said Rockman, "Our research, and that of other evolutionary biologists, is directing us toward a new, more nuanced view of genetic variants which is that, in fact, variation is part of what it means to be human. And that this variation is not just harmful mutation but really a process that contributes to the health of populations." Such studies, said Rockman, should include not just the segments of genes that code for the structure of proteins that make up the cell’s machinery. They also should include the evolutionary processes that shape the gene segments that regulate a gene’s activity. Thus, in their study, Wray, Rockman and their colleagues explored the evolutionary history of one particular variant in a gene called MMP3. Such variants are called "alleles."

The MMP3 gene is one of a family of genes that serves as the blueprint for a protein enzyme with a broad array of functions in the body. However, the variant they studied does not affect the structure of the protein itself, but regulates how much of the protein is produced in the cell. The variation, or polymorphism, is tiny, adding one genetic unit, or nucleotide, to the more than 1,600 that make up the regulatory region of the gene.

However, the single alteration in the MMP3 protein regulatory region causes a functional difference that has important clinical implications. The MMP3 protein is an enzyme that plays a role in regulating the elasticity and thickness of blood vessels. While its effects are complex, said the researchers, overall the variant they studied tends to retard the progress of coronary artery heart disease

Because of this clinical effect, considerable human data had been gathered on the MMP3 variant, said Rockman, making the gene attractive in exploring the possible effect of natural selection on the frequency of the variant. Also, he said, the nature of the variation offered an opportunity to study how mutation, selection and the demography of populations contribute to the variation in the gene and its effects on disease. "People have long been studying the evolutionary role of variation in genes that affect the structure of the proteins for which they code," he said. "However, a huge fraction of the genome consists of segments that don’t code for a protein, but are regulatory regions for the gene. This is really an under-explored region of the genome, and we we’re hoping to find out more about how it evolves and what role it plays in complex traits."

Rockman, Wray and their colleagues first compared the structure of the gene region among non-human primates -- including the chimpanzee, gorilla, orangutan and baboon. This comparison revealed that that the region of the gene is rapidly evolving and had been a "hotspot" of mutation for tens of millions of years.

The researchers next compared the variation in the regulatory region of the MMP3 gene among seven populations from around the world -- Cameroon, China, England, Ethiopia, India, Southern Italy and Papua New Guinea. They compared the pattern of variation with the random genetic variation taking place in a group of neutral genetic markers. These analyses revealed that the variation in the gene among populations could be attributed to evolutionary positive selection.

Particularly interesting they said, was that their analyses of data on the genetic variation among the sample of British middle-aged men indicated that the men would have suffered 43 percent more heart attacks had the positive selection for the gene variant not occurred.

"We really don’t know why this selection occurred, because this gene is involved in so many different processes," said Rockman. "Because heart disease is a relatively recent disease, it’s more likely that the selection was for some other function of MMP3, and the heart disease effect was incidental," he said

Beyond the insight into evolution of the MMP3 gene, the research offers broader lessons, said Wray. "I think for the medical profession, one lesson is to not to think of alleles as good alleles or bad alleles," he said. "Rather, there is a complex set of interactions, and in certain circumstances and in certain combination with certain other alleles, which allele is best can differ. So we’re advocating a more nuanced view of how we view the genetic bases of disease.

"Also, we’d like the evolutionary biologist to take away from this study that traditional evolutionary biology has all but ignored the evolution of regulatory regions, versus those regions that code for protein structure," he said. "However, with new analytical techniques at our disposal, we can now start to look at the ’wiring diagram’ of the genome and how it is influenced by evolution."

Both groups working together can bridge the gap between genes and health, said Wray, gaining a much better insight into how evolution influences the form of genes that affect health.

Dennis Meredith | EurekAlert!
Further information:
http://www.duke.edu

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