Thesis defense Bas Castelijns: Enhancing evolution

Each cell in the human body contains the same DNA, but at the same time, there are hundreds of different cell types. Therefore, each cell activates different parts of the DNA, in order to activate the correct genes. This is regulated by, among others, enhancers – small regions on the DNA that can activate genes. Only approximately 1-2% of our DNA consists of genes. These genes are largely conserved between different species: approximately 98% of our genes overlap with those of chimpanzees, and approximately 90% with those of mice. Most of the variation between species is actually located in the rest of the DNA, where enhancers are located as well. A change in an enhancer usually only has a small effect on the activity of a gene, which means that the risk of such changes is also relatively small. This makes it likely that enhancers contribute to evolution. In addition, large studies from the previous decades show that many of the variations between individual humans that are involved in a variety of diseases are also often located in enhancers.

Primates

Because changes in the regulations of genes, through changes in enhancers, are likely to have a large impact on the development of diseases and evolution, Castelijns decided to study these changes in humans, chimpanzees, macaques and marmosets. He identified enhancers in the prefrontal cortex and the cerebellum of these species and compared the enhancers in humans and chimpanzees with the enhancers in macaques and marmosets. Chimpanzees and humans are hominins, a subgroup of the larger family of apes, to which also the macaques and marmosets belong. Castelijns: “Chimpanzees, like humans, are social animals with a social network. Therefore, it makes sense that the brain characteristics needed to form social networks were already evolved in the common ancestor of chimpanzees and humans.” He discovered approximately 700 enhancers that exist in the prefrontal cortex of humans and chimpanzees, but not in the prefrontal cortex of macaques and marmosets. These enhancers therefore likely developed later in evolution and may have contributed to the evolution of the human brain.

Oligodendrocytes

In addition, Castelijns observed that these enhancers are active in oligodendrocytes, cells that support the neurons, but not in the neurons themselves. Castelijns: “That actually makes a lot of sense, because there are no large differences in the number of neurons between hominins and monkeys. However, the connections between the neurons, the axons, are longer in hominins. To support these long axons, they need a stronger support system, which is what we see.” The enhancers should be tested in future research, to investigate what their exact function is.

Heritable diseases

Many variations in the DNA that are involved in heritable diseases are located in enhancers, including those involved in brain diseases such as Alzheimer’s and Parkinson’s. Because these are diseases that do not occur naturally in monkeys, the 700 enhancers that are relatively new on an evolutionary scale can be investigated for potential involvement in the development of diseases such as Alzheimer’s and Parkinson’s.

With his research, Castelijns has shown the importance of enhancers for studying evolution and human-specific diseases, by showing differences in such enhancers between hominins and monkeys.