Clues to the evolution of humans' large brain 8/3/04. By John Pickrell A birth defect gene may be key to the evolution of the large brain of humans.

The human brain may have tripled in size over the last 2.5 million years. Despite having bodies only around one-fifth larger than chimpanzees, our brains are around 250 per cent heavier. This dramatic expansion, during our evolution, is thought to have paved the way for language, higher thought and other unique aspects of human mental capacity.

Now, for the first time, researchers - working independently in two US universities - have uncovered a gene that may have contributed in the evolution of the human brain. That gene, ASPM, was linked in 2001 to a disease called microcephaly, which can cause a 70 per cent reduction in the size of the human brain, and associated mental retardation.

"People have studied the evolution of the brain for a long time, but they have traditionally focused on comparative anatomy and physiology," said Bruce Lahn, a Howard Hughes Medical Institute geneticist at the University of Chicago in Illinois. "There really hasn't been any convincing evidence until now, of any gene whose changes might have contributed to the evolution of the brain."

Lahn and his team in Chicago, and evolutionary biologist Jianzhi Zhang at the University of Michigan in Ann Arbor, independently hit upon the idea that ASPM might have played a role in brain expansion, after a study linked the gene to microcephaly in 2001.

By comparing human ASPM with a version of that gene in animals, both investigators have shown rapid changes in the primate lineage leading to humans. Differences in ASPM between apes and humans might therefore explain the relative growth of the cerebral cortex - seat of reasoning and higher thought.

Scientists completed the draft version of the chimpanzee genome last December, providing more of the kind of raw data that makes these comparative studies possible.

Loss of function of abnormal spindle-like microcephaly associated gene (ASPM), to give it its full name, is linked to the brain-shrinking birth defect which crops in somewhere between four to 40 per million live births in Western nations. The genetic defect causes a massive reduction in the cerebral cortex, creating a brain similarly sized to that of our 2.3 to 3 million-year-old ancestor Australopithecus afarensis, of which the fossil known as Lucy is the most famous example. Lucy may have had a brain less than 450 grams; today, normal human brains weigh 1350 to 1450 grams.

To test the idea that changes in ASPM led to increased brain size, Lahn's team and Zhang both set out to look for signatures of accelerated evolution, by comparing it to versions of ASPM in other animals.

Lahn, co-authors Patrick Evans, Jeffrey Anderson and colleagues compared the DNA sequence of ASPM with six other apes and monkeys, each sequentially more primitive in the primate family tree: chimp, gorilla, orangutan, gibbon, macaque and owl monkey. The findings were published online in January 2004 in the journal Human Molecular Genetics.

Zhang, who details his study in the December 2003 issue of the journal Genetics, chose to look at ASPM's sequence in most of these monkeys. Both he and Lahn also compared the gene to that in many other animals, including pigs, whales, dogs, hamsters, bears and others.

The researchers looked for 'positive selection' as evidence those alterations in ASPM were often advantageous to human ancestors.

Positive selection is when changes to the DNA sequence of a gene are frequently also translated into changes in the amino acid sequence of the protein that gene codes for (as opposed to changes that make no difference to the protein). If natural selection does not favour changes to the gene, fewer will find their way into the protein product.

Both Zhang and Lahn's team found evidence that changes in human ASPM had been sped up by natural selection. There was also some less-pronounced evidence of accelerated sequence evolution in great apes. There was little evidence of accelerated change in that gene of other animals tested.

According to Lahn's team, the highest rates of positive selection were seen in those lineages which led to great apes and then directly to humans from the last common ancestor with chimpanzees. "These are periods when hominoid brains underwent dramatic expansion in size, as well as growth in structural and functional complexity," the researchers wrote.

However, ASPM's beneficial effect on brain size may have reached a limit, says Zhang. The fossil record suggest that the main period of expansion started 2 to 2.5 million years ago and ended around 200 000 to 400 000 years ago. "The episode of rapid evolution in ASPM had ended by 100 000 years ago, and the gene is currently stabilised in modern humans," said Zhang.

"Big brains are related to strong social bonds, high levels of intelligence, intense parenting, long periods of learning, and ability to deal with volatile environments," added Zhang. "Exactly which one was the initial force driving the human brain expansion is unknown. In comparison to the great apes, early hominids lived in more open and dry areas, which made it difficult to escape from predators and find water. Thus, the brain size expansion may be related to the ability to cope with volatile environments, as some people believe. But, there is no definite answer yet."

Now we should look for genes that might explain the shape of the human brain, not just its large size, commented neurologist Christopher Walsh at Harvard Medical School in Boston. Walsh was part of the team that, led by Dr Geoff Woods at the University of Leeds, linked the ASPM gene to microcephaly in 2002. "Primates have very big frontal lobes, necessary for social interactions, language, and cognition… genes were probably also subject to evolutionary selection to regulate the shape of the brain," he said.

"Neanderthal man had a brain that was about the same size … but was shaped differently – more upright, and less football-shaped," said Walsh. "A genetic change may explain that difference, and ultimately we may discover a family of genes responsible for regulating different aspects of human brain structure."

Image credit: Matthew Herring

Further reading

Bond J, et al. (2002) ASPM is a major determinant of cerebral cortex size. Nature Genetics 32: 316-320.

Zhang J (2003) Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165: 2063-70. Abstract

Evans et al (2004) Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13: 489-494. Abstract