The enigmatic facial morphology of our Neanderthal cousins, characterized by a robust and prominent jaw, finds part of its explanation in the least known areas of our genetic heritage. A team from the University of Edinburgh has highlighted the decisive role of a tiny portion of DNA, devoid of genes, in the development of this anatomical particularity.
Their work suggests that subtle variations in this regulatory region could have influenced the expression of key genes during facial formation. This scientific breakthrough is based on the comparative analysis of human and Neanderthal genomes, which are separated by only 0.3% divergence.
A Neanderthal skull and a human skull are displayed at the National Museum of Scotland.
Credit: Hannah Long
The researchers were particularly interested in a regulatory sequence (an "enhancer") of the SOX9 gene, a major player in craniofacial development. Their investigation revealed that major alterations in this area are associated, in modern humans, with a specific pathology affecting mandible growth. This observation formed the starting point for exploring the hypothesis that more subtle modifications could have shaped, in a more attenuated way, the physiognomy of Neanderthal Man.
The unexpected role of non-coding DNA
Long considered superfluous, the non-coding part of the genome, which represents about 98% of our DNA, is now seen as a conductor of genetic activity. It houses regulatory sequences that act as molecular switches. Their function is to modulate gene expression, determining the timing, location, and intensity of their activation without producing proteins themselves. The discovery of their involvement in facial morphogenesis marks a turning point in our understanding of evolution.
The study published in
Development focused on a specific enhancer, identified under the code EC1.45, known to regulate the SOX9 gene. The researchers compared the sequence of this enhancer between modern humans and Neanderthals. Their analysis highlighted three specific nucleotide differences, meaning three distinct "letters" in a sequence of three billion.
To verify this hypothesis, the scientists used an animal model, the zebrafish. They introduced the human and Neanderthal versions of the EC1.45 enhancer into embryos, each coupled to a different colored fluorescent reporter gene. This ingenious approach allowed them to visualize in real time the activity of the two sequences during embryonic development. The results were unequivocal: although active in the same cell populations, the Neanderthal version showed significantly higher activity than its human counterpart.
From gene to facial morphology
The most significant observation located this increased activity within a very specific cell group: the progenitor cells derived from the neural crest. These cells, fundamental in vertebrates, give rise to the skeletal structures of the face, including the jaw bones. A stronger activation of the Neanderthal enhancer in these cells indicates a greater stimulation of the SOX9 gene, which in turn could promote more robust growth of the mandibular cartilage and bone during key stages of facial formation.
To confirm the causal link between SOX9 activity and jaw size, the team conducted a complementary experiment. By providing zebrafish embryos with an additional dose of the SOX9 protein, they observed a notable expansion of the area containing the cells that give rise to the mandible. This manipulation, which mimics the effect of the more active Neanderthal enhancer, directly resulted in an enlargement of the forming mandibular structures, corroborating the hypothesis of a morphological effect.
These discoveries elegantly illustrate how minute modifications in regulatory regions of DNA can have perceptible anatomical consequences on an evolutionary scale. The prominent jaw of Neanderthals would thus not be the result of brutal mutations in structural genes, but rather the result of a fine-tuning of the intensity of a developmental gene. This mechanism of variation offers a model for understanding facial diversity within our own species and the genetic basis of certain congenital malformations.
To go further: What is the non-coding genome?
The non-coding genome refers to the vast majority of our DNA that does not contain direct instructions for making proteins. It was once called "junk" DNA. Recent research has established its role in gene regulation. It acts as a control panel, determining which genes are activated, when, and in which cells.
It includes regulatory sequences like promoters and enhancers. These regions serve as binding sites for specialized proteins that orchestrate the reading of genetic information. Their variations, even minimal, can alter anatomy without necessarily causing diseases, thus contributing to the natural diversity of populations.
Unlike coding genes whose mutations are often deleterious, changes in the non-coding part allow for a more gradual and nuanced evolution of physical traits. The study of ancient genomes reveals how these adjustments have shaped human evolution. They represent a field of investigation for medical and evolutionary genetics.
Article author: Cédric DEPOND