University of Edinburgh scientist Hannah Long and her colleagues show how a region of Neanderthal DNA is better at activating a jaw-forming gene than its human counterpart, revealing one potential reason for Neanderthal's larger mandibles.
Neanderthal. Image credit: Trustees of the Natural History Museum, London.
“The Neanderthal genome is 99.7% identical to the modern human genome, and differences between species are likely responsible for the variation in appearance,” Dr Hannah said.
“Both the human and Neanderthal genomes are made up of approximately 3 billion letters that code for proteins and regulate how genes are used in the cell, so finding regions that influence appearance is like looking for a needle in a haystack.”
Dr. Long and co-authors had an educated guess on where to look first: a region of the genome associated with the Pierre Robin sequence, a syndrome in which the mandible is disproportionately small.
“Some people with 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 of about 3,000 letters long, there were only three single-letter differences between the species.
Although this stretch of DNA does not contain any genes, it regulates how and when a gene is activated, specifically a gene called SOX9key facilitator of the face development process.
To demonstrate that these Neanderthal-specific differences were important for facial development, the 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 Neanderthal and human versions of this region into zebrafish DNA and programmed zebrafish cells to produce a different color of fluorescent protein depending on whether the human or Neanderthal region was active.
By observing the development of zebrafish embryos, they found that both the human and Neanderthal regions were active in zebrafish cells that are involved in the formation of 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 snout in a specific population of cells close to the developing jaw, and even more so when we noticed that Neanderthal-specific differences could alter its developmental activity,” Dr. Long said.
“This got us thinking about what the consequences of these differences might be and how to investigate them experimentally.”
Knowing that the Neanderthal sequence was more potent at activating genes, the authors then asked whether the activity of its target increased as a result. SOX9can change the shape and function of an adult's jaw.
To test this theory, they provided zebrafish embryos with extra SOX9 and found that the cells that contribute to jaw formation occupy a larger area.
“In our laboratory, we are interested in studying the impact of additional differences in DNA sequences using a technique that mimics aspects of facial development in a dish,” Dr. Long said.
“We hope this will help us understand the sequence of changes in people with facial diseases and help us make a diagnosis.”
“This study shows that by studying extinct species, we can learn how our own DNA contributes to facial variation, development and evolution.”
results appear in the magazine Development.
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Kirsty Uttley etc.. 2025. Increasing number of Neanderthal variants. SOX9 enhancer activity in craniofacial progenitors that shape jaw development. Development 152 (21): dev204779; doi: 10.1242/dev.204779
