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ing population—but human populations
have never met those conditions.
Nevertheless, geneticists have succeeded
in finding a few clear examples of directional selection, in which a particular version or allele of a gene has been so beneficial that it has spread quickly and widely,
thus reducing levels of genetic variation.
The allele that allows adults to digest lacNew genetic techniques are spurring the search for evidence of natural
tose is a good example: The pastoralists
selection at work in human prehistory, and they may offer insight into
who carried it could drink milk as adults,
ancient and modern pathogens
boosting their survival and reproduction, so
A woman miscarries; a child dies of malar- Spring Harbor Laboratory,* about 150 an- the allele became common and in relatively
ia; a young man is ravaged by AIDS. Each thropologists, geneticists, and pharmaceuti- short order displaced other versions of the
is a human tragedy that leaves its mark on cal company researchers spent 5 days exam- gene in those populations. Geneticists also
lives and families. But over the sweep of ining progress in the hunt so far and the im- have found some cases of what’s called balhuman history, such tragedies also can plications for biomedicine. “What this meet- ancing selection, in which a gene shows
leave their mark on the human genome. ing represents is a fusion of anthropology, more variation than expected because peoGenetic mutations that help protect against population genetics, and clinical medicine to ple with two different versions of it—
viral infections, for example, should give create a new field, evolutionary medicine,” heterozygotes—have an advantage over
those who inherit them an advantage in the said meeting co-organizer Douglas Wallace, those who carry two copies of the same alreproduction and survival sweepstakes. The director of the new Center for Molecular and lele. The classic example is a hemoglobin
theory of natural selection predicts that over Mitochondrial Medicine at the University of allele that causes sickle cell anemia if inherited from both parents but protects
many generations, these mutations will California, Irvine.
against malaria if paired with a normal verspread through populations and so appear
sion of the gene.
in genomes today.
Direction and balance
But beyond these well-known examples,
Scientists have long sought the genetic The effort to understand human traits and
imprint of natural selection to understand diseases in terms of natural selection began the pickings have been slim. “For directional
selection, people have been able
the forces that have shaped
to find a handful of genes,” says
human traits. But it’s been a
Mutation rare
geneticist Michael Bamshad of
bit like trying to solve a crossin population
Young, neutral mutations
the University of Utah in Salt
word puzzle in which the
Lake City. “For balancing selecclues have been scrambled.
tion, they have found even fewer.”
Other demographic events
But now that geneticists can
such as migrations, populaMutation rare
sequence
thousands of base
tion contractions and expanor common
Old, neutral mutations
pairs from global samples of
sions, and mating traditions
hundreds of people, the search
have also left their mark on
has gained new life. For examour genomes, making the efple, Bamshad and his colleagues
fects of selection and history
Mutation common
have sequenced the regions surhard to untangle.
in population
Young mutations favored by selection
rounding a cell surface receptor
So until recently, regene called CCR5 in more than
searchers had uncovered few
200 people worldwide. This is a
solid cases of human genes uncrucial receptor because many
der selective pressure. But they
now have two powerful tools to
Selection stands out. Mutations favored by viruses, including HIV, seem to
Linked DNA
guide the search: eff icient
selection are both abundant in populations and use it to gain entry to cells.
Mixed DNA
surrounded by large blocks of linked DNA (a
In work published 6 August
sequencing techniques and
sign of youth).
in the Proceedings of the Nathe almost complete human
tional Academy of Sciences,
genome sequence. These have
already helped add several new genes to the with Darwin, who sought in his last book, Bamshad found up to twice as much genetic
list of those affected by selection (see table). The Descent of Man, “to see how far the variation as usual in a noncoding, regulatory
And because some of the most potent selec- general conclusions arrived at in my former region of CCR5, and characteristics of the
tive forces have been pathogens, researchers works were applicable to man.” But as the variation suggest that it has been maintained
are hoping the search will help them zero in quest moved to the genetic level in the 20th for a long time. Bamshad believes that those
on parts of the genome involved in disease. century, the task proved more difficult than patterns are the result of balancing selection:
“We should be able to find disease genes expected. To detect selection, researchers As in the case of sickle cell anemia, people
without actually having patients, because we first must determine how a genetic sequence with two different copies of the gene apparare descended from people who were resis- would change under neutral conditions in ently suffered from fewer or milder illnesses,
tant to diseases, and that resistance is en- which selection was not a factor. That’s easy thus leaving a legacy of variability that congraved in our genes,” explains geneticist to do for an infinitely large, randomly mat- tinues to have advantages today. Indeed,
among people infected with HIV, heterozyDavid Reich of the Whitehead Institute in
* “Human Origins and Disease,” 30 October to 3
gosity in the CCR5 gene seems to slow the
Cambridge, Massachusetts.
progression to AIDS. HIV itself is too new
Earlier this month, in the fourth of a
November, Cold Spring Harbor Laboratory, Cold
Spring Harbor, New York.
to have been the selective force on CCR5,
series of sesquiannual meetings at Cold
1324
P O P U L AT I O N G E N E T I C S
Seeking the Signs
Of Selection
15 NOVEMBER 2002
VOL 298
SCIENCE
www.sciencemag.org
CREDIT: E. LANDER, P. SABETI, AND E. WALSH
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but older candidates include poxviruses, in some populations. Such common young considerable interest in the pharmaceutical
which ravaged human populations in the variants can be a sign of selection, because industry. If a pathogen has exerted selective
past, says Bamshad.
new mutations favored by selection replace pressure on a gene, that gene could be a
Ken Kidd of Yale University has taken a other alleles faster than if they were neutral.
promising target for a new drug or vaccine.
