FEATURE
FEATURE
Ancient footsteps in our genes:
evolution and human disease
Gene variants selected during evolution may
underlie many common diseases
here are about 10 million single
T nucleotide polymorphisms in the
human genome, any one of which could
hold the key to understanding disease
risk or drug responses. So where do you
start to look for polymorphisms that
have medical relevance? Which do you
study first?
One approach, says David Goldstein,
Wolfson professor of genetics at
University College London (UK), is
to look for “signatures of selection”,
polymorphisms that change a protein’s
aminoacid sequence, for example,
or that have a striking geographical
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Some researchers suggest Yersinia pestis, the cause of Black Death, has caused a
genetic change that helps some people resist HIV
distribution. “If a polymorphism has a
low frequency in one part of the world
and a high one somewhere else, then
there is a better chance that it is doing
something important”, says Goldstein,
and that it may have been selected
during evolution.
Traditionally, evolutionary scientists
and doctors have not worked together.
But now it is becoming clear that many
gene variants that are important in
health and disease are the result of
natural selection—the selective pressure
that leads to the “survival of the fittest”.
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this last category: glucose-6-phosphate
dehydrogenase (G6PD). Deficiencies in
this gene, which can cause severe
anaemia, are present at high frequencies
in areas where malaria is or was
historically present, suggesting that
G6PD variants may provide protection
against malaria.
To discover if GP6D variants were
selected as people spread around the
Identifying those genetic variants that
have been selected in human
populations and determining how they
world, Tishkoff’s team compared the
patterns of genetic variation around
the G6PD gene in individuals with
alter the function or expression of the normal G6PD with those in people
proteins they encode is providing with G6PD deficiencies. From her
insights into how our biology is linked analyses, Tishkoff estimates that
to important diseases. selection of G6PD variants occurred
Infectious diseases, for example, have about 10 000 years ago in Africa,
driven changes in the human genome. when the introduction of agriculture,
“It is hard to imagine anything else that which caused people to live in
could wipe out an entire population so larger communities, allowed the
rapidly”, says molecular anthropologist mosquito–human infection cycle to
Sarah Tishkoff (University of Maryland, become established.
College Park, MD, USA). “Only those Tishkoff’s findings provide a detailed
people who have some sort of resistance description of when and why G6PD
variants emerged. But for the AIDS
restriction genes, which prevent HIV-1
infection or slow AIDS progression, the
story is less complete. Stephen O’Brien,
chief of the Laboratory of Genomic
Diversity at the US National Cancer
Institute (Frederick, MD, USA), and
co-workers discovered the first of
these—the ⌬32 variant of CCR5, a
co-receptor for HIV-1—in 1996. About
15 AIDS restriction genes have now
been identified, most of which show
geographical variations in allele
frequency (Hum Mol Genet, published
online Feb 5; DOI: 1093/hmg/ddh075).
However, to date, a strong signature of
selection has been shown for only two or
Wellcome Library, London
three AIDS restriction genes. Even for
CCR5-⌬32, for which there is clear
evidence of strong selective pressure,
most recently about 700 years ago, the
selective agent is not clear. Not HIV-1,
because that only emerged in the past
century; O’Brien favours Yersinia pestis,
the cause of bubonic plague, but
smallpox and other infectious agents are
survive and pass on their genes.” also suspects, and CCR5-⌬32 recently
Tishkoff uses molecular genetics to failed to provide protection in a mouse
investigate how human populations model of plague (Nature 2004; 427:
have changed over time—their origins, 606).
migration patterns, and cultural history. Another infectious agent that has left
Her particular interest is in gene a selective signature in the human
variants that provide protection to genome is the prion protein. In the case
malaria. of prion diseases, says Goldstein, the
There are 10–20 candidate malaria global pattern of genetic variation at the
resistance genes, encoding immune prion gene is consistent with “balancing
system proteins, erythrocyte surface selection”, which could have been
proteins, and proteins involved in caused by prehistoric kuru-like
erythrocyte physiology. Tishkoff and epidemics. In balancing selection,
co-workers have been studying a gene in heterozygous individuals are “fitter”
THE LANCET • Vol 363 • March 20, 2004 • www.thelancet.com

than either type of homozygous
individuals—the best known example of
this type of selection being the
protection afforded against malaria by
heterozygosity for HbS. Although the
case for selection at the prion gene is
still only circumstantial, says Goldstein,
“this is a possible example of how
selection influences polymorphisms that
are of medical significance today”.
Infectious agents are not the only
evolutionary selective pressures that
have acted on the human genome. Diet
may also have shaped human genes.
