University of Edinburgh scientist Hannah Long and colleagues show how a region of Neanderthal DNA is better at activating a jaw-forming gene than the 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-day humans and the differences between species are likely responsible for altering appearance,” Dr. Hannah said.
“Both human and Neanderthal genomes consist of about 3 billion letters that code for proteins and regulate how genes are used in the cell, which makes finding regions that impact appearance like looking for a needle in a haystack.”
Dr. Long and co-authors had an informed idea where to look first: a region of the genome that is linked to Pierre Robin sequence, a syndrome in which the lower jaw is disproportionately small.
“Some individuals with Pierre Robin sequence have large deletions or DNA rearrangements in this part of the genome that change face development and limit jaw formation,” Dr. Hannah said.
“We predicted that smaller differences in the DNA might have more subtle effects on face shape.”
By comparing human and Neanderthal genomes, the researchers found that in this region, roughly 3,000 letters in length, there were just three single-letter differences between the species.
Although this region of DNA doesn’t contain any genes, it regulates how and when a gene is activated, specifically a gene called SOX9, a key coordinator of the process of face development.
To demonstrate that these Neanderthal-specific differences are important for the development of the face, the scientists needed to show that the Neanderthal region could activate genes in the right cells at the right time as the embryo develops.
They simultaneously inserted the Neanderthal and human versions of the region into the DNA of zebrafish and programmed the zebrafish cells to produce different colors of fluorescent protein depending on whether the human or Neanderthal region was active.
Watching the zebrafish embryos develop, they found that both the human and Neanderthal regions were active in the zebrafish cells that are involved in forming the lower jaw and 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 so when we observed that the Neanderthal-specific differences could change its activity in development,” Dr. Long said.
“This led us to think about what the consequences of these differences could be, and how to explore these experimentally.”
Knowing that the Neanderthal sequence was more powerful at activating genes, the authors then asked if the resulting increased activity of its target, SOX9, might change the shape and function of the adult jaw.
To test this theory, they provided the zebrafish embryos with extra SOX9 and found that cells that contribute to forming the jaw occupied a larger area.
“In our lab, we are interested in exploring the impact of additional DNA sequence differences, using a technique that mimics aspects of facial development in a dish,” Dr. Long said.
“We hope this will inform our understanding of sequence changes in people with facial conditions and inform diagnosis.”
“This research shows that by studying extinct species we can learn how our own DNA contributes to face variation, development and evolution.”
The results appear in the journal Development.
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Kirsty Uttley et al. 2025. Neanderthal-derived variants increase SOX9 enhancer activity in craniofacial progenitors that shape jaw development. Development 152 (21): dev204779; doi: 10.1242/dev.204779
