Genetic breakthroughs are allowing us to understand the development of the human brain, say Bruce Lahn and Nitzan Mekel-Bobrov, and also show that we are still evolving

What are the essential features that unite us as a species yet set us apart from the countless other species? This question has captivated human curiosity for millennia and is one of the most enduring preoccupations of scientists, philosophers and the general public.

Anthropologists distinguish humans from other animals by a number of traits. Erect posture, developed vocal organs and bipedal locomotion are all important features of the human form, but none compares to our extraordinarily large and complex brain. It is this trait that forms the basis of our uniquely-advanced cognitive abilities, without which none of the many cultural achievements of humans would have been possible, including language, technology and art.

Traditionally, scientists have studied the evolution of the human brain by comparing the neuroanatomy and behaviour of humans with other living primates, and by examining cranial fossils of extinct hominid species to identify the intermediate steps leading to the current brain morphology (form and structure) of modern humans. Rapid advancements in molecular biology over recent decades, however, are revolutionizing the study of human brain evolution, allowing us, for the first time, to tease out the specific genes that have been acted upon by natural selection to produce the modern human brain.

Natural selection can drive a variety of changes in brain-related genes. These changes can be generally classified into two categories. One category is changes in gene products, that is, changes in the DNA sequences of genes that alter the chemical composition of the proteins they encode. The other category is changes in gene expression, that is, changes that alter the quantity (but not the chemical composition) of the proteins produced by these genes. Recent studies have made important progress in identifying both types of changes that might be relevant to the evolution of the human brain.

Changes in genes that alter the proteins they encode are likely an important aspect of many evolutionary adaptations. But these changes are not easy for natural selection to accomplish because mutations that alter the chemical composition of proteins are often harmful, or lethal, to the organism. Only rarely are they beneficial, but when they are, these mutations, which first emerge in a single individual, are driven by selection to spread in the population and eventually take over the species. This is known as positive selection. Studies have shown that if a gene shows an unusually high number of DNA sequence changes that alter their protein products, such changes are likely driven by positive selection (the gene has been evolving adaptively).

This logic has been applied to studies of brain-related genes, in both large-scale surveys of many genes and in detailed analyses of individual genes. In one study, our lab compared a large set of brain-related genes across several primate and nonprimate species. It showed that brain-related genes have accumulated a large number of beneficial changes in primates, especially in the lineage leading to humans. This provides a molecular underpinning for the dramatic morphological and functional changes in the brain during the evolution of our species. With the recent completion of the chimpanzee genome, other labs further corroborated this finding. Although brain-related genes as a whole show limited difference between chimpanzees and humans, many of the changes appear to be driven by positive selection.

Big brains

The most striking feature of the modern human brain is its exceptional size. Fossil studies show a rapid expansion in cranial size beginning around 2 million years ago, culminating in the large brain of Homo sapiens – almost four times larger than that of chimpanzees. What genes underlie the evolutionary expansion? Tentative answers to this question are emerging from recent studies of two genes, ASPM and microcephalin. Mutations in these cause a developmental disorder of the brain known as primary microcephaly, whose key feature is a severe reduction in brain size (by three to four-fold). It was concluded that ASPM and microcephalin are intimately involved in the regulation of brain size during development.
Comparisons of ASPM and microcephalin sequences among humans and numerous other species have shown a strong signature of adaptive evolution in primates generally, and in the lineage leading to humans in particular. Our recent analysis of the pattern of DNA variation within humans in these two genes uncovered evidence of continuing adaptive evolution in modern humans. We found that in both genes, a sequence variant that first emerged in a single copy during the recent history of our species has since spread to very high frequencies worldwide due to positive selection.

Coupled with what is known about the developmental functions of ASPM and microcephalin, these studies strongly suggest that these two genes may be key players in the evolution of the human brain and may have significantly contributed to its remarkable expansion.

The increased size of the human brain and the increased complexity it affords have generated a plethora of complicated behavioural attributes, which we associate with what it means to be human. Perhaps the most important is our unique linguistic ability. Consequently, there is great interest in identifying the genes that have contributed to the evolution of human language.
Pathological mutations in the FOXP2 gene cause a severe disorder in vocal articulation in humans, strongly suggesting a role of the gene in speech production. Evolutionary studies of FOXP2 have uncovered DNA changes that altered the composition of its protein product between humans and nonhuman primates. The nature of these changes suggests they may have been driven by positive selection, thus implicating FOXP2 as potentially playing a role.

Changes in gene expression

Natural selection can also produce changes in genes that alter gene expression. Recent advances in genomics, especially the introduction of microarray technology, allow for rapid, quantitative characterization of the expression of thousands of genes simultaneously. Consequently, evolutionary studies are now able to carry out large-scale, interspecies comparisons of gene expression in tissue types, including the brain, to identify genes whose changes in expression may be relevant to the evolution of a species.

An early study compared gene expression in blood, brain and liver cells of humans and several nonhuman primates, and found that brain-related genes showed the greatest change in expression during human evolution. This analysis was repeated in three mouse species and was shown to be a specific feature of human evolution, rather than of mammals. More recently, a study characterized the changes in brain-related gene dosage and showed most changes in humans involve a significant increase in gene expression.
A recent study focused on a gene called prodynorphin, which encodes an opioid hormone (a natural opiate produced by the brain) known to be involved in the regulation of perception and behaviour. It found that the expression of prodynorphin in humans is increased relative to nonhuman primates, and this increase is likely driven by positive selection. This gene thus represents an example where changes in the expression of a brain-related gene may have contributed to the evolution of human brain function.

Genetic studies of human brain evolution are providing details on the molecular changes shaping our evolutionary history and shedding light on the evolution of human cognition.

Despite decades of research into human evolutionary history, and a widespread adoption of a Darwinian concept of human origins, there is still a pervasive assumption among many people that the evolution of the human brain and the cognitive abilities it underlies are qualitatively different from those of other species, and so not subject to the same evolutionary processes.

This assumption plays out in both our concept of where we come from as a species, and our notion of where we are going. Thus, the human brain is thought of as a qualitative break from other primates, rather than an extension of the processes that had been under way for millions of years before the emergence of our species, and its present state is held to be the end-point in a long progression towards the pinnacle of cognitive development, rather than a snapshot of a continuing process.

Evolution of brain function

It is not surprising that we maintain an anachronistic attachment to a pre-Darwinian notion of the mind, given how deeply it is entrenched in western thinking, from the Judaeo-Christian dichotomy between body and soul, and the creation of man above all other species, to the mind-body duality of Cartesian philosophy. But just as the revelation that we share close to 99% of our DNA sequence with chimpanzees underscored how unexceptional we are after all, molecular studies of human brain evolution now show the same trend, but regarding the evolution of human cognition.

Thus, both large-scale surveys of evolutionary changes in human brain-related genes, and single-gene studies of individual genes such as ASPM, microcephalin, FOXP2 and prodynorphin, have found that the pattern of human adaptive evolution is generally a subset of a larger trend found throughout primates. Our recent studies of genetic variation in ASPM and microcephalin within humans provide the first empirical demonstration that the human brain may still be undergoing adaptive evolution, which underscores the continuous nature of human cognitive evolution. These discoveries strike at the core of what it means to be human, and demand a re-evaluation of our assumptions about how we relate to other species, and where our own species is headed.

CV Bruce Lahn and Nitzan Mekel-Bobrov

Bruce Lahn (above) is assistant professor of human genetics at the University of Chicago. Nitzan Mekel-Bobrov is a PhD candidate at the University of Chicago, working with Lahn on characterizing the molecular underpinnings of human brain evolution.