According to the thrifty gene hypothesis,
proposed in 1962 by James Neel, when
people lived as hunter-gatherers, gene
variants that made the most of an
intermittent food supply were selected
for. Now, with most of us leading
sedentary lives in which food is always
available, these same variants may
underlie the global epidemic of obesity,
diabetes, and heart disease.
“many gene variants that are
important in health and
disease are the result of
natural selection”
Population geneticist Rosa Maria
Corbo (La Sapienza University, Rome,
Italy) believes that a variant of the
apolipoprotein E gene may be one such
thrifty gene. APOE*4, the ancestral
allele of this gene, is present at a high
frequency in Pygmies, Lapps, and
other populations where a foraging
economy still exists. In these
populations, says Corbo, this allele may
still be useful, but in present-day
western populations, because of dietary
changes and longer lifespans, it has
become a risk allele for diseases of old
age such as coronary artery disease and
Alzheimer’s disease. What advantage
APOE*4 gave in the past is not clear
but, says Corbo, in conjunction with
the diet of our ancestors, it may have
increased the number of offspring
produced by a woman by affecting
cholesterol concentrations and hence
steroidogenesis.
Effects on fertility may also underlie
the unusual tolerance to milk of adults
in some northern populations, says
Charles Scriver, emeritus professor of
human genetics at McGill University
(Montreal, Canada). Retention of
post-weaning lactase sufficiency might
have given pastoral nomadic tribes a
breeding advantage, he suggests. “Being
able to drink milk during adulthood
might be advantageous in cold, dark
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FEATURE
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countries where reduced exposure to to include this image in
sunlight could mean that women can’t electronic media.
make enough vitamin D to form a
strong pelvic bone structure to help
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them deliver enough babies to carry on printed journal.
their pedigree”—although this, Scriver
admits, is pure speculation.
Doug Wallace, professor of biological
chemistry and ecology and evolutionary
biology at the University of California
Irvine (CA, USA), is using a battery of
tests to investigate how environmental
selection has shaped global
mitochondrial DNA (mtDNA)
variations. The mtDNA encodes 13
proteins, all of which are required for
the mitochondrial energy production
system, oxidative phosphorylation. The
mitochondrial genome is effectively the
local blueprint for a powerplant that
turns dietary carbohydrates and fats into
ATP—to do work—and heat to
maintain our body temperature.
Wallace discovered some years ago
that different mtDNA lineages are
confined to specific geographical regions
Panos Pictures
and he recently reported that climatic
selection has shaped this pattern (Science
2004; 903: 223–26). The distribution of
calories into heat versus calories into The “thrifty gene” APOE*4 is common
ATP is determined by mitochondrial among Pygmies
oxidative phosphorylation coupling
efficiency—loosely coupled tropical mtDNA variants may have a
mitochondria make more heat, tightly higher risk of developing diabetes and
coupled mitochondria make more degenerative diseases than carriers of the
ATP—and coupling is determined by northern mtDNA variants.
mtDNA variations. So, as human beings For now, identifying mitochondrial or
migrated out of the tropical and nuclear gene variants that have been
subtropical regions of Africa into colder selected during human evolution
Eurasia, says Wallace, they had to remains a difficult task. For example,
allocate more dietary calories to heat says Tishkoff, “it is hard to distinguish
production to survive the colder winters. between the effects of demographic
This selected for mtDNA mutations history and selection because they can
that reduced coupling efficiency and result in almost identical patterns of
ATP production. To compensate for genetic variation”. Approaches such as
this, the migrants had to eat higher comparing real genomes to statistical
calorie diets, and so the northern models in which only neutral selection is
European fat-rich diet was born. allowed should uncover significant
Although these variations in deviations indicative of adaptive
mitochondrial geneotype were selection, but at present, says Goldstein,
appropriate to the conditions that “for most genes, we are only in the
existed when they were selected, the position of being able to say ‘the weight
same is not true today. All the world’s of evidence points towards selection’”.
mitochondrial genotypes are being O’Brien believes that eventually
brought together in cities where ambient hundreds, maybe thousands, of our
temperature is regulated, and people live genes will turn out to have been
sedentary lifestyles but eat high-calorie “sculpted” by historic selection events.
diets. Consequently, people with tightly And finding the genetic signatures of
coupled, “tropical” mitochondria, which those events in our genomes, he
are more energy efficient than loosely concludes, should yield insights that will
coupled mitochondria, are in chronic help us deal not only with ancient
calorie overload, says Wallace. microbial foes but also with the modern
Unfortunately, mitochondria produce afflictions of affluence.
more toxic oxygen radicals when
calories are in excess, so carriers of the Jane Bradbury
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