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GENE LINKED TO GROWTH OFHUMAN CEREBRAL CORTEX
NATURAL SELECTION ACCELERATED OTHER CHANGES, GENOME STUDIES FIND

Geneticists believe they have identified a gene that played a key role in the adaptive development of the relatively massive size of the human cerebral cortex after humans left the forest canopy some five million years ago.

Using a gene associated with microcephaly as a marker, Howard Hughes Medical Institute (HHMI) scientists were able to puzzle out the genetic conditions that led to the enhanced cerebral development of Homo sapiens as human and chimp parted ways on the evolutionary ladder. Further, the differences seem to be have been pressure-driven by “positive” Darwinian selection.

“This is the only example to my knowledge where a gene is linked to the evolutionary enlargement of the human brain,” said lead author Bruce T. Lahn, PhD, Assistant Professor of Human Genetics at the University of Chicago. “Other genes might have been linked to brain evolution but none is supported by such strong evidence, and none of the previous examples specifically address enlargement of the brain.”

Dr. Lahn and his co-authors examined the genetic sequences of humans, non-human primates, and other animals, looking for similarities and differences in areas responsible for the development of the cerebral cortex, the seat of higher learning, judgment, and other advanced behavior. The findings were published in a January 13th Advance Access article from the journal Human Molecular Genetics.

ASPM GENE

The scientists focused on the abnormal spindle-like microcephaly-associated (ASPM) gene, mutations of which lead to formation of truncated proteins responsible for mitotic activity in neuronal embryonic stem cells. The truncated proteins are unstable and the result is autosomal recessive primary microcephaly, a birth defect characterized by grossly small brain and small head size.

A comparison of the gene's developmental architecture – between humans and other non-human primates – reinforced the view that the cerebral cortex of humans and chimpanzees shared a common lineage. But at some unknown point our genes gradually took separate paths and positive natural selection reinforced developments that led to our larger brains, Dr. Lahn said.

The ASPM gene encodes for IQ domains, 20 amino-acid repeats beginning with isoleucine and glutamate, Dr. Lahn explained. Microcephalic individuals express a shorter version of the gene, and therefore have fewer cerebral neurons and a significantly smaller cerebral cortex. By statistically comparing changes in protein expression and the development of neurons and cerebral cortex growth in microcephalic children, normal humans, chimpanzees, other mammals, the researchers were able to measure the degree of species separation and profile the relative genetic effects of these differences.

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Dr. Bruce T. Lahn: “Evolutionary changes in the ASPM gene in the human lineage might have altered the dynamics of neurogenesis, and perhaps such alterations would allow more neurons to be produced, but this is just a hypothesis.”

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Dr. Christopher Walsh: “We are not sure that ASPM is directly responsible for the larger cerebral cortex as the Lahn study found. Its likely, but it has yet to be definitely concluded.”

“Evolutionary changes in the ASPM gene in the human lineage might have altered the dynamics of neurogenesis,” Dr. Lahn said, “and perhaps such alterations would allow more neurons to be produced, but this is just a hypothesis.”

The paradox is that ASPM is an ancient gene. In a paper published in December in Genetics, Jianzsi Zhang, PhD, a researcher at the University of Michigan in Ann Arbor, noted that the human brain tripled in size over a period of about two million years, and that the ASPM gene is believed important to the emergence of language and other higher order intellectual traits in humans (2003;165(4):2063–2070).

Dr. Zhang, an evolutionary biologist, presented evidence that ASPM went through a period of accelerated sequence evolution after humans and chimpanzees separated, but before the separation of modern non-Africans from Africa.

“Because positive selection acts on a gene only when the gene function is altered and the fitness of the organism increases, my results suggest that adaptive functional modifications occurred in human ASPM and that it may be a major genetic component underlying the evolution of the human brain,” he concluded.

Dr. Lahn said he and his colleagues would next try to determine exactly how evolutionary changes in the biological functions of ASPM might lead to specific developmental differences of the brain.

OLFACTORY, AUDITORY DIFFERENCES

The finding came just one month after Cornell University investigators published evidence suggesting that humans and chimpanzees developed similar yet different olfactory and auditory sense perception, as well differences in the ability to metabolize certain foods. These differences were also driven by positive natural selection, the evidence indicates.

