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**Blackbear** · 06-23-2005, 08:13 PM

In fact, a massive international effort, which includes many Canadian
researchers, has been quietly under way for nearly four years to catalogue and
compare the genetics of people with African, Asian and European ancestry.

It is called the Haplotype Project. You may not have heard a word about it
before now. But by the end of this year, society may have to start facing its
implications.

It was not supposed to be this way.

When the Human Genome Project was completed in 2000, its most touted result
was that it showed no genetic basis for race. In fact, some scientists went so
far as to dub race a “biological fiction.”

The project was a 13-year international drive to map all of the three billion
chemical bits, or nucleotides, that make up human DNA. Particular nucleotide
sequences (represented by the letters A, C, G and T) combine to form the
estimated 25,000 genes whose proteins help to produce human traits, from the way
your heart beats to the wave in your hair.

The map indicated that humans as a species are 99.9 per cent genetically
identical — that, in fact, there are greater differences between two frogs in a
pond than between any two people who find themselves waiting for a bus.

A teeny 0.1 per cent, a mere genetic sliver, helps to account for all the
profound diversity within the human race, with its freckles, dimples, afros and
crimson tresses, its shy and bombastic types, its Donald Trumps and Dalai
Lamas, Madonnas and Mr. Dressups, Bill Gates, Billie Holidays, George W. Bushes and
Osama bin Ladens.

It was a message of harmony: Hardly a hair of code separates us.

But five years later, one of scientists' main preoccupations has become to
chart the genetic variations between and within racial groups — to parse that
0.1 per cent. These differences arise through mutations, which all begin as
one-time flukes, but become more prevalent in a particular place if they offer a
survival advantage, carriers have more children or they result in a trait a
society finds desirable.

Now, teams are panning for gene types to help explain why West Africa
produces the fastest runners in the world. A University of Toronto researcher is
hunting the gene types that account for skin colours.

A Pennsylvania State University scientist is teasing out the biology behind
other variable physical traits, such as height or hair texture.

More crucially, it has become obvious that the 0.1 per cent may add up to the
difference between sickness and health.

In Canada, researchers from McMaster and McGill Universities are breaking
down heart disease by nationality to understand the interplay of genes and
environment. The answers may explain why South Asians suffer high rates of high
blood pressure, why heart attacks hit Middle Eastern men 10 years earlier than
Europeans, or why the Chinese seem to boast the trimmest waistlines in the world.

The genes discussed in Dr. Harpending's team's paper, meanwhile, are known to
be the ones that account for the high Ashkenazi rates of breast cancer, the
neurological disorder Tay-Sachs and other conditions. The mystery is why these
traits have persisted at high rates over generations. The Utah group's
conclusion (to be published in the Cambridge University Press Journal of Biosocial
Science) is that the diseases are a tragic side effect of genes selected for
their role in boosting brain function.

Given the explosion of research in race and genetics, Francis Collins, a
former leader of the Human Genome Project, had to admit in the journal Nature
Genetics last fall that “well-intentioned statements” about the biological
insignificance of race may have left the wrong impression: “It is not strictly true
that race or ethnicity has no biological connection. It must be emphasized,
however, that the connection is generally quite blurry.”

Alan Bernstein had warned him. In the fall of 2000, the president of the
Canadian Institutes of Health Research heard Dr. Collins speak at Harvard about
there being no significant differences between races. “That's going to come back
at you,” he said.

According to Dr. Bernstein, 0.1 per cent is actually far from an
insignificant difference in the genome's chemical sequence. In fact, he said, the genetic
distance between humans and gorillas is not much greater. “It's silly to try
and be politically correct about it.” What matters, Dr. Bernstein said, is to
treat it scientifically.

**Blackbear** · 06-23-2005, 08:13 PM

The most organized effort to do that to date is the International Haplotype
Project. Scientists in Canada, the United States, Britain, China, Japan and
Nigeria are spending $185-million to chart the genomes of people from Tokyo,
residents of Beijing, the Yoruba in Nigeria and Americans of Western and Northern
European descent — 270 people in all.

