[tt] NYT: David B. Goldstein Finds Fault in Effort to Decode Human Genome to Fight Disease

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David B. Goldstein Finds Fault in Effort to Decode Human Genome to Fight 
Disease
http://www.nytimes.com/2008/09/16/science/16prof.html

Scientist at Work | David B. Goldstein
A Dissenting Voice as the Genome Is Sifted to Fight Disease
By NICHOLAS WADE

The principal rationale for the $3 billion spent to decode the human
genome was that it would enable the discovery of the variant genes
that predispose people to common diseases like cancer and
Alzheimer's. A major expectation was that these variants had not
been eliminated by natural selection because they harm people only
later in life after their reproductive years are over, and hence
that they would be common.

This idea, called the common disease/common variant hypothesis,
drove major developments in biology over the last five years.
Washington financed the HapMap, a catalog of common genetic
variation in the human population. Companies like Affymetrix and
Illumina developed powerful gene chips for scanning the human
genome. Medical statisticians designed the genomewide association
study, a robust methodology for discovering true disease genes and
sidestepping the many false positives that have plagued the field.

But David B. Goldstein of Duke University, a leading young
population geneticist known partly for his research into the genetic
roots of Jewish ancestry, says the effort to nail down the genetics
of most common diseases is not working. "There is absolutely no
question," he said, "that for the whole hope of personalized
medicine, the news has been just about as bleak as it could be."

Of the HapMap and other techniques developed to make sense of the
human genome, Dr. Goldstein said, "Technically, it was a tour de
force." But in his view, this prodigious labor has produced just a
handful of genes that account for very little of the overall genetic
risk.

"After doing comprehensive studies for common diseases, we can
explain only a few percent of the genetic component of most of these
traits," he said. "For schizophrenia and bipolar disorder, we get
almost nothing; for Type 2 diabetes, 20 variants, but they explain
only 2 to 3 percent of familial clustering, and so on."

The reason for this disappointing outcome, in his view, is that
natural selection has been far more efficient than many researchers
expected at screening out disease-causing variants. The common
disease/common variant idea is largely wrong. What has happened is
that a multitude of rare variants lie at the root of most common
diseases, being rigorously pruned away as soon as any starts to
become widespread.

It takes large, expensive trials with hundreds of patients in
different countries to find even common variants behind a disease.
Rare variants lie beyond present reach. "It's an astounding thing,"
Dr. Goldstein said, "that we have cracked open the human genome and
can look at the entire complement of common genetic variants, and
what do we find? Almost nothing. That is absolutely beyond belief."

If rare variants account for most of the genetic burden of disease,
then the idea of decoding everyone's genome to see to what diseases
they are vulnerable to will not work, at least not in the form
envisaged. "I don't believe we should do more and more genomewide
association studies for common diseases," Dr. Goldstein said.
Instead, he suggested, the "missing heritability" might be tracked
by thoroughly studying the genome of specific patients.

Researchers hunting for disease genes strongly disagree. They say
genomewide association studies with larger numbers of patients will
bring more disease-promoting variants to light.

Dr. Kari Stefansson, chief executive of the Icelandic gene-hunting
company Decode Genetics, says it does not matter whether
disease-causing variants are common or rare as long as they yield
insights into the biochemical pathways by which disease develops,
and which will provide targets for drugs.

The HapMap project was started amid much skepticism but has proved a
technical success, even if it has brought to light fewer common
disease variants than hoped. "There is no doubt it has succeeded far
beyond what some skeptics proposed," said Dr. David Altshuler, an
architect of the HapMap at the Harvard Medical School. He defends
the common disease/common variant hypothesis, saying it meant only
that some, not all, of the genetic burden of a disease would be
conveyed by common variants. And the genomewide association study,
currently the gold standard of gene discovery, is in his view only
one step along the road.

Dr. Goldstein does not shy away from unpopular positions or
research. In a new book, "Jacob's Legacy" (Yale University Press),
he recounts how he delved into the genetic history of Jews.

Given the abuses of the past, geneticists approach with caution
research in the genetics of racial or ethnic groups. But genetics
can provide powerful insights into history. Because some Jewish
communities, for instance, have for centuries married only within
their religion, they have developed certain distinctive genetic
profiles. One is a genetic signature on the Y chromosome of the
hereditary Jewish priests known as cohens. Dr. Goldstein, as he
describes in his book, found a set of DNA variations in the
signature that allowed him to estimate when that signature first
appeared -- about 3,000 years ago. The date fit nicely with the
presumed date of King Solomon's reign and supported the claim that
cohens were indeed descended from a high priest of around that time,
even if that priest may not have been Aaron, as tradition holds.

He gleaned an even deeper insight into Jewish origins from analysis
of mitochondrial DNA taken from Jewish communities around the world.
In 2000, a team led by Dr. Michael Hammer of the University of
Arizona found that men from Jewish communities all carry a certain
lineage of Y chromosomes, one that is shared by many Near Eastern
peoples. That established the origin of the founding fathers of
Jewish communities, but where did the founding mothers come from?

Two years later, a team led by Dr. Goldstein provided the surprising
answer: the mitochondrial DNA of many Jewish communities looks as if
it was derived, a long time ago, from the population of the host
community. Jewish communities may therefore have been founded by
Jewish men, arriving perhaps as traders, who took local wives,
converted them to Judaism, and thereafter married only within the
religion.

Dr. Goldstein had never been bar mitzvahed and had taken little
interest in his Jewish heritage until as a graduate student at
Stanford during the Persian Gulf war he was moved by the plight of
Israeli civilians being bombarded by Saddam Hussein's Scud missiles.
After gaining his Ph.D. in 1994, he moved to England, to Oxford
University and University College, London

He later took an appointment at Duke, where he has focused on
pharmacogenetics, the interaction between drugs and the genome. He
has laid aside, at least for the moment, further research into
Jewish genetic history.

Another pursuit that interests him, one of high promise for
reconstructing human evolutionary history, is that of discovering
which genes bear the mark of recent natural selection. When a new
version of a gene becomes more common, it leaves a pattern of
changes that geneticists can detect with various statistical tests.
Many of these selected genes reflect new diets or defenses against
disease or adaptations to new climates. But they tend to differ from
one race to another because each human population, after the
dispersal from Africa some 50,000 years ago, has had to adapt to
different circumstances.

This newish finding has raised fears that other, more significant
differences might emerge among races, spurring a resurrection of
racist doctrines. "There is a part of the scientific community which
is trying to make this work off limits, and that I think is hugely
counterproductive," Dr. Goldstein said.

He says he thinks that no significant genetic differences will be
found between races because of his belief in the efficiency of
natural selection. Just as selection turns out to have pruned away
most disease-causing variants, it has also maximized human cognitive
capacities because these are so critical to survival. "My best guess
is that human intelligence was always a helpful thing in most places
and times and we have all been under strong selection to be as
bright as we can be," he said.

This is more than just a guess, however. As part of a project on
schizophrenia, Dr. Goldstein has done a genomewide association study
on 2,000 volunteers of all races who were put through cognitive
tests. "We have looked at the effect of common variation on
cognition, and there is nothing," Dr. Goldstein said, meaning that
he can find no common genetic variants that affect intelligence. His
view is that intelligence was developed early in human evolutionary
history and was then standardized.

At Duke, he revels in the greater freedom to pursue his own
interests. "In England, there's a much greater tendency to be wary
of something too ambitious," he said. "The feeling in the American
scientific community is one of confidence -- let's get the job
done."