Web address:
http://www.sciencedaily.com/releases/2011/02/
110207165424.htm
Evolution Led to Genetic Variation That May Affect Diabetes, Scientist Says
Sheau Yu "Teddy" Hsu and his colleagues have found genetic variations in a
hormone that are linked to the way blood-sugar levels are regulated in humans.
(Credit: Steve Fisch)
ScienceDaily (Feb. 7, 2011) The root causes of complex diseases such as
type-2 diabetes and obesity have been difficult to identify because the
diseases are, well, complex. They occur at the dicey biological intersection of
genes and environment, and, because they arose in our relatively recent past,
it's not easy to simply compare DNA sequences from "then" and "now" to pinpoint
likely genetic culprits.
Now researchers at the Stanford University School of Medicine have identified
genetic variations in a hormone involved in the secretion of insulin -- a
molecule that regulates blood sugar levels -- that occur more frequently in
some human populations than others. People with the "new" variants, which are
thought to have first occurred 2,000 to 12,000 years ago, have higher fasting
levels of blood glucose than those with the more traditional, or ancestral,
form of the gene. High blood glucose levels are associated with the development
of diabetes, which occurs when the body is unable to produce or respond
properly to insulin.
The finding may help scientists better understand the subtle changes in human
metabolism, or "energy balance regulation," that occurred as our species
shifted from being primarily hunter-gatherers to a more agriculturally based
society. It may also help clinicians identify individuals likely to develop
diabetes, and direct the development of new therapies for diabetes and obesity.
"These studies are fascinating because it shows how much the selection process
has affected human energy-balance regulation in just a few thousand years and
how complex it could be for the future practice of personalized medicine," said
Sheau Yu "Teddy" Hsu, PhD, assistant professor of obstetrics and gynecology and
senior author of the study.
The research will be published online Feb. 7 in Diabetes. It follows a similar
paper in the January issue of Genome Research that also explored the recent
evolution of energy balance regulation, or how humans choose whether and how to
store excess calories, among populations.
In the new paper, Hsu and his colleagues at Chang Gung Memorial Hospital in
Taiwan and Texas A&M University first identified 207 genetic regions that have
been associated with diabetes or obesity. They then looked to see which of
these had increased in prevalence in the time since humans began to move out of
Africa about 60,000 years ago. They identified 59 genetic regions of particular
interest, and homed in on those that occurred in at least 30 percent of people
in the HapMap project -- a worldwide survey of genetic differences among
populations. (Restricting their search to relatively common variants ensured
that their findings would be widely applicable and would provide a more
powerful tool to identify any associated phenotype differences.)
The researchers identified five genes with genetic differences that occurred
frequently in Asians and/or Europeans, but infrequently in Africans. (These
groups were pre-identified as part of the HapMap project, which sampled people
of Nigerian, Chinese, Japanese and European ancestry.) Hsu's team selected GIP,
one of the five genes, for further study because the GIP protein was known to
be involved in stimulating insulin secretion in humans after a meal.
"We thought GIP was the most interesting because the newly selected form occurs
in about 50 percent of people from Europe or Asia, but in only about 5 percent
of Africans. That indicates this gene is highly adaptable to new environments,"
said Hsu.
He and his colleagues identified three individual changes in the regulatory
region of GIP -- that is, the DNA adjacent to the GIP gene that affects when
and how it is translated into protein -- that reduced the levels of the
hormone. What's more, these three also tended to occur with another mutation in
the coding region that results in a slightly different form of the protein.
This alternate form is degraded more slowly in human blood.
"So now we know there are two different forms of the protein, which allowed one
form to be selected in one population, and the other in a different
population," said Hsu. "But we still needed to show that these variants led to
phenotypic differences in modern humans."
Because previous studies of GIP variants hadn't showed any conclusive
differences among their human carriers, Hsu and his colleagues focused their
study more narrowly on a population that is not only metabolically challenged,
but also critical to evolutionary success: pregnant women. They found that, out
of 123 East Asian pregnant women, those who carried two copies of the newly
evolved variant had significantly lower levels of GIP circulating in their
blood. These women were also at a significantly increased risk to have fasting
blood glucose levels that exceeded the recommended threshold of 140 mg/dL (48.3
percent vs. 20.9 percent of those who carry the ancestral variant).
The finding is particularly interesting because it may help clinicians identify
pregnant women likely to develop gestational diabetes, according to Hsu. But it
also gives a glimpse into our not-so-distant past and the ways our ancestors
grappled with environmental change.
"Like other humans at the time, the Eurasian population really had to fight for
survival," said Hsu. "Now we're starting to pinpoint how they did that on a
molecular level. These gene variants, and the resulting higher blood sugar
levels it fostered, may have helped women maintain successful pregnancies in
the face of the inevitable famines that occur in an agriculturally based
society. Now, in a more food-secure environment, variations in GIP could
contribute to the development of diabetes or obesity."
In addition to Hsu, James Cai, PhD, a former Stanford postdoctoral scholar in
biology, was also involved in the study. He is now an assistant professor at
Texas A&M University.
The research was funded by the National Institutes of Health, the Avon
Foundation and Chang Gung Memorial Hospital.
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Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by Stanford University Medical Center. The
original article was written by Krista Conger.
Journal References:
1. Chia Lin Chang, James J. Cai, Po Jen Cheng, Ho Yen Chueh, Sheau Yu Teddy
Hsu. Identification of Metabolic Modifiers That Underlie Phenotypic Variations
in Energy-Balance Regulation Diabetes. Diabetes, 2011; DOI: 10.2337/db10-1331
2. C. L. Chang, J. J. Cai, C. Lo, J. Amigo, J.-I. Park, S. Y. T. Hsu.
Adaptive selection of an incretin gene in Eurasian populations. Genome
Research, 2010; 21 (1): 21 DOI: 10.1101/gr.110593.110
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Stanford University Medical Center (2011, February 7). Evolution led to genetic
variation that may affect diabetes, scientist says. ScienceDaily. Retrieved
February 8, 2011, from http://www.sciencedaily.com
/releases/2011/02/110207165424.htm
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Disclaimer: This article is not intended to provide medical advice, diagnosis
or treatment. Views expressed here do not necessarily reflect those of
ScienceDaily or its staff.
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