Using these maps to find genetic differences between ethnic groups could lay
the groundwork for new treatments and cures. It might help predict a person's
response to a given drug, and allow for tailor-made medications with fewer
side effects. It could bring the medical advances genetics has long promised.

On the other hand, the knowledge may raise more questions about the meaning
of racial differences than anyone cares to answer.

The Quebec Genome Innovation Centre at McGill University is a cold, sleek
structure that screams clinical precision, with its glass walls, concrete columns
and lateral steel beams. The equipment inside is as expensive as the
$30-million, 50,000-square-foot building that houses it.

Its three floors of labs and DNA sequencing technology crunch genetic data at
a rate no one even imagined five years ago. In 2001, it took a year to run
50,000 genetic tests. Today, said the centre's director, Tom Hudson, they can
shoot out the results of 20 million tests in a week.

This speed comes courtesy of such mind-boggling gadgets as the array centrix,
a small board of 96 fibre-optic spikes, the tips of which can be coated in
DNA and 1,500 genetic tests run on each tip — at the same time.

“From one drop of blood, you can do hundreds of thousands of tests,” Dr.
Hudson enthused.

From one drop of blood you also can discern the ethnic background of the
person being tested with fairly good certainty.

So it is here, where technology has shrunk costs to just pennies per test,
that major sections of the Haplotype Project's “HapMap” are being generated.

The project was born in the summer before Sept. 11, 2001. At first, it seemed
destined for obscurity. Scientists at the University of Toronto, McGill and
the Massachusetts Institute of Technology had been hunting gene mutations that
increased the risk of Crohn's disease in 200 Toronto-area families of mostly
European heritage — British, Polish, French and Greek.

In the process, they stumbled on a remarkable discovery. The genome's three
billion chemical letters appear to be arranged in blocks — like paragraphs in a
text. Some are longer, some shorter, but all have fairly clear beginnings and
ends.

The pattern seemed to make sense. In the genetic mix and mingle of
conception, the mother's and father's DNA are passed down to the next generation in
these kinds of heritable chunks. Researchers estimate there are 100,000 such
blocks in each person's genome.

What's more, gene mutations within those blocks seem to fall in the same
places, even in different families. It's like a library in which every book
contains a typo in the first paragraph on the second page, or the fourth paragraph
on every fifth page. The misprints might be different, Dr. Hudson explained,
but they occur in the same locations. For finding genetic mutations, the pattern
seemed as good as an index: Instead of scanning the whole book, you could
flip straight to page 2 or page 5.

The discovery seemed to cry out for a new map of the human genome, one that
would show the haplotype blocks and highlight each paragraph in the book of
life.

“Everyone knew this was important,” Dr. Hudson said. “But there was no big
press release.” Coming out a month after Sept. 11, the discovery of haplotype
blocks attracted little initial attention. But for scientists it couldn't have
come at a better time.

Traditional methods to find mutated genes in family studies and remote
populations had hit a wall. Yes, they could find the lone mutation that led to a
rare disorder such as Huntington's disease or cystic fibrosis. But trying to find
the dozens of mutations that increase the risk of common diseases like
cancers or asthma would simply require too many patients and too much data
crunching.

With a haplotype map, they would be able to search the genomes of huge
numbers of people with a particular disease, in search of a common typo in a
particular paragraph.

First, however, the HapMap researchers had to find out if their theory would
apply to the genomes of people around the world. The maps provided by the
Human Genome Project would offer little help, because they had been rough
compilations based on various people, with little regard for ethnic background.

The next question was, whose genomes should they use?

When HapMap scientists met in Washington in 2002 to discuss the issue, Dr.
Hudson — a 44-year-old, buttoned-down geneticist much more comfortable with
technical issues than social ones — was taken aback at the incendiary debate that
broke out. It was the kind of battle that seems bound to become more frequent
as scientists continue to explore this sensitive area.

