New York Times - January 14, 2004

Evolution of Gene Related to Brain's Growth Is Detailed


A gene that helps determine the size of the human brain has been under intense Darwinian pressure in the last few million years, changing its structure 15 times since humans and chimps separated from their common ancestor, biologists have found.

The gene came to light two years ago, when a disrupted form of it was identified as the cause of microcephaly, a disease in which people are born with an abnormally small cerebral cortex.

Dr. Bruce T. Lahn and fellow geneticists at the University of Chicago have decoded the DNA sequence of the gene in apes, monkeys and people and have identified the changes caused by the pressure exerted by natural selection. Most of the other changes in DNA units generally make no difference to the protein specified by the gene, and evolutionary forces are neutral to them.

The gene, known as the ASPM gene, has been under steady selective pressure throughout the evolution of the great apes, a group that includes orangutans, gorillas, chimpanzees and humans, Dr. Lahn and colleagues say in an article being published today in the journal Human Molecular Genetics. By contrast, the versions of the gene possessed by monkeys, dogs, cats and cows show no particular sign of being under selective pressure.

The progressive change in the architecture of the ASPM protein over the last 18 million years is correlated with a steady increase in the size of the cerebral cortex, the part of the brain responsible for higher cognitive function, during the ape and human lineage. Evolution has been particularly intense in the five million years since humans split from chimpanzees.

"There has been a sweep every 300,000 to 400,000 years, with the last sweep occurring between 200,000 and 500,000 years ago," Dr. Lahn said, referring to a genetic change so advantageous that it sweeps through a population, endowing everyone with the same improved version of a gene.

But since the last sweep, the gene seems to have been kept stable by what geneticists call purifying selection, the removal of any change that makes a significant difference to the gene's protein product, according to an independent study by Dr. Jianzhi Zhang, an evolutionary biologist at the University of Michigan. Dr. Zhang's report was published last month in the journal Genetics.

Early hominids like Australopithecus africanus, which lived some three million years ago, had a brain that weighed about 420 grams (15 ounces); modern human brains range from 1,350 to 1,450 grams, an increase that Dr. Zhang calls "one of the most rapid morphological changes in evolution." The brain of a typical patient with microcephaly is the same weight as that of an australopithecus, Dr. Zhang noted, as if disruption of the gene negated three million years of development.

Disruption of the ASPM gene was identified as a cause of microcephaly two years ago by Dr. Geoffrey Woods, a British pediatrician, and Dr. Christopher Walsh, a neurogeneticist at the Harvard Medical School. Their finding instantly caught the interest of evolutionary geneticists.

At least five other genes, yet to be identified, can cause microcephaly when disrupted by a mutation, so ASPM is not the only determinant of human brain size. But given what is now known about its evolutionary history, it does seem to be an important one. It acts during fetal development to prescribe the number of cells in the future cerebral cortex.

Most human genes exist as families of similar members, formed when one gene gets accidentally duplicated one or several times. The ASPM gene is "almost unique," Dr. Walsh wrote by e-mail, because in all known animal genomes, it has resisted the usual duplication events and been maintained as a single copy. Single-copy genes can cause serious disease if disrupted by mutation. But their advantage, in terms of evolution, is that "you only have to edit them once to create a lasting change," Dr. Walsh said.

Evidently, the ASPM gene has been heavily edited, but with an apparently fortunate result.

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