September 09, 2005
Human Brain Is Still Evolving
Howard Hughes Medical Institute researchers who have analyzed
sequence variations in two genes that regulate brain size in human
populations have found evidence that the human brain is still
evolving.
They speculate that if the human species continues to survive, the
human brain may continue to evolve, driven by the pressures of natural
selection. Their data suggest that major variants in these genes arose
at roughly the same times as the origin of culture in human populations
as well as the advent of agriculture and written language.
“We want to know how broad a trend these two genes represent. Did we get really lucky and hit on two rare examples of such genes? Or, are they representative of many other such genes throughout the genome?”
Bruce T. Lahn
The research team, which was led by Bruce T. Lahn, a Howard Hughes
Medical Institute investigator at the University of Chicago, published
its findings in two articles in the September 9, 2005, issue of the
journal Science.
Their analyses focused on detecting sequence changes in two genes -
Microcephalin and “abnormal spindle-like microcephaly
associated” (ASPM) - across different human populations.
In humans, mutations in either of these genes can render the gene
nonfunctional and cause microcephaly - a clinical syndrome in which the
brain develops to a much smaller size than normal.
In earlier studies of non-human primates and humans, Lahn and his
colleagues determined that both Microcephalin and ASPM
showed significant changes under the pressure of natural selection
during the making of the human species. “Our earlier studies
showed that Microcephalin showed evidence of accelerated
evolution along the entire primate lineage leading to humans, for the
entire thirty to thirty-five million years that we sampled,” he
said. “However, it seemed to have evolved slightly slower later
on. By contrast, ASPM has evolved most rapidly in the last six
million years of hominid evolution, after the divergence of humans and
chimpanzees.”
In order to identify sequence changes that occurred in
Microcephalin and ASPM in the evolutionary lineage
leading to humans, Lahn and his colleagues took the following approach:
They determined the DNA sequences of the two genes among a large number
of primate species and searched for sequence differences between humans
and nonhuman primates. By doing statistical analysis on these sequence
differences, they could demonstrate that the differences were due to
natural selection that drove significant sequence changes in the
lineage leading to humans. These changes accumulated presumably because
they conferred some competitive advantage.
The evidence that Microcephalin and ASPM were evolving
under strong natural selection in the lineage leading to humans led
Lahn and his colleagues to consider exploring whether these two genes
are still evolving under selection in modern human populations.
“In the earlier studies, we looked at differences that had
already been set in the human genome,” he said. “The next
logical question was to ask whether the same process is still going on
today, given that these genes have been under such strong selective
pressure, leading to the accumulation of advantageous changes in the
human lineage. If that is the case, we reasoned we might be able to see
variants within the human population that are rising in frequency due
to positive selection, but haven't gone to completion yet.”
The researchers first sequenced the two genes in an ethnically
diverse selection of about 90 individuals. The researchers also
sequenced the genes in the chimpanzee, to determine the
“ancestral” state of polymorphisms in the genes and to
assess the extent of human-chimpanzee divergence.
In each gene, the researchers found distinctive sets of
polymorphisms, which are sequence differences between different
individuals. Blocks of linked polymorphisms are called haplotypes,
whereby each haplotype is, in essence, a distinct genetic variant of
the gene. They found that they could further break the haplotypes down
into related variants called haplogroups. Their analysis indicated that
for each of the two genes, one haplogroup occurs at a frequency far
higher than that expected by chance, indicating that natural selection
has driven up the frequency of the haplogroup. They referred to the
high-frequency haplogroup as haplogroup D.
When the researchers compared the ethnic groups in their sample for
haplogroup D of ASPM, they found that it occurs more frequently
in European and related populations, including Iberians, Basques,
Russians, North Africans, Middle Easterners and South Asians. That
haplogroup was found at a lower incidence in East Asians, sub-Saharan
Africans and New World Indians. For Microcephalin, the
researchers found that haplogroup D is more abundant in populations
outside of Africa than in populations from sub-Saharan Africa.
To produce more informative statistical data on the frequency of
haplotype D among population groups, the researchers applied their
methods to a larger population sample of more than one thousand people.
That analysis also showed the same distribution of haplogroups.
Their statistical analysis indicated that the Microcephalin
haplogroup D appeared about 37,000 years ago, and the ASPM
haplogroup D appeared about 5,800 years ago - both well after the
emergence of modern humans about 200,000 years ago. “In the case
of Microcephalin, the origin of the new variant coincides with
the emergence of culturally modern humans,” said Lahn. “And
the ASPM new variant originated at a time that coincides with
the spread of agriculture, settled cities, and the first record of
written language. So, a major question is whether the coincidence
between the genetic evolution that we see and the cultural evolution of
humans was causative, or did they synergize with each other?”
Lahn said that the geographic origin and circumstances surrounding
the spread of the haplogroups can only be surmised at this point.
“One can make guesses, but our study doesn't reveal how these
positively selected variants arrived," he said. "They may have arisen
in Europe or the Middle East and spread more readily east and west due
to human migrations, as opposed to south to Africa because of
geographic barriers. Or, they could have arisen in Africa, and
increased in frequency once early humans migrated out of
Africa.”
While the roles of Microcephalin and ASPM in
regulating brain size suggest that the selective pressure on the new
variants may relate to cognition, Lahn emphasized that this possibility
remains speculative. “What we can say is that our findings
provide evidence that the human brain, the most important organ that
distinguishes our species, is evolutionarily plastic,” he said.
Finding evidence of selection in two such genes is mutually
reinforcing, he pointed out. “Finding this effect in one gene
could be anecdotal, but finding it in two genes would make it a trend.
Here we have two microcephaly genes that show evidence of selection in
the evolutionary history of the human species and that also show
evidence of ongoing selection in humans.”
Lahn emphasized that it would not be correct to interpret the
findings as indicating that one ethnic group is more
“evolved” than another. Any differences among groups would
be minor compared to the large differences in such traits as
intelligence within those groups, he said. “We're talking about
the average impact of such variants,” he said. “We still
have to treat each individual as an individual. Just because you have
one gene that makes you more likely to be a little taller, doesn't mean
you will be tall, given the complex effect of all your other genes and
of environment.” Lahn also said that a multitude of other genes
likely exist that influence brain size and development, and further
research could reveal far more complex effects of natural selection on
such genes.
Lahn speculated that the new findings suggest that the human brain
will continue to evolve under the pressure of natural selection.
“Our studies indicate that the trend that is the defining
characteristic of human evolution - the growth of brain size and
complexity - is likely still going on. If our species survives for
another million years or so, I would imagine that the brain by then
would show significant structural differences from the human brain of
today.”
For both Microcephalin and ASPM, Lahn and his
colleagues are trying to find out the precise traits that are under
natural selection. They are also performing more detailed studies of
the two genes in human populations to better understand their
evolutionary history. And they are searching for other brain-related
genes that have changed under the pressure of natural selection.
“We want to know how broad a trend these two genes
represent,” said Lahn. “Did we get really lucky and hit on
two rare examples of such genes? Or, are they representative of many
other such genes throughout the genome. I would bet, though, that we
will find evidence of selection in a lot more genes.”
Lahn and his colleagues are now working to understand how subtle
changes in the sequences of these two genes can alter their function in
such a way that would result in favorable selection. While there is
some evidence from earlier studies that Microcephalin and
ASPM code for proteins that regulate the proliferation of brain
cells from immature neural stem cells, their function has not yet been
determined, said Lahn.
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Cindy Fox Aisen
