Researchers Using Neanderthal DNA to Learn More About How Human Faces Develop and Evolve

Hannah Long, a scientist at the University of Edinburgh, and colleagues show how a region of Neanderthal DNA is more effective at activating a jaw-forming gene than its human counterpart, revealing one potential reason for Neanderthal’s larger lower jaws.

Neanderthal. Image credit: Trustees of the Natural History Museum, London.

“The Neanderthal genome is 99.7% identical to the genome of modern humans and differences between species are likely responsible for the change in appearance,” Dr Hannah said.

“The human and Neanderthal genomes are made up of about 3 billion letters that code for proteins and regulate how genes are used in the cell, making searching for regions that impact appearance like looking for a needle in a haystack.”

Dr. Long and his co-authors had an enlightened idea of ​​where to look first: a region of the genome linked to the Pierre Robin sequence, a syndrome in which the lower jaw is disproportionately small.

“Some individuals carrying the Pierre Robin sequence have large deletions or DNA rearrangements in this part of the genome that alter facial development and limit jaw formation,” Dr Hannah said.

“We predicted that smaller differences in DNA might have more subtle effects on facial shape.”

By comparing the human and Neanderthal genomes, the researchers found that in this region, about 3,000 letters long, there were only three single-letter differences between the species.

Although this region of DNA does not contain any genes, it regulates how and when a gene is activated, particularly a gene called SOX9a key coordinator of the facial development process.

To demonstrate that these Neanderthal-specific differences are important for facial development, scientists needed to show that the Neanderthal region could activate genes in the right cells at the right time as the embryo developed.

They simultaneously inserted the Neanderthal and human versions of the region into the zebrafish’s DNA and programmed the zebrafish cells to produce different colors of fluorescent protein depending on whether the human or Neanderthal region was active.

By observing the development of zebrafish embryos, they discovered that both the human and Neanderthal regions were active in the zebrafish cells involved in the formation of the lower jaw and that the Neanderthal region was more active than the human version.

“It was very exciting when we first observed activity in the developing zebrafish face in a specific cell population close to the developing jaw, and even more exciting when we observed that Neanderthal-specific differences could alter its activity during development,” Dr. Long said.

“This got us thinking about the possible consequences of these differences and how to explore them experimentally.”

Knowing that the Neanderthal sequence was more powerful at activating genes, the authors then wondered whether the resulting increased activity of its target, SOX9could alter the shape and function of the adult jaw.

To test this theory, they provided the zebrafish embryos with additional nutrients. SOX9 and found that the cells that contribute to jaw formation took up a larger surface area.

“In our lab, we want to explore the impact of additional differences in DNA sequences, using a technique that mimics aspects of facial development on a plate,” Dr. Long said.

“We hope this will inform our understanding of sequence changes in people with facial diseases and inform diagnosis.” »

“This research shows that by studying extinct species, we can discover how our own DNA helps cope with variation, development and evolution.”

The results appear in the newspaper Development.

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Kirsty Uttley and others. 2025. Neanderthal-derived variants increase SOX9 activating activity in craniofacial progenitors that shape jaw development. Development 152 (21): dev204779; doi:10.1242/dev.204779