“As Canadians, we are not used to the high emotions around race, as they are
in the U.S.,” he said. In that two-day meeting and others to come,
African-American community leaders, ethicists and philosophers unleashed their fears and
frustrations.

**Blackbear** · 06-23-2005, 08:14 PM

“There were two points of view,” Dr. Hudson recalled. “One of them is, ‘
You're only going to be studying Caucasian chromosomes, clearly, because you only
want to find tests for North Americans and U.S. people with money.' ”

But if Africans and other populations were included in the map, there was
serious concern that any differences found in their genomes might leave them open
to another tier of discrimination, perhaps from health-insurance companies.

In the United States, where the mortality rates for a range of diseases are
higher among blacks than whites, such disputes are common. For example,
scientists and sociologists continue to argue over whether African Americans' high
rates of hypertension are due to genes or to environment.

One contentious theory suggests African Americans descend from those slaves
who were able to survive the dry and hungry trip from Africa thanks to a
genetic quirk that enabled them to retain moisture and salt — which also can
contribute to high blood pressure.

But others say it is due to diet and stress. As New York University
sociologist Troy Duster told The New York Times last fall, “If you follow me around
Nordstrom's and put me in jail at nine times the rate of whites and refuse to
give me a bank loan, I might get hypertensive.”

In the end, the HapMap team decided to include African chromosomes, along
with those from Japan, China and the United States. It was a diverse enough
sampling to tell them if the haplotype theory would hold up, but selective enough
for their limited budget.

At the same time, ethicists joined the project to ensure that all DNA donors
would be aware of the risks of participating — namely, that any dramatic
genetic differences the project discovered could end up stigmatizing their
communities.

“Certainly,” Dr. Hudson said, “there's enough examples already of racism in
the world — before genetics, during genetics and after genetics — that
there's no doubt someone would try to use the information for genetic discrimination.
”

Despite the long and ugly social history of race, there is no clear-cut
definition for the term. Is a person's race defined by skin colour, that most
visible of markers? By language, country of birth, the food they eat or the
religion they practice? Not even scientists can agree.

“If you have a [genetic] sample from Nigeria, can you really say that it
represents Africans? Is that the same as African Americans? [In some studies],
Jews are white, sometimes they're not. Sometimes they're compared to Caucasians,”
said Celeste Condit, a professor of speech communication at the University of
Georgia who specializes in biomedical issues.

“The scientists have been irresponsible for not developing a language for
this,” Prof. Condit said. “Usually scientists are very careful in developing
their technical vocabulary. But it's hard to describe the geographic dispersion
of people properly — and they have these easy [racial] terms in their heads.”

Of course, geneticists already know that since people have ancestors from all
over the world, no one fits neatly into any one racial box. We are all of us
mixed, even if our complexions suggest otherwise. There also can be greater
genetic differences within racial groups than between them.

But since no one now has the resources to uncover the secrets in every
patient's DNA, both science and medicine are using “race” as an easy, if dangerous,
shortcut.

“Until we can scan the genome of every individual,” said Tim Caulfield,
director of the Health Law Institute at the University of Alberta, “race has
become this rough proxy.”

Yet HapMap researchers are indeed finding that the genetic lines between
their groups are terribly blurry. In fact, the block structures are similar in all
of them.

“Humans as a species are just so young there hasn't been enough time for the
genome to alter that dramatically,” Dr. Hudson said. (Frogs, on the other
hand, have a few more millennia behind them than people.)

As expected, they are finding the most variations in the DNA of donors from
Africa, where modern humans are believed to have arisen 150,000 years ago. It
is thought that the rest of the planet's populations are all descendents of a
small group who only wandered out of Africa roughly 60,000 years ago, so there
has been less time for those genes to mutate in the rest of the world.

What they do know, Dr. Hudson stressed, is that the mutations they are
cataloguing — the 10 million or so most common ones — appear to exist in all
populations. Just not at the same frequencies.

