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.
Editor's Note: The original news release can be found here.
