Neanderthal genes influence brain development of modern humans

A characteristic feature of modern humans is the unusually round skull and brain, in contrast to the elongated shape seen in other human species. By studying Neanderthal DNA fragments found in the genomes of living Europeans, scientists have now discovered genes that influence this globular shape. An interdisciplinary research team, led by the Max Planck Institutes for Psycholinguistics and Evolutionary Anthropology, brought together fossil skull data, brain imaging and genomics, as reported in Current Biology.

Computed tomographic scan of a Neanderthal fossil (La Ferrassie 1; left) and of a modern human (right). One of the
features that distinguishes modern humans from Neanderthals is a globular shape of the braincase. ​The cranium
was cut open virtually to reveal the inside of the braincase [Credit: © Philipp Gunz]

Modern human skulls have a unique 'globular' (round) shape. Our closest cousins, the long extinct Neanderthals, had the elongated skulls that are typical of most primates. This striking shape difference is suspected to reflect evolutionary changes in the relative sizes of structures of the human brain, perhaps even in the ways that key brain areas are connected to each other. However, brain tissue doesn't itself fossilize, so the underlying biological explanation has remained elusive.

An international research team, led by paleoanthropologist Philipp Gunz (MPI, Leipzig) and geneticists Simon Fisher and Amanda Tilot (MPI, Nijmegen), developed a new strategy to investigate this question. The team combined analysis of fossil skulls, ancient genome sequence data and brain imaging.

"Our aim was to identify potential candidate genes and biological pathways that are related to brain globularity," says Tilot. To focus their search, they took advantage of the fact that living humans with European ancestry carry rare fragments of Neanderthal DNA buried in their genomes, as a result of interbreeding between Neanderthals and the ancestors of modern Europeans. Different people carry different fragments, which are scattered through the genome.

The authors combine paleoanthropology, archaic genomics, neuroimaging and gene expression to study biological
foundations of the characteristic modern human endocranial shape. Shown here are the coordinate measurements
used to capture endocranial shape from magnetic resonance images of several thousand modern humans
[Credit: © Philipp Gunz]

The researchers first used computed tomographic scans of fossil Neanderthal skulls and skulls of modern humans to make endocasts—virtual imprints of the interior of the braincase. They then developed a single measure of globularity, based on the differences in skull shape between humans and Neanderthals. Next, the scientists teamed up with colleagues at the Radboud University, the University of Greifswald and UC Irvine, to determine the degree of globularity of thousands of healthy present-day humans, using data from magnetic resonance imaging.

Although modern human brain and skull shapes are all clearly distinct from those of Neanderthals, the scientists still found considerable differences in globularity among the participants. Finally, the researchers studied the genomes of around 4,500 of the participants to identify the fragments of Neanderthal DNA that each person carried. Would any of these Neanderthal DNA fragments influence brain globularity in their living human sample?

The team found Neanderthal DNA fragments on chromosomes 1 and 18 that were associated with less globular (more elongated) brains. These fragments were associated with altered activity of two genes, UBR4 and PHLPP1, which are already known to play roles in important aspects of brain development (neurogenesis and myelination respectively). The strongest evidence for effects of these Neanderthal DNA fragments on gene activity were in the putamen (in the basal ganglia) and the cerebellum.

Computed tomographicscan of the Neanderthal fossil from La Chapelle-aux-Saints (left) with a typical elongated
endocranial imprint (red) and of a modern human (right) showing the characteristic globular endocranial shape (blue).
 Arrows highlight the enlarged posterior cranial fossa (housing the cerebellum) as well as bulging of parietal bones
in modern humans compared to Neanderthals [Credit: © Philipp Gunz]

"The potential for links between evolutionary changes in brain globularity and mechanisms affecting the basal ganglia and cerebellum is intriguing," says Gunz. Both structures receive direct input from the motor cortex and are involved in the preparation, learning, and coordination of movements. The basal ganglia also contribute to cognitive functions such as memory, attention, planning, skill learning, and potentially speech and language evolution.

The authors stress that recent archaeological evidence has documented sophisticated symbolic behaviours in Neanderthals that had previously been attributed exclusively to modern humans, such as the enigmatic structure built deep inside Bruniquel cave, and Neanderthal cave-art from Iberia. As Gunz notes, "The focus of our study is on understanding the unusual brain shape of modern humans. These results cannot be used to make inferences about what Neanderthals could or could not do."

"The effects of carrying these rare Neanderthal DNA fragments are really subtle, but detectable due to the large sample size," explains Fisher, adding "This is only our first glimpse of the molecular underpinnings of globularity. Like other aspects of brain structure, globularity is a trait that is likely to be influenced by the combined effects of many different genetic variants."