Unravelling the evolution of the human brain

There is no doubt that one of the big scientific challenges ahead is to understand how brain activity is translated into specific mental states. If we are to solve this question, we must first obtain a deeper knowledge of the outer layer of the brain, made up of billions of neurons, which is known as the neocortex. The neocortex is organized into functional areas associated with movement, perception and with higher cognitive abilities typical of humans. In Homo sapiens, the neocortex amounts roughly to 80% of the total mass of the brain, an evolutionary leap compared to other primates and even great apes. How was such innovation achieved?

As with any other body structure, the formation of the brain is determined by a very specific developmental program. So the previous question could be more appropriately formulated as: how has brain development been modified in humans with respect to other animals? As development is basically the result of genetic programs, the answer might very well be in our genome. So far, however, attempts to find genomic changes that explain the evolution of the brain have been largely fruitless. This is due, in part, to the fact that we have been searching in the coding part of the genome; that is, in protein-coding genes. Apart from the well-known story of FOXP2, no conclusive examples of protein-coding changes responsible for brain evolution have been reported.

In order to find the answer, then, we must look elsewhere in the genome. A few years ago, several international research projects created an extensive catalogue of all the functional elements in the human genome, which includes millions of small regions that act like switches to turn on and off the expression of genes. Like other researchers, I am interested in studying a type of regulatory elements called enhancers, that determine which genes are more active and in what particular tissues. Some of these enhancers play a very specific and crucial role in brain development in humans, as highlighted by a recent paper published in Science.

Yale scientists compared these enhancer elements in the genomes of humans, rhesus macaque and mouse, measuring two epigenetic marks that are known to reveal which enhancers are active. They did this in brain samples of these three species taken at various embryonic stages of development, so they could pinpoint those enhancers that are active during the formation of the neocortex specifically in humans, but not in monkeys or in mice. 

In total, they found around twelve thousand elements out of fifty thousand enhancers analysed. Using data about gene activity in the developing brain, generated by another research Project called BrainSpan, the authors of the study could confirm that this collection of enhancers is largely responsible for the development of human neocortex. Interestingly, when they looked at the genes regulated by all these elements they identified several genetic networks that include biochemical processes and cellular pathways related to pattern formation in the brain, neuronal migration, neural stem cell renewal, etc.

All this opens up new avenues of research for those who, like me, are interested in studying the role played by these short enhancer elements in the evolution of neural systems, from the first metazoans all the way down to the human brain. Unravelling such a complex process will undoubtedly take many years of work by scientists around the world. It is thrilling to be part of the adventure.

Javier Novo

Professor, Biochemistry and Genetics Department, School of Sciences 

University of Navarra