Modern humans differ from Neanderthals in around 100 amino acids, but the biological consequences of this are still unclear. Now researchers have found out for six of these human-type mutations what advantages they bring to our species. Experiments with mice and brain organoids showed that these changes contribute to a more precise arrangement and division of the chromosomes during cell division. As a result, erroneous divisions occur less frequently. Because the proteins with these altered amino acids are primarily active during embryonic development of our brain, this could have contributed to the superior brain function of Homo sapiens.
Neanderthals and Denisovans were the closest relatives of our ancestors and were similar to Homo sapiens in many ways. They, too, already had relatively large brains, used tools, and successfully spread across much of Eurasia. Nevertheless, they died out, leaving Homo sapiens as the only human species left. But why? It is known that these early humans differed genetically from us through changes in the code for around 100 amino acids. However, what functions the proteins affected by these changes have and what biological differences this brought to Homo sapiens is largely unknown.
Three proteins under scrutiny
A team led by Felipe Mora-Bermudez from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden has now examined six of these amino acid changes newly acquired by Homo sapiens. These amino acids are located in three proteins that are particularly active in the growing embryo in the neocortex, the evolutionarily youngest part of our cerebral cortex. “These three proteins stand out because they carry amino acid changes that are common to all modern humans but not to great apes, Neanderthals, or Denisovans,” the scientists explain. “Every functional consequence of this amino acid exchange would therefore be unique for modern humans.” It is already known that all three proteins play an important role in cell division: KIF18a is a motor protein that ensures the correct positioning of the chromosomes shortly before they are divided into the daughter cells ensures. KNL1 is part of the spindle apparatus and is required for attachment of the microtubules to the kinetochore in the chromosome center. SPAG5 is important in stabilizing this attachment.
However, the question is whether and how the human-typical changes in these three proteins influence their function – and what consequences this had for the brain development of Homo sapiens in contrast to its two relatives. To investigate this, Mora-Bermudez and his colleagues changed the blueprint of these three proteins to the human variant in mouse embryos using Crispr/Cas9 gene scissors. The researchers then observed the dividing behavior of cells in the neocortex of the animals. It was found that the mouse cells with the human variant of the proteins stayed longer in the metaphase of cell division – the phase in which the chromosomes are lined up by the spindle apparatus in the middle of the cell. On average, the metaphase lasted 4.6 minutes in normal mice compared to 5.8 minutes in the “humanized” ones. Because mice share these three proteins with Neanderthals and other hominids, it suggests that this was a difference our ancestors showed from their ancestors and relatives.
Fewer chromosomal errors during cell division
This was confirmed by another experiment in which the scientists examined brain organoids cultivated from human neuronal stem cells. When they incorporated the Neanderthal version of the proteins into some of these organoids, there were also differences: the brain cells with the “old” variant had a shorter metaphase and chromosomes that were less stably bound to the spindle. In addition, there were twice as many chromosomes in these cells, which at the end of this division phase were still “dancing out of line” and not correctly lined up in the middle, as the team reports. Such lagging chromosomes are a common source of erroneous allocation of these genotypes to daughter cells. “And having the wrong number of chromosomes is usually not a good idea for a cell, as you can see with trisomy 21 and cancer,” says Mora-Bermudez.
The scientists say these results suggest that the amino acid changes they studied conferred an important benefit on our ancestors. Because they could have ensured that there were fewer errors in cell division – especially during human brain development. “These changes led to increased precision in chromosome segregation in the apical progenitor cells of the developing neocortex,” write Mora-Bermudez and his colleagues. “That could have had significant consequences.” Because almost all brain cells of the neocortex arise from these apical cells. In other words, brain function in Neanderthals, Denisovans, and other early human forms may have been more affected by such chromosomal defects. In Homo sapiens, on the other hand, this was optimized and could have given his brain improved functionality. Further studies must now show which functions are actually involved and how much the optimization acquired from our ancestors affects them.
Source: Felipe Mora-Bermudez (Max Planck Institute for Molecular Cell Biology and Genetics, Dresden) et al., Science Advances, doi: 10.1126/sciadv.abn7702