Neanderthal DNA Reveals Secrets of Jaw Development

Every human face is unique, allowing us to distinguish between individuals. We know little about how facial features are encoded in our DNA, but we may be able to learn more about how our faces develop by looking at our ancient relatives, the Neanderthals.

Neanderthal faces were quite distinctive from our own, with large noses, pronounced brows and a robust lower jaw. Now, scientists from the MRC Human Genetics Unit in the Institute of Genetics and Cancer at the University of Edinburgh, UK, are using the DNA of our extinct distant relatives to learn more about how faces develop and evolve. Published today in the journal Development, they 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.

Hannah Long (University of Edinburgh, UK), who led the study, explains that scientists have sequenced the Neanderthal genome using DNA extracted from ancient bone and says, "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". 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. Fortunately, Long and her colleagues 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. We predicted that smaller differences in the DNA might have more subtle effects on face shape."

Hannah Long, University of Edinburgh

By comparing human and Neanderthal genomes, the team found that in this region, roughly 3000 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, Long and colleagues needed to show that the Neanderthal region could activate genes in the right cells at the right time as the embryo develops.

The researchers simultaneously inserted the Neanderthal and human versions of the region into the DNA of zebrafish and programmed the zebrafish cells to produce different colours of fluorescent protein depending on whether the human or Neanderthal region was active. Watching the zebrafish embryos develop, the researchers 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," said Long.

"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, Long and colleagues 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. We hope this will inform our understanding of sequence changes in people with facial conditions and inform diagnosis," says Long. This research shows that by studying extinct species we can learn how our own DNA contributes to face variation, development and evolution.