“Almost all the differences you see in people in North America are
differences you see in Africa, are differences you see in Asia,” he said. “It's very
rare to have something you only see in [one place].” And when you do, he said,
it's uncommon even in that population.

One stunning example is a gene variant that makes 1 per cent of Caucasians
(and an estimated 10 per cent of Ashkenazi Jews) immune to HIV infection. It
blocks receptors on the surface of cells where the AIDS virus would otherwise
enter. Scientists suspect the trait was passed down from Europeans who survived
medieval smallpox plagues thanks to the same mutation.

Another variant known to be fairly exclusive to a particular people is the “
Duffy null” mutation in people from sub-Saharan Africa. Penn State genetic
anthropologist Mark Shriver explained that it likely became prevalent there
because it offered protection against a particular type of malaria, “but it didn't
spread widely outside of Africa.”

Yet Dr. Shriver, who by all outward appearances is a white man, happens to
carry it. A scan of his genome suggests that while he is predominantly European,
he is also about 11 per cent West African and 3 per cent native American.

“Race just doesn't exist in a critical line,” he said. “It's more of a
gradient.”

Dr. Shriver applauds the information flowing in from the HapMap project
(which is freely available on-line), calling it “a revolutionary tool” for
science. But others are not so impressed.

“Basically, it is a total waste of money,” Columbia University geneticist
Joseph Terwilliger said.

Dr. Terwilliger argued that by focusing on the most common genetic mutations,
the project would overlook the most specific differences to be found in any
group. It would make “populations look systematically more similar to one
another than they really are.”

Medically important traits — such as the HIV-resisting gene type — could be
missed if researchers do not deliberately hone in on the rarer quirks in each
particular racial group.

“Different populations have enormous differences,” Dr. Terwilliger said. “If
this were not true, then there is no way we can determine how we are related
and how populations migrated historically.

“You cannot put people neatly in a small number of meaningful categories like
black, white or Asian. That said, Koreans and Chinese are genetically vastly
more similar than either are to Germans.”

**Blackbear** · 06-23-2005, 08:19 PM

The controversy around the scientific meaning of race is already spilling
over from the lab to the medical clinic. Researchers continue to debate
definitions, but the age of race-based medicine is upon us.

The U.S. Food and Drug Administration approved the world's first “ethnic”
medication last fall, a heart-failure drug for African Americans known as BiDil.
Pharmaceutical giant AstraZeneca is developing marketing plans for a
lung-cancer drug that flopped in Caucasians but seems to work for Asians.

No one yet fully understands the actual genetic traits that make these drugs
effective in these groups. And scientists have every reason to believe people
other than blacks or Asians may carry these traits. But for now, prescriptions
for such medications are to be based on little more than physical appearances
and questions about a patient's heritage.

And this, Prof. Condit argued, could lead to significant risks. Doctors may
end up denying a drug to Caucasians who might benefit from it, because it is
touted to work only in South Asians. Or they might prescribe a pill to a black
person who actually would benefit from some other treatment. (For example,
research has found that as many as 30 per cent of African-American men have a
white male ancestor, a fact attributed to the sexual politics of slavery.)

Prof. Condit has tried to bring the inherent dangers of race-based science to
the attention of the researchers involved. She has published journal
articles, held focus groups and arranged meetings that few scientists leave their labs
to attend. Without careful consideration and communication, she warned,
modern medicine could set race relations back decades.

She offered this scenario: Imagine a drug marketed only for blacks, a simple
pain reliever, prescribed in the millions. Now imagine that, like a certain
now-notorious pain medication, it turns out to have the horrible side effect of
increasing the risk of heart attacks. Result: Tens of thousands of North
American blacks — and only blacks — die.

“What happens if you get a Vioxx situation with one of these drugs? And the
likelihood of this happening is very high,” she said. “But until there's a
catastrophe, people don't want to deal with it. You are playing with fire.”

Those watching the field of modern racial genetics explode are already
concerned.

