A series of fortunate events 01/10/05. By Penny Bailey Scientists are analysing genetic differences between humans and chimpanzees to shed light on the evolution of the human brain.

Take the brain, for example. Although our bodies are only about one-fifth larger than chimpanzees, our brains are two to three times heavier. The human cerebral cortex in particular has three or four times more surface area than that of a chimpanzee.

Since the cerebral cortex is responsible for 'higher' mental functions such as language and abstract thought, this dramatic expansion is thought to have sown the seeds for the design and building of cities, aeroplanes and computers, the writing of novels, sitcoms and operas, and other capabilities unique to humans.

But how did this come about? What evolutionary pathways brought us to this point?

Researchers are hoping to find the answer in genetic differences between the two species – by mining human and chimpanzee genome sequence data.

In particular, they are looking for evidence of positive selection: genetic mutations that occurred at a higher rate than other changes in the genome. Such alterations hint at changes that offered a survival advantage to human ancestors. The changes might, for example, have conferred the ability to cope with a volatile environment, or enhanced mobility. Or they might have improved communication and the ability to coordinate social groups. If we are searching for the origins of what makes us human, this is where we need to look.

Size and form

Professors Bruce Lahn at the University of Chicago and Jianzhi Zhang at the University of Michigan recently homed in on a gene that could have played a role in brain expansion: ASPM.^{1 ,2}

While the investigators found little evidence of accelerated change in ASPM in other animals, there were higher rates in the lineages leading to the great apes – and highest of all in those leading from chimpanzees to humans. Excitingly, those lineages coincide with the period during which early human (hominoid) brains expanded dramatically – both in size and in complexity.

ASPM and several other genes could have played a role in the expansion of the cerebral cortex. However, precisely how the protein product regulates the size of the cerebral cortex remains unclear. Moreover, Professor Lahn cautions against trying to find the answer to brain evolution in one gene. "It takes thousands, if not tens of thousands of genes, for the brain to develop properly," he warns.

A larger brain by itself may not be much use, so many researchers believe that reorganisation of the structures and neural pathways inside the human brain were just as important. This seems to have been borne out by the findings of Professor Todd Preuss at Emory University in Georgia, who recently identified 169 genes expressed differently in the human and chimpanzee cortices.³

He found that 90 per cent of these genes were more active in human brains, in striking contrast to the heart and liver, where the numbers more active were about the same as those down-regulated. So some genes may be different in humans, but those that are identical seem to be working harder in us.

The complexity involved in establishing the precise function of a gene in the brain is illustrated by work on FOXP2 – a gene that was discovered by Professor Anthony Monaco and Dr Simon Fisher at the Wellcome Trust Centre for Human Genetics at the University of Oxford.⁴

In humans, mutations in FOXP2 lead to difficulties articulating speech. Since chimpanzees have the gene – but do not speak – researchers hope that pinpointing the functional differences of this gene in the two species could shed light on the evolution of spoken language. This is particularly the case since the human version of FOXP2 underwent positive selection within the past 200 000 years – at a time when humans were beginning to speak.

Dr Fisher suggests that evolution might have recruited a gene that was originally concerned with controlling movement sequences to aid the development of speech and language. "Changes to FOXP2 in recent human history spread rapidly through the population until they were the same in all people, and this process has left a signature or footprint of Darwinian selection in the genome. Now, in modern human populations, the gene shows very little variation."

Subtle influences

The subtlety and complexity of genetic influences in brain evolution were highlighted in two recent studies by Professors Andrew Clark and Rasmus Nielsen – comparing selections of 7645 and 13 731 chimp and human genes respectively.⁵

Surprisingly, they found that genes expressed in the brain showed little or no evidence for positive selection. This suggests that the huge differences between human and chimpanzee brains may be due to minute changes in patterns of gene expression – or that tiny genetic changes in developmental processes could have magnified effects later in life.

Interestingly, though, human enzymes for amino acid breakdown have been under positive selection. The genetic alterations are likely to have occurred when early humans began to eat more meat than chimpanzees. This higher-protein diet would have been necessary before the brain – one of the most metabolically expensive tissues in our body – could increase in size.

In addition, three out of 21 hearing genes tested had undergone positive selection in the human lineage – possibly linked to understanding of spoken language. Oddly, 27 of the 48 human olfactory genes also showed high levels of positive selection, even though smell is not now a sense we rely greatly on.

But hidden for years among all this genetic sophistication, one – highly unlikely – gene may have proved pivotal. Professor Hansell Stedman of the University of Pennsylvania, a surgeon specialising in muscle diseases, came across the MYH16 gene while combing the human genome for genes affecting muscle proteins.

His laboratory discovered that every human from every population he studied was missing two base pairs seen in the MYH16 gene of non-human primates. The long version of MYH16, it turns out, creates the huge jaw muscles seen in primates.⁶ This large muscle has to be attached to extra bone on the top of a chimpanzee's skull to work properly. Anatomical studies suggest that the extra bone interferes with continued cranial expansion at the sutures (growth plates), imposing an evolutionary constraint on brain growth.

The short MYH16 gene gives us less jaw-muscle protein, so we have smaller jaws, but we do not need extra bone on top of our skulls. So our skulls can keep growing. And so can our brains. The researchers estimate that the mutation, which has been aptly named RFT, 'room for thought', appeared 2.4 million years ago – just before our early human ancestors started acquiring smaller jaws and larger skulls.

So RFT may have played a role in enabling the expansion of the modern human brain – as well as helping to highlight the strange combination of circumstances that led to human beings.

References

1 Evans PD et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 2004;13(5):489–94. Abstract ; full text

2 Zhang J. Evolution of the human ASPM gene, a major determinant of brain size. Genetics 2003 Dec;165(4):2063–70. Abstract

3 Cáceres M et al. Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci USA 2003;100(22):13030–5. Abstract ; full text

4 Enard W et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 2002;418(6900):869–72. Abstract

5 Nielsen R et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 2005;3(6):e170. Full text

6 Stedman HH. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 2004;428(6981):415–8. Abstract