Summary: The answer to what makes the human brain unique may lie in junk DNA.

Source: Lund University

Our DNA is very similar to that of the chimpanzee, which in evolutionary terms is our closest living relative. Stem cell researchers at Lund University in Sweden have now found a previously overlooked part of our DNA, so-called non-coded DNA, that appears to contribute to a difference which, despite all our similarities, may explain why our brains work differently.

The study is published in the journal Cell Stem Cell.

The chimpanzee is our closest living relative in evolutionary terms and research suggests our kinship derives from a common ancestor. About five to six million years ago, our evolutionary paths separated, leading to the chimpanzee of today, and Homo Sapiens, humankind in the 21st century. 

In a new study, stem cell researchers at Lund examined what it is in our DNA that makes human and chimpanzee brains different – and they have found answers.

“Instead of studying living humans and chimpanzees, we used stem cells grown in a lab. The stem cells were reprogrammed from skin cells by our partners in Germany, the USA and Japan. Then we examined the stem cells that we had developed into brain cells”, explains Johan Jakobsson, professor of neuroscience at Lund University, who led the study.

Using the stem cells, the researchers specifically grew brain cells from humans and chimpanzees and compared the two cell types. The researchers then found that humans and chimpanzees use a part of their DNA in different ways, which appears to play a considerable role in the development of our brains.

“The part of our DNA identified as different was unexpected. It was a so-called structural variant of DNA that were previously called “junk DNA”, a long repetitive DNA string which has long been deemed to have no function. Previously, researchers have looked for answers in the part of the DNA where the protein-producing genes are – which only makes up about two percent of our entire DNA – and examined the proteins themselves to find examples of differences.”

The new findings thus indicate that the differences appear to lie outside the protein-coding genes in what has been labelled as “junk DNA”, which was thought to have no function and which constitutes the majority of our DNA. 

“This suggests that the basis for the human brain’s evolution are genetic mechanisms that are probably a lot more complex than previously thought, as it was supposed that the answer was in those two per cent of the genetic DNA. Our results indicate that what has been significant for the brain’s development is instead perhaps hidden in the overlooked 98 per cent, which appears to be important. This is a surprising finding.”

In a new study, stem cell researchers at Lund examined what it is in our DNA that makes human and chimpanzee brains different – and they have found answers. Image is in the public domain

The stem cell technique used by the researchers in Lund is revolutionary and has enabled this type of research. The technique was recognised by the 2012 Nobel Prize in Physiology or Medicine. It was the Japanese researcher Shinya Yamanaka who discovered that specialised cells can be reprogrammed and developed into all types of body tissue. And in the Lund researchers’ case, into brain cells. Without this technique, it would not have been possible to study the differences between humans and chimpanzees using ethically defensible methods.

Why did the researchers want to investigate the difference between humans and chimpanzees?

“I believe that the brain is the key to understanding what it is that makes humans human. How did it come about that humans can use their brain in such a way that they can build societies, educate their children and develop advanced technology? It is fascinating!”

Johan Jakobsson believes that in the future the new findings may also contribute to genetically-based answers to questions about psychiatric disorders, such as schizophrenia, a disorder that appears to be unique to humans.

“But there is a long way to go before we reach that point, as instead of carrying out further research on the two percent of coded DNA, we may now be forced to delve deeper into all 100 percent – a considerably more complicated task for research”, he concludes.

About this evolution and genetics research news

Author: Lotte Billing
Source: Lund University
Contact: Lotte Billing – Lund University
Image: The image is in the public domain

Original Research: Open access.
“A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development” by Johan Jakobsson et al. Cell Stem Cell


Abstract

See also

This is a diagram of a neuron

cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development

The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution.

Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells.

ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population.

Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.



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