“If genes predispose groups to certain diseases or health conditions, might
we also find information that hints at more socially loaded conclusions?” the
University of Alberta's Tim Caulfield wondered.

Last summer, Prof. Caulfield was surprised to read an article in the
prestigious journal Science titled, “Peering Under the Hood of Africa's Runners.” It
noted that all but six of the 500 fastest times for the 100-metre dash have
come from sprinters of West African descent, which includes most U.S. blacks.
Kenyans, meanwhile, dominate world records in long-distance races.

According to the report, Swedish physiologists trying to penetrate the “
Kenyan mystique” compared runners from Africa and Scandinavia on treadmill times,
lung capacity, heart rates and body weights. Limb measurements indicated that
the Kenyans carried 400 grams less flesh on each calf. The report referred to
their “birdlike legs,” explaining how Kenyan runners squeeze more power from
their oxygen intake, since “they need less energy to swing their limbs.”

Research on West Africa's sprinters, meanwhile, revealed a body type of
heavier “fast-twitch” muscles, versus the lighter “slow-twitch” muscles of
endurance runners, as well as denser bones, narrower hips, thicker thighs, longer
legs and lighter calves. Efforts are now under way to decode the genetics behind
all these traits.

Like Prof. Harpending's paper on Ashkenazi Jews, the report on African
runners presented a positive picture of its subjects, albeit a stereotypical one.
Yet it seemed eerily reminiscent of ugly 19th-century efforts to gauge racial
differences with calipers and cranial measurements.

Prof. Caulfield, who holds the Canada Research Chair in Health Law and
Policy, was mostly concerned about where such research would lead. Already, he said,
an Australian company is cashing in on the notion that some people are born
to run, offering to test a child's genes for fast- or slow-twitch muscles — “
so you know which sport to put your kid in.”

While he said he loathes the idea of restricting scientific research in a
free, democratic society, Prof. Caulfield described the race-based search for
disease genes as a Pandora's box.

**Blackbear** · 06-23-2005, 08:19 PM

Studies are sure to appear on genes linked to complex characteristics in
racial groups, such as athletic or cognitive ability or even criminal behaviour.
But these traits, he stressed, are anything but a simple story of genetics.

“It's like beauty,” he said. “Being beautiful will involve the interplay of
thousands of genes and social factors that dictate at a given time what is
beautiful. It's a very complex story, it involves culture, socio-economic class,
experience. . . . So how do you handle that information?”

As Penn State's Mark Shriver put it, “It's not that genes for IQ, athletic
ability and musical ability don't exist. But you just can't tease apart the
affect of environment in shaping these abilities.”

If people are starting to overestimate the role genes play in shaping human
health and behaviour — and underestimate the huge impact of experience,
environment and social forces — Columbia's Joseph Terwilliger said that scientists
must share the blame.

“In many ways, scientists over-hyped the information in the genome, or at
least what we know about it, to the point where now people are getting
unnecessarily nervous about societal implications,” he said.

“The fact is that to get the funding they sold genetic determinism, which of
course is nothing close to reality. And now they are paying the price.”

This year, the journal American Psychologist devoted an entire issue to the
impact race and genetics could have on its field, raising a list of the
difficult questions ahead. It included three papers on the controversial issue of
intelligence, including one commentary arguing that genes should get more
attention in studies of racial intellectual differences.

For Dr. Harpending, who admitted he would never have “even muttered in public”
his theories about Ashkenazi Jews and intelligence were he not a senior
professor with tenure, this type of conversation cannot come soon enough.

“There is this massive disconnect between public and private discourse;
between what's said in the public arena and what your neighbour tells you [about
racial groups] over the fence,” he said. “Some of those things are wrong and
bigoted, but some of those are right.”

Perhaps. But would Prof. Harpending dare match his Ashkenazi study with one
of India's lowest Hindu caste, the so-called untouchables, who like European
Jews have historically been an isolated society — except, in this case,
relegated to centuries of cleaning latrines?

