Their isolation creates gene lab
Research: Limited diversity of their gene pool has made groups such as Lancaster's Amish valuable in fighting diseases.

By David Kohn - Sun Staff
Originally published October 6, 2003

Almost 300 years ago, a few dozen Amish families, tired of Catholic persecution in Switzerland, fled to America. They
settled in Lancaster County, Pa., and built a prosperous farming community that today numbers around 30,000.

Unlike most immigrant groups, the Amish have kept their culture and traditions almost intact. They speak an archaic
German dialect, shun modern technology, and don't mix - no outsider has joined the group for almost 140 years.

In a convergence of the 18th and 21st centuries, their isolation has created a powerful means for scientists to find
the genes that lead to common diseases.

Because they have kept to themselves, marrying almost exclusively within the group, Lancaster County's Amish are more
genetically homogeneous than almost any other population.

"Fifty or so sets of chromosomes came over in the 1700s. For the next 14 generations these same 50 sets have been
passed on to everyone there," said Dr. Alan Shuldiner, a University of Maryland endocrinologist who has been studying
Amish genes for a decade. This genetic similarity simplifies the search for mutant genes that lead to disease, he says.

The Amish are not the only community scientists are studying for genetic clues. Researchers are finding "genetic
isolates" all over the world - including Sardinians, Ashkenazi Jews, Afrikaners, Micronesians, Mennonites and certain
subgroups of Pakistanis and Costa Ricans.

"In these populations, there's a greater chance they'll carry the same piece of DNA. So, you're getting rid of
background noise," said Susan Smalley, a psychiatric geneticist at the University of California, Los Angeles. She's
studying a secluded northern Finnish population to find genes linked to attention deficit hyperactivity disorder.

The largest of these projects is in Iceland, where a private company, DeCode, is trying to gather DNA data on all of
the country's 270,000 inhabitants. Ironically, the project has shown that Icelanders are not as homogeneous as thought -
 much less so than the Amish. Still, the company has collected samples from over a third of the population - and has
some promising leads.

Last month, DeCode researchers isolated a gene linked to a three- to five-fold increase in stroke risk. Earlier this
year, they identified a genetic region that seems to contribute to schizophrenia.

Known as "founder populations" because they tend to preserve the genetic makeup of the founders, these groups have two
key attributes: a small number of primary ancestors - not more than a few thousand - and little intermarriage in
succeeding generations.

The groups are scattered across the globe, many in unexpected places. "These patterns of history present a tremendous
genetic opportunity," said Dr. Chris Walsh, a Harvard Medical School neurologist who is studying brain diseases in
specific Pakistani tribes.

Some "isolates" are quite large: Ashkenazi Jews, mostly from Eastern Europe, are the most widely dispersed; they number
around 10 million.

Another large founder population inhabits Costa Rica's Central Valley. The group, which has 2.5 million members,
originated in the 16th century, when Spanish settlers mixed with native inhabitants. The region thrived, but because
the area was surrounded by rugged mountains, there was little subsequent migration until the middle of the 20th
century.

"It was purely a matter of geography," said Dr. Nelson Freimer, a UCLA psychiatric geneticist who has used that
homogeneous gene pool to study bipolar disorder, Tourette's syndrome and asthma.

Over the past six years, he has identified several chromosome regions that seem to occur more often in Costa Ricans
with manic depression. (Chromosomes are aggregates of genetic material. Each human cell has 23 pairs; each pair
contains about 30,000 genes.) Freimer is focusing on these chromosomes, trying to locate specific bipolar-related
genes.

Until recently, studies of isolates were limited to rare diseases caused by single mutations. These disorders tend to
strike such groups more often, because any uncommon mutation carried by the original ancestors is spread through the
population. The Lancaster County Old Order Mennonites, for example, have a 1 in 400 chance of being born with a rare
metabolic disease called MSUD; for the general population the risk is 1 in 200,000.

But scientists are now using these groups to study common diseases such as diabetes and heart disease. These ailments,
which are caused by a complex interaction of genetics and environment, have generally baffled gene researchers. So,
some have turned to isolates.

"We aren't having a lot of success in looking for the genetic causes for complex disorders. This may be a way in," said
Dani Fallin, a genetic epidemiologist at the Johns Hopkins University.

She and two Hopkins colleagues are studying genetic material from Ashkenazi Jewish families with histories of
schizophrenia. The have located a mutated region on Chromosome 10 that seems to occur more frequently in
schizophrenics. Now they're trying to pinpoint which of the 70 or so genes along that chromosomal region might
contribute to the disease.

Most isolates are no more prone to common diseases than the general population. Ashkenazi Jews, for example, don't have
a particularly high frequency of schizophrenia. But like other isolates, its members tend to share mutations. For
researchers, this narrows the list of possible suspects.

Among Ashkenazi Jews, schizophrenia is probably connected to the same few variant genes. In the general population, by
comparison, schizophrenia is likely linked to scores - or even hundreds - of genes. "We want to make a situation where
we are comparing apples to apples," said Hopkins researcher David Valle, who works with Fallin on the project.

In addition to looking for schizophrenia genes, researchers are scanning Ashkenazi chromosomes for leads on bipolar
disorder and longevity. An Israeli company, IDGene, is collecting Ashkenazi DNA samples for studies of an even wider
range of illnesses, including Parkinson's disease and asthma.

Shuldiner has branched into studying the Amish to find genes linked to osteoporosis, heart disease and hypertension.
He's collaborating with other isolate researchers, including NIH scientists studying the Pima, a Native American tribe
predisposed to diabetes.

Even if founder populations do yield key clues to common diseases, finding cures won't be easy. "But it will be a
start," Shuldiner said. "Once we have our finger on the gene, we can understand much more about the disease. And once
we understand the disease we can come up with better treatments."

SOURCE: The Baltimore Sun
http://tinyurl.com/pv80

Reference:

IDgene Pharmaceuticals Ltd. is a population genomics company focusing on identifying the genetic basis of common
diseases.
http://www.idgene.com/home.html

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