The first animal model of recent human evolution reveals that a single
mutation produced several traits common in East Asian peoples, from
thicker hair to denser sweat glands, an international team of
researchers reports
The team, led by researchers from Harvard Medical School, Harvard
University, the Broad Institute of MIT and Harvard, Massachusetts
General Hospital, Fudan University and University College London, also
modeled the spread of the gene mutation across Asia and North America,
concluding that it most likely arose about 30,000 years ago in what is
today central China. The findings are reported in the cover story of the
Feb. 14 issue of Cell.
"This interdisciplinary approach yields unique insight into the
generation of adaptive variation among modern humans," said Pardis
Sabeti, associate professor in the Center for Systems Biology and
Department of Organismic and Evolutionary Biology at Harvard University,
and one of the paper's senior authors.
"This paper tells a story about human evolution in three parts," said
Cliff Tabin, head of the HMS Department of Genetics and co-senior
author. "The mouse model links multiple traits to a single mutation, the
related association study finds these traits in humans, and computer
models tell us where and when the mutation likely arose and spread."
Previous research in Sabeti's lab had identified the mutation as a
strong candidate for positive selection. That is, evidence within the
genetic code suggested the mutant gene conferred an evolutionary
advantage, though what advantage was unclear.
The mutation was found in a gene for ectodysplasin receptor, or EDAR,
part of a signaling pathway known to play a key role in the development
of hair, sweat glands and other skin features. While human populations
in Africa and Europe had one, ancestral, version of the gene, most East
Asians had a derived variant, EDARV370A, which studies had linked to
thicker scalp hair and an altered tooth shape in humans.
The ectodysplasin pathway is highly conserved across vertebrates --
the same genes do the same thing in humans and mice and zebrafish. For
that reason, and because its effects on skin, hair and scales can be
observed directly, it is widely studied.
This evolutionary conservation led Yana Kamberov, one of two first
authors on the paper, to reason that EDARV370A would exert similar
biological effects in an animal model as in humans. The HMS research
fellow in genetics developed a mouse model with the exact mutation of
EDARV370A -- a difference of one DNA letter from the original, or
wild-type, population. That mouse manifested thicker hair, more densely
branched mammary glands and an increased number of eccrine, or sweat,
glands.
"This not only directly pointed us to the subset of organs and
tissues that were sensitive to the mutation, but also gave us the key
biological evidence that EDARV370A could have been acted on by natural
selection," Kamberov said.
The findings prompted the team to look for similar traits in human
populations. When co-first author Sijia Wang and the team including
collaborators at Fudan examined the fingertips of Chinese volunteers at
colleges and farming villages, they found that the sweat glands of Han
Chinese, who carry the derived variant of the gene, were packed about 15
percent more densely than those of a control population with the
ancestral variant.
At the same time, Wang and the team including collaborators at
University College London were working to zero in on when and where the
mutation arose. Computer models suggested that the derived variant of
the gene emerged in central China between 13,175 and 39,575 years ago,
with a median estimate of 30,925 years. Researchers concluded the
derived variant is at least 15,000 years old, predating the migration
from Asia by Native Americans, who also carry the mutation.
That time span suggests that different traits could have been under
selection at different times. The mutation's many effects, known as
pleiotropy, only complicate the question. If changes to the sweat glands
conferred an advantage in new climates -- one of the theories the
researchers plan to explore further -- changes to hair and to mammary
glands could have conferred other advantages at other times.
Not all of these advantages need be direct effects on fitness. "When
Pardis started this work, I would not have predicted that a gene that
makes good hair would top of a list of mutations that confer
evolutionary advantage among humans," said Bruce Morgan, HMS associate
professor of dermatology at Massachusetts General Hospital and co-senior
author on the paper. "However, in this case 'good hair' may have a
biological meaning because it is genetically linked to a physiologically
adaptive trait like increased sweating capacity. A cultural preference
for a physically obvious trait like hair type could have arisen because
individuals with it were more successful, and this would help increase
selection on the new variant."
"That (pleiotropy) makes it harder for us to make a guess," Wang
said. "If there were only one associated trait, we could say with
confidence that's where the selective advantage comes from. But with
many traits, we don't know which is the target of selection, and which
are just hitchhiking." Wang intends to focus on that question in his new
role, as a Max Planck independent research group leader in
dermatogenomics at Chinese Academy of Sciences -- Max Planck Partner
Institute for Computational Biology in Shanghai.
By leveraging the power of diverse fields, the team is piecing
together the foundation for understanding how selected mutations like
EDARV370A have impacted human diversity. But, they say, this is only the
beginning.
"These findings point to what mutations, when, where and how," said
Daniel Lieberman, a professor of human evolutionary biology at Harvard
University and a co-senior author on the study. "We still want to know
why."
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