In a new study, stem cell scientists at the Lund University, Sweden, explore the role of non-coding regions of the genome—previously deemed to be functionless “junk” DNA—and find humans and chimpanzees use a part of their non-coding DNA in different ways. This they claim affects how and when the human brain develops.

Chimpanzees are our closest living relatives. Despite significant similarities in our DNA and few differences in our protein-coding genes, the human forebrain is larger and more complex than that of the chimpanzee.

Johan Jakobsson, PhD, professor of neuroscience at Lund University, who is the first author of the paper says, “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.”

In the new study, the researchers have discovered a transcription regulating protein called ZNF558 that is expressed in the human but not chimpanzee forebrain neural progenitor cells. Originally, about 100 million years ago, ZNF558, evolved to regulate the expression of a family of transposable elements, but now it regulates a gene called SPATA18 that regulates the selective dismantling of mitochondria.

The expression of ZNF558 itself is regulated by the size of a non-coding structural element in DNA called a VNTR, short for variable number tandem repeat that is longer in chimpanzees than in humans. VNTRs, also called minisatellites, are families of DNA sequences where a short nucleotide sequence is consecutively repeated, with variations in length between individuals.

The study is published in an article titled “A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development,” in the journal Cell Stem Cell and provides mechanistic insight into how structural variations in DNA establish a regulatory network that affects human brain evolution. Jakobsson believes these insights may contribute to genetics-based answers to questions about psychiatric disorders, such as schizophrenia that appears to be unique to humans.

The authors show ZNF558 plays a role in maintaining normal mitochondrial function. In experiments on cerebral organoids, they show, if ZHF558 function is lost, the organoids are smaller during the early stages of differentiation, with transcriptomic analysis indicating the presence of more mature neurons at later stages of differentiation. Based on these observations, the team concludes ZNF558 influences developmental timing during early human brain development.

“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 Jakobsson.

The team conducted the experiments in cell cultures of forebrain neural progenitor cells (fbNPCs) established through the differentiation of chimpanzee and human induced pluripotent stem cells (iPSCs). To show that their differentiation protocol is reproducible and gives rise to time and trait-matched, homogeneous cultures of human and chimpanzee fbNPCs suitable for comparative analysis, they conduct immunocytochemistry and transcriptome analyses.

ZNF558 expression is controlled by the size of a downstream noncoding repeat element (VNTR) [Source: Jakobsson et al, 2021/ Cell Stem Cell]
Jakobsson says, “The basis for the human brain’s evolution is genetic mechanisms that are probably a lot more complex than previously thought, as it was supposed that the answer was in those two percent of the [protein-coding] genetic DNA. Our results indicate that what has been significant for the brain’s development is instead perhaps hidden in the overlooked 98 percent, which appears to be important. This is a surprising finding.”

The underlying impetus for the study lies in the need to understand what makes us human. Jakobsson says, “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 brains in such a way that they can build societies, educate their children, and develop advanced technology? It is fascinating!”

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