similar survey of a different set of genes: the
But the example is controversial because “We can use the experiment that nature has
ADH genes that produce alcohol-metaboliz- it’s hard to know why an allele that now pre- already conducted to give us a clue about
ing enzymes. Many members of eastern disposes people to ADHD might have had a how to combat a disease,” said Genaissance’s
Asian populations have a variety of unpleas- selective advantage, admits Moyzis. He notes J. Claiborne Stephens.
ant reactions to alcohol, including flushed that the allele appeared during an “interesting”
But many geneticists have cautioned that
faces, racing hearts, and upset stomachs. time in human history, when modern humans the new efforts to detect selection will face
Partly as a result, these populations tend to expanded into new environments worldwide. many of the obstacles that have previously
have low levels of alcoholism. These reac- He speculates that the allele increased the stymied researchers. One problem is that
tions are due to a variety of mutations, some probability that some individuals would leave demographic processes and random
of which hasten the metabolism of ethanol their homelands and seek out new challenges.
chance can mimic selection. For example,
to toxic acetaldehyde and
the seven-repeat allele
trigger the adverse effects.
of the dopamine recepSELECTION AT WORK IN HUMANS: A SAMPLER
But any selection seems not
tor is common in Native
to have been acting on huAmericans but virtually
Gene
Signs of Selection
Possible Selective Force
man drinking habits; inabsent in eastern Asians.
Sickle cell gene
Unusual genetic variability
Malaria, sickle cell disease
stead, many researchers beBut that could be an ac(hemoglobin β)
(balancing selection)
lieve that the reactions ofcident of history, not a
CCR5
Unusual genetic variability
Smallpox, other diseases
fered protection against an
sign of selection, if the
(balancing selection)
unknown parasite that was
first people to colonize
Lactase
Young, common variant;
Ability to drink milk in
even more sensitive to acthe Americas just haplow sequence variability
adulthood
etaldehyde than humans are.
pened to have the allele.
(directional selection)
When Kidd examined the
Also, genes and
ADH
Common variant;
Unknown parasite sensifrequency of these mutations
human traits generally
low sequence variability
tive to acetaldehyde?
throughout eastern Asia, he
have a complex linkage,
(directional
selection)
found that certain mutations
not a one-to-one correDRD4
Young, common variant
?
often occurred together, crespondence. “No one has
(seven-repeat allele) (directional selection?)
ating a unique combination
found a variant that exof genetic variants that toplains more than a couG6PD and CD40L
Young, common variants
Malaria
gether promote acetaldehyde
ple of percent of any
(directional selection)
production. This combinacommon disease, and all
tion occurred so frequently
of these diseases are gothat it was unlikely to have spread by chance, Seeking youth and abundance
ing to be highly multigenic,” said geneticist
says Kidd. Thus although no one knows As these researchers examine particular Jody Hey of Rutgers University in Piscataway,
what parasite might have been involved, the genes, others are looking more broadly for New Jersey. “That’s bad news for the gene
prevalence of the mutations suggests that se- signs of selection. For example, Pardis Sa- mappers and pharmaceutical companies.”
beti, David Reich, Eric Lander, and their collection was indeed at work, he says.
For example, Kidd calls the link between
In a more controversial study, Robert leagues at the Whitehead Institute have de- certain genetic variants and low levels of alMoyzis of the University of California, veloped a technique that spotlights the com- coholism in eastern Asian populations “one
Irvine, reported on efforts in his lab by Yuan- mon young variants that can signal direction- of the strongest associations found in the
Chun Ding and others to detect selection in al selection: They seek common alleles sur- study of complex diseases.” Yet he acknowlthe human dopamine receptor DRD4. A par- rounded by extensive linkage disequilibrium edges that alcoholism has social and psychoticular version of the receptor—an allele (see diagram). The team applied this method logical dimensions too. And although certain
with seven repeats of a 48–base pair insert— to variants of two genes, G6PD and CD40L, alleles might protect against alcoholism,
has been linked with the personality traits known to confer partial protection against their absence does not boost susceptibility,
of novelty-seeking and attention-deficit/ malaria. In work described last month in Na- because the mechanisms of addiction are
ture, they uncovered a clear selective signal: distinct from those of alcohol metabolism.
hyperactivity disorder (ADHD).
Moyzis’s team found that the seven- Each gene appears to be just a few thousand
No one expects the search for signs of serepeat allele is surrounded by a large block years old but is much more widespread than lection to suddenly become easy. But after
of sequence in which genetic variations tend expected under a neutral model. Now the years of frustration, researchers are welcomto be inherited together, a pattern called team is extending its method to scan the en- ing the new data and methods that might filinkage disequilibrium. This means that the tire genome for other selective episodes that nally yield progress. “We’re starting to see a
ancestral chromosomal region on which the have occurred over the past 10,000 years. clear connection between the study of histomutation first appeared has not yet been (Before that, recombination probably would ry and practical biomedical applications,”
broken up by the recombination events that have scrambled the signal.) “It seems to be a says geneticist Stephen Wooding of the Unioccur each generation, during the formation very powerful way of looking for selection versity of Utah. “We can generate clinically
of sperm and egg cells. That suggests that and pinpointing important functional varia- testable hypotheses that we were never able
the allele is much younger than the other tion,” said Benjamin Salisbury of Genais- to generate before.”
–STEVE OLSON
common DRD4 alleles, perhaps appearing sance Pharmaceuticals in New Haven, Connecticut, which is conducting its own search Steve Olson is a science writer in the Washington,
just 30,000 to 50,000 years ago.
Normally an allele this young would be for selection in 7000 genes.
D.C., area and is the author of Mapping Human
The search for selection is generating History: Discovering the Past Through Our Genes.
relatively rare, but instead it is quite common
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VOL 298
15 NOVEMBER 2002
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