Fossils may provide
tantalizing clues to human history, but they also lack some vital information,
such as revealing which pieces of human DNA have been favored by evolution
because they confer beneficial traits — resistance to infection or the ability
to digest milk, for example. These signs can only be revealed through genetic
studies of modern humans and other related species, though the task has proven
Now, in a paper appearing in today’s edition of Science Express, Harvard and Broad Institute researchers
describe a method for pinpointing these preferred regions within the human
genome that offers greater precision and resolution than ever before, and the
possibility of deeply understanding both our genetic past and present.
“It’s clear that positive natural selection has been a critical force in
shaping the human genome, but there are remarkably few examples that have been
clearly identified,” said senior author Pardis Sabeti, an associate member
of the Broad Institute of Harvard and MIT and an assistant professor of in Harvard’s department of organismic and evolutionary biology. “The method
we’ve developed makes it possible to zero in on individual genes as well as the
specific changes within them that are driving important evolutionary
Positive natural selection is a process in which advantageous traits become
more common in a population. That is because these traits boost an individual’s
chances of survival and reproduction, so they are readily passed on to future
generations. Identifying such traits — and the genes underlying them — is a
cornerstone of current efforts to dissect the biological history of the human
species as well as the diseases that threaten human health today.
“In the human genome, positive natural selection leaves behind very
distinctive signals,” said co-first author Sharon Grossman, a research
assistant at Harvard’s FAS Center for Systems Biology and at the Broad Institute. Yet earlier methods
for detecting these signals are limited, highlighting relatively large chunks
of the genome that are hundreds of thousands to millions of genetic letters or
“bases” in length, and that can contain many genes.
Of the hundreds of these large genomic regions thought to be under positive
natural selection in humans, only a handful have so far been winnowed to a
precise genetic change.
“Finding the specific genetic changes that are under selection can be like
looking for a needle in a haystack,” said Grossman.
Sabeti, Grossman, and their colleagues wondered if there might be a way to
enhance this genomic search. Because existing methods for detecting natural
selection individually measure distinct genomic features, the researchers
predicted that an approach that combines them could yield even better results.
After some initial simulations to test their new method, the research team
applied it to more than 180 regions of the human genome that are thought to be
under recent positive selection, yet, in most cases, the specific gene or
genetic variant under selection is unknown.
The researchers’ method, called “Composite of Multiple Signals” or
CMS, enabled them to dramatically narrow the size of the candidate regions,
reducing them from an average of eight genes per region to one. Moreover the
number of candidate genetic changes was reduced from thousands to just a handful,
helping the researchers to tease out the needles from the haystack.
“The list of genes and genetic loci we identified includes many intriguing
candidates to follow up,” said co-first author Ilya Shlyakhter, a
computational biologist in Harvard’s department of organismic and evolutionary biology and at the Broad Institute.
“For example, a number of genes identified are involved in metabolism,
skin pigmentation, and the immune system.”
In some cases, the researchers were able to identify a specific genetic change
that is the likely focal point of natural selection. For example, a variation
in a gene called protocadherin 15, which functions in sensory perception,
including hearing and vision, appears to be under selection in some East Asian
populations. Several other genes involved in sensory perception also appear to
be under selection in Asia. In addition, the team uncovered strong evidence of
selection in East Asians at a specific point within the leptin receptor gene,
which is linked to blood pressure, body mass index, and other important metabolic
The researchers also localized signals to regions outside of genes, suggesting
that they function not by altering gene structure per se, but by changing how certain genes are turned on and off.
While the findings in the Science paper offer a deep glimpse of evolution’s
handiwork, the researchers emphasize that further studies of individual genetic
variations, involving experiments that explore how certain genetic changes
influence biological function, are necessary to fully dissect the role of
natural selection and its impact on human biology.
“This method allows us to trace evolution’s footprints with a much finer
level of granularity than before, but it’s one piece of a much larger
puzzle,” said Sabeti. “As more data on human genetic variation
becomes available in the coming years, an even more detailed evolutionary
picture should emerge.”