not just iceland: more refs on more countries w/ DNA db

27 Jul 2001

      http://www.genomics.ee/media/scientprindi.html

A good gene
pool, like love, is where you find it. Now genomics researchers have two

new ones to swoon over: one from Estonia, a crossroads of Scandinavian
cultures and the northernmost of the former Soviet Union's Baltic
republics;
and from Tonga, an island kingdom half a world away where a Polynesian
people has lived in near-perfect isolation se to 3,500 years. Tonga and
Estonia laid final plans last November and December, respectively, for
national gene pool exploration programs aimed at discovering
disease-associated
genes and developing therapies based on the
discoveries. 
They follow
the trail blazed by Iceland,1 where for several years the gene pool of
275,000 Icelanders has been the fishing preserve of Reykjavik-based
deCODE
Genetics which is hunting for gene variants that affect serious, often
chronic diseases by finding statistical links between Icelanders'
genotypes
and their inherited illnesses. The Tongan project will be a commercial
affair run by AutoGen Ltd. of Melbourne, Australia, with permission of
the Tongan Ministry of Health. Two organizations, one nonprofit, the
other
for-profit, will control Estonia's project; both are property of the
Estonian
government. 
Eesti
Geenivaramu
<table BORDER=0 WIDTH="100%" >
<tr>
<td>Prior to the

Estonian parliament's action of December 13, only the nonprofit Eesti
Geenikeskus
(the Estonian Genome Center Foundation) was in place; now it will be
joined
by Eesti Geenivaramu (the Estonian Genebank Foundation), the engine of
the venture. Eesti Geenivaramu will carry out the project; Eesti
Geenikeskus
will own the data. 
The project
enjoys enormous popular support. A poll indicates 90 percent of 1.4
million
Estonians like the idea of a big project with potential benefits to
themselves,
and that also helps the country's fledgling biotech industry.
Individuals
may freely access their own data, otherwise strictly secret, and get
word
if project research yields treatments that might be beneficial. If 1
million
Estonians are genotyped within five years, as officials predict, Estonia

will own the behemoth of population genotyping projects, the only one
with
a database sized in terabytes. </font></font></td>

<td><img SRC="andreas.jpg" height=311 width=250>
Andres
Metspalu
<hr SIZE=1 NOSHADE WIDTH="100%"></td>
</tr>
</table>
The Estonian
Genebank
Foundation officially opens in March in the city of Tartu. Kickoff money

of 20 million kroons (US$1.3 million) funds a pilot genotyping project
scheduled to begin in the fall. But the real money--$100-150 million
over
five years--will come from payments for nonexclusive licenses for data
access and intellectual property rights to drugs and diagnostics
resulting
from research. Part of the genebank foundation's mission is to sign up
international partners, chiefly research institutes and biotech and
pharmaceutical
companies.
Which
diseases
the 10,000-patient pilot project will focus on hasn't been decided, but
the search for volunteers will take advantage of patient group
registries
for cancer, Parkinson's disease, osteoporosis, and diabetes. Patients in

for checkups will be invited to participate (strictly on a voluntary
basis)
by filling out extensive health questionnaires and donating 50 ml blood
samples for DNA extraction. 
When many
genes
influence an illness, as in heart disease, cancer, and diabetes,
population
genotyping is preferable to family studies. Family studies work well
when
a single gene underlies a disease. They rely on linkage analysis, where
researchers find genetic markers matching disease inheritance patterns,
and then use the markers to map the chromosomal region containing the
gene
as the first step toward its isolation. With polygenic diseases, where
individual alleles seldom sharply increase the relative risk of disease,

correlating genetic markers and inherited predisposition to disease
requires
genotyping hundreds or thousands of people. When gene hunting becomes a
game of sifting through massive amounts of data, the Estonian project
"will
show strength through numbers," says Andres Metspalu, the driving force
of Estonia's gene pool expedition. 
Estonians
(average
life span: 70 years) see themselves as representative westerners; they
suffer the same diseases prevalent elsewhere in the West, in similar
proportions.
Ensconced by the Baltic Sea for some 5,000 years, they have not been
isolated;
crisscrossing contacts with neighboring nations have made their gene
pool
more heterogeneous than Iceland's or Tonga's. "Estonia has been sort of
a highway," says Kalev Kask, a Stanford neuroscientist who acts as the
project's U.S. representative, "Everybody has come and downloaded their
genotype there." 
 deCODE
navigates the Icelandic gene pool aided by the country's unprecedented
genealogies, recorded meticulously for more than a thousand years, back
to days when lineages were set down in blood on scraps of leather.
"Though
many Estonian genealogies go back to the 1600s, we'll take a more ad hoc