“One is the mirror image of the other, I suppose,” he admitted. “I would
personally find that distasteful. But if I had a theory about it, I would hope
that I would publish it.”

If the race debate in science seems sticky now, it's only going to get worse.

This summer, scientists from all over the world are gathering to discuss
plans for yet another map of the human genome. This one is based again on a
discovery involving Canadian research — and in scientific terms, it is hard to
overstate its significance.

Geneticist Steve Scherer, a senior scientist at Toronto's Hospital for Sick
Children, working with colleagues at Harvard University, discovered last August
that the basic model of simple genetic inheritance science has clung to for
100 years is wrong: Mom and dad don't always make equal genetic contributions
in the creation of a child's genome.

Instead, some people might end up with three, four or even more copies of a
gene from one parent, instead of the single copy of each gene scientists
thought each parent always contributed.

The implications could be huge. There might be greater genetic differences
between individuals — and certain populations — than anyone imagined.
Certainly, there are more than the HapMap is charting, Dr. Scherer said.

Might one ethnic group, for example, carry an overload or an underload of
genes for a particular trait?

“I think it was premature to say that the difference between people might
only be 0.1 per cent,” Dr. Scherer said. “Based on what we know now, it is
probably in the 0.2 per cent range. And in the end it may even be as high as 1 per
cent.”

Dr. Scherer spent two days last August fielding media calls when the news
first broke. He did most of the interviews by phone, but in a few cases it was
easiest to respond by e-mail.

Then came a call from his Harvard collaborators informing him that one of
those e-mail interviews had been with a writer who worked for a neo-Nazi website.
The writer spun the news as scientific proof of genetic differences between
races — without even misquoting or twisting Dr. Scherer's words.

“As a geneticist,” the 41-year-old Dr. Scherer said, “it's your worst
nightmare.”

The HapMap's Tom Hudson in Montreal has had the same one. A colleague
recently referred him to an Internet hate site that declared the HapMap would finally
prove the biological basis of race.

“It made me queasy, because they actually name the name of my friend, my
colleague in Boston. And they actually say, ‘He's going to prove us right.'

“I didn't understand what I was reading when I first read it,” Dr. Hudson
said. “I never read something that was so disgusting.”

It wasn't an isolated incident.

Morris Foster, an associate professor of anthropology at the University of
Oklahoma and one of the HapMap's leaders, said researchers are tracking racist
sites for references to the HapMap, which logs 20,000 downloads a week from its
public database. They have amassed quite a collection.

Not only do the hate sites keep abreast of what HapMap information has become
available (such as recent data on Japanese and Nigerians), but they anxiously
await findings that will help unveil genetic traits linked to such things as
crime and cognitive ability by race.

“Once it is scientifically demonstrated,” one web contributor writes, “that
will be the beginning of the end for the Marxist-egalitarian argument over
race. Personally, I can't wait.”

Even Western Ontario's infamous J. Philippe Rushton has seized upon modern
genetics as an opportunity to make his case again, in the company of Arthur
Jensen, a University of California psychology professor who argues that race
determines IQ.

This month, the unpopular scholars have the lead article in the journal
Psychology, Public Policy and Law , presenting 60 pages of evidence arguing that
genes explain 50 per cent of the IQ differences between races, in which Asians
rank higher than whites and whites higher than blacks.

(The publisher, the American Psychological Association, invited scientists to
rebut the paper in the same issue.)

And yet, despite all the social hazards of modern genetics, Dr. Scherer said
scientists should not “have to fear discussing their results of their
research, so long as they are open-minded and listen to criticisms and comments from
others, including the public.

“I always wonder what Darwin would have done in today's world.”

The ultimate test, Dr. Harpending pointed out, lies not with researchers, but
with the public.

He described projects under way involving genes potentially associated with
controversial behaviours such as sexual promiscuity, adultery and family
abandonment.

“A number of things are coming down the pipe,” he said, “that we are going
to have to figure out how to cope with as a decent and moral society.”

Carolyn Abraham is The Globe and Mail's medical reporter.

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