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Neanderthal-Origin DNA Gives Insight Into Modern Human Skull Shape

NEW YORK (GenomeWeb) – Modern humans who carry certain stretches of Neanderthal DNA have slightly less rounded heads, according to a new study.

Modern humans have more globular skulls as compared to other primates and even ancient hominins, both of which have more elongated skulls. This difference in skull shape is thought to be a key step in the evolution of the modern human brain.

An international team of researchers analyzed the shapes of modern human and Neanderthal skulls and developed a score of skull globularity. As the genomes of modern non-African individuals harbor between 1 percent and 2 percent Neanderthal DNA due to ancient admixture, the researchers searched for Neanderthal-origin regions that influence skull shape. As they reported today in Current Biology, they found multiple Neanderthal-origin alleles that influence the expression of two genes involved in neurogenesis and myelination, respectively.

"Our aim was to identify potential candidate genes and biological pathways that are related to brain globularity," co-first author Amanda Tilot from the Max Planck Institute for Psycholinguistics said in a statement.

The researchers generated computer tomographic scans of both fossil Neanderthal skulls and the skulls of modern humans and created endocasts, virtual imprints of the braincase interior. Based on the differences between the Neanderthal and modern human skull shapes, they generated a globularity score.

They then applied this approach to structural MRI scans taken for 6,575 healthy human adults, mostly of European ancestry. While the researchers noted that people have varying degrees of skull globularity, they said that the modern human skull shapes were all clearly distinct from those of Neanderthals.

They also used this skull globularity score to assess MRI brain images of about 4,500 individuals of European ancestry who underwent genotyping. In particular, the researchers analyzed more than 50,000 archaic SNPs to determine whether any Neanderthal-introgressed fragments were linked to a more elongated skull shape. These Neanderthal-origin SNPs in modern Europeans cover about 42 percent of known Neanderthal haplotypes.

Through this, the researchers linked Neanderthal-origin SNPs on chromosomes 1 and 18 to less globular skulls. These SNPs fall outside protein-coding regions, though the researchers noted they could still influence the expression of nearby genes.

Using the GTEx database of expression quantitative trait loci, the researchers found that the haplotypes tagged by the top two SNPs on each chromosome were associated with the downregulation of UBR4 in the putamen and with the upregulation of PHLPP1 in the cerebellum. UBR4 encodes a ubiquitin ligase that regulates neurogenesis, while PHLPP1, encodes a negative regulator of the PI3K/Akt growth factor signaling pathway that is involved in myelination.

As first author Philipp Gunz from the Max Planck Institute for Evolutionary Anthropology noted in a statement, both the putamen — which is part of the basal ganglia — and the cerebellum are important for movement, as both receive direct input from the motor cortex. He added that the basal ganglia also contribute to cognitive functions like memory, attention and planning, and possibly speech and language evolution.

However, he and his colleagues added that the effects of these SNPs are subtle. "The Neanderthal variants lead to small changes in gene activity and only push people slightly towards a less globular brain shape," senior author Simon Fisher, a geneticist at the Max Planck Institute for Psycholinguistics, said in a statement. "This is just our first glimpse of the molecular underpinnings of this phenotype, which is likely to involve many other genes."

The researchers said they are working to scale up their approach and plan to apply it to an even larger cohort of tens of thousands of individuals to tease out additional genes linked to skull shape.