approach using them," Metspalu says. De-emphasizing those records is in
part because nearly 30 percent of Estonia is Russian speaking,
reflecting
recent era immigration and family records carrying back only a
generation
or two. 
Finding genes

exerting relatively small effects on diseases means scanning the entire
genome. Estonian genotyping will employ single nucleotide polymorphism
(SNP) assays, where SNP oligonucleotide hybridization probes detect
single
base sequence differences between DNA molecules. (deCODE genotypes with
microsatellites.) There is no lack of SNPs to choose from--Public
databases
span the genome with hundreds of thousands of SNP sequences. What is
lacking
is consensus on which ones to use, a matter of economic as well as
scientific
importance. 
Depending on
how completely the chosen SNPs cover the genome, genotyping most of
Estonia
could conceivably require billions of assays. Even at a penny apiece
(Metspalu
estimates a SNP assay now costs about 20 cents), that could send the
project's
cost soaring into hundreds of millions of dollars. So automated,
high-speed
SNP testing must drastically cut per-assay price, and judicious choices
will have to be made about which SNPs to use. These decisions will
depend
heavily on the preferences and resources of the eventual commercial
partners. 
  
  
<table BORDER=0 WIDTH="100%" >
<tr>
<td><img SRC="collier.jpg" height=270 width=180>
Greg
Collier
<hr SIZE=1 NOSHADE WIDTH="100%"></td>

<td></td>

<td>Genes in
Paradise
A South
Pacific
archipelago situated just west of where the international dateline cuts
across the Tropic of Capricorn, Tonga's only significant immigration
occurred
when it became the home of the Polynesians who first found it centuries
before the appearance of Alexander, Caesar, and Christ. AutoGen's
project
in Tonga grows out of the diabetes studies it has done there for several

years. The primary thrust of its research will be discovery of genes
involved
in diabetes and obesity, major health concerns among Tonga's 108,000
inhabitants.
AutoGen will
establish a research lab at a hospital in Nuku'Alofa, the constitutional

monarchy's capital, provide annual research funding to the health
ministry,
and pay royalties to the government if any drugs are developed as a
result
of the project. </td>
</tr>
</table>
 As in
Estonia,
research participation is purely voluntary. DNA samples will belong to
Tonga; AutoGen may use the data to create new therapies. "Initially
we'll
use traditional genome scans with microsatellites to localize areas of
interest, and then use SNP approaches for fine mapping," says Greg
Collier,
AutoGen's chief scientific officer. The Tongan family structure should
make correlating genotypes and phenotypes somewhat easier; in most small

Tongan villages inhabitants are blood relatives. </font></font>
<p><font face="Arial, Helvetica, sans-serif"><font size=-1>The project
comes just as some researchers have changed their minds about the
advantages
of studying isolated homogenous gene pools instead of heterogeneous gene

pools in America and Europe. A few years ago, it was believed that
disease-associated
genes would stand out more clearly against the simpler genetic
backgrounds
of isolated populations such as those of Tonga and Iceland. But standing

out depends on the frequency of the allele and how much it raises the
relative
risk of disease. Recent theoretical and experimental results suggest
genes
with weak effects on relative risk may be no easier to find in a small
isolated population than in a large heterogeneous
one. 
This finding
may bear on scientific and financial decisions about which gene pools to

explore next. Undoubtedly, so will deCODE's demonstration that isolated
gene pools yield rich finds. Over the past year, deCODE isolated a gene
linked to schizophrenia, mapped genes linked to stroke and late-onset
Alzheimer's
disease, and pinpointed chromosomal regions containing genes
contributing
to osteoporosis and peripheral arterial occlusive
disease. 
In any event,

once a population has been chosen and monetary commitments made, what
counts
are results--and getting them before anyone else. Pressure to set a
breakneck
pace is mounting as new competitors join in; for this is not a three-way

race. Last year, Newfound Genomics began to study Newfoundland Canadians

for genes contributing to psoriasis, rheumatoid arthritis, and diabetes.

Myriad Genetics is at work in Utah, Sardinia, and Quebec. One thing they

all know is that finding a gene connected to an important disease can be

a tremendous thrill, but little more if it turns out that somebody else
found it first. </font></font>

not just iceland: more refs on more countries w/ DNA db

Subcommander Bob