In a review of chimpanzee and human genomes to date, a team led by Andrew G. Clark, PhD, Professor of Molecular Biology and Genetics at Cornell University School of Health Sciences in Ithaca, NY, discovered two major differences in how humans and chimpanzees detect and process olfactory information and how they digest foods (Science 2003;302(5652):1960–1963).

With the help of researchers at Celera Genomics in Rockville, MD, more than 7,500 gene sequences from humans, chimpanzees, and mice were linked out of almost 23,000 genes they share in common.

“Hundreds of genes showed a pattern of sequence change consistent with adaptive evolution in human ancestors,” Dr. Clark said in a telephone interview. “Those genes are involved in the sense of smell, in digestion, in long-bone growth, in hairiness, and in hearing.”

According to Dr. Clark, all mammals have many olfactory receptors, but chimpanzee and human genes have evolved receptors unique in the ability to recognize smells, even subtle ones, that are important in finding food and mates.

Commenting on the Clark paper, Dr. Lahn said there is no exact explanation for the evolutionary differences in chimpanzees and humans for adaptive olfactory and auditory senses.

“If we assume that genes underlying auditory and olfactory senses and food metabolism have indeed evolved [differently] in humans, then there are two interpretations,” he said. “One is that these genes have become less functional.” The other is that these genes were subject to adaptive evolution.

“At this point, it is not possible to gauge which one is true,” Dr. Lahn continued. “In the case of olfactory genes, there is ample evidence that these genes have become less functional in humans because we rely less on the sense of smell than did our ancestors.”

Much of the work involving the ASPM gene was conducted in 2002 by HHMI investigator and Harvard University Neurology Professor Christopher Walsh, MD, PhD, at Harvard/Beth Israel Deaconess Medical Center in Boston, MA. Commenting on the Lahn study, Dr. Walsh said further research is likely to reveal additional gene involvement.

“We are not sure that ASPM is directly responsible for the larger cerebral cortex as the Lahn study found. It's likely, but it has yet to be definitely concluded,” said Dr. Walsh, who first reported an association between ASPM and brain size.

ARTICLE IN BRIEF

  • ✓ Geneticists believe they have identified a gene – abnormal spindle-like microcephaly-associated gene (ASPM) – that played a key role in the adaptive development of the relatively massive size of the human cerebral cortex after humans left the forest canopy some five million years ago.
  • ✓ In another study, investigators published evidence suggesting that humans and chimpanzees developed similar yet different olfactory and auditory sense perception, as well differences in the ability to metabolize certain foods.

THE ASSOCIATION BETWEEN BRAIN SIZE AND ASPM

In 2002, Christopher Walsh, MD, PhD, of Harvard, along with colleagues Geoffrey Woods, PhD, and Jacquelyn Bond, PhD, of St. James University Hospital in Leeds, England, reported on mutations of the ASPM gene in a group of children with autosomal recessive primary microcephaly (Nat Genet 2002;32(2):316–320).

Using DNA sequencing, the scientists found the children expressed shortened versions of the ASPM gene and he and his colleagues concluded the gene to be “a major determinant of cerebral cortex size.”

Earlier research by Dr. Walsh and others in mice and fruit flies, as well as other animals, suggested versions of the abnormal-spindle microcephaly gene played a key role in brain development.

“We had observed similarities between mice and human [ASPM] genes but we lacked the statistical tools for sequencing ASPM in primate species. These genes are relatively close together and, paradoxically, that makes them easier to see,” said Dr. Walsh.

At that time he and his colleagues in the US and abroad reported that two genes appear to influence brain growth, one in mice (beta-catenin) and the other in microcephalic humans (ASPM). The protein produced by ASPM might regulate the number of neurons produced by cell division in the cerebral cortex, but it was unclear if genetically engineering either beta-catenin or ASPM to overexpress protein would result in larger human brains.

Mutations in many metabolic genes can cause microcephaly, often by the brain being put together properly, but then falling apart again because the cells cannot keep up with their metabolic requirements, he said, citing Tay-Sachs disease and Rett syndrome as examples.

“ASPM represents a kind of fixed, developmental microcephaly, where cells seem to function fine, but are just deficient in number, hence the interest in them as developmental genes. Even among these, some of these genes are going to be essential without necessarily being evolutionarily important. ASPM is probably just the first of many such genes,” he said.

Dr. Walsh and his colleagues have discovered a gene in mice that shows similar evolutionary selection in frontal lobe development. Results are under review and will be published later this year, he noted, adding that his team has just begun analysis in primates.