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European Mesolithic Hunter-Gatherer Genome Contains Ancestral as well as Derived Alleles

NEW YORK (GenomeWeb Daily News) – An international team of researchers sequenced the genome and characterized a handful of alleles from a Mesolithic skeleton dating back some 7,000 years.

As the team reported in Nature on Sunday, this Mesolithic European hunter-gather has swaths of DNA in common with modern Northern Europeans and carries ancestral as well as derived alleles for some traits. For instance, the researchers determined that the hunter-gather likely had dark skin and blue eyes.

"[T]he biggest surprise was to discover that this individual possessed
African versions in the genes that determine the light pigmentation of the current Europeans, which indicates that he had dark skin, although we cannot know the exact shade," said senior author Carles Lalueza-Fox, the group leader of the paleogenomics lab at the Spanish National Research Council, in a statement.

Next-generation sequencing has enabled researchers to peek further back in time to examine human roots. For instance, Ötzi the Iceman's genome, a Neolithic man, was published last year, and other researchers have studied the genomes of human relatives, including Neandertals and Denisovans.

Here, Lalueza-Fox and his colleagues turned to a sample found in 2006 in a cave in León, Spain, to study the genome of a Mesolithic hunter-gatherer. The advent of farming, they noted, likely had an effect on a number of human genes related to immunity and diet.

The cave contained two male skeletons that were fairly well preserved due to the cold but stable conditions there, the researchers said. The samples were dubbed La Braña 1 and La Braña 2.

The researchers focused on La Braña 1 as a tooth from that skeleton had ample amounts of DNA, which they then sequenced to 3.4x depth of coverage using the Illumina HiSeq platform. Using the Burrows Wheeler Aligner, they mapped those reads to the human reference genome. They noted that the La Braña 1 appears to have low amounts of decay as well as low levels of contamination.

Through a principal components analysis, the researchers compared the La Braña 1 genome to the genomes of modern Europeans and found that while the Mesolithic man was distinct from existing European populations, it was placed in proximity to Northern Europeans.

In addition, they found that another ancient human from Siberia who lived during the Upper Paleolithic period — and whose genome was recently published — was more closely related to La Braña 1 than to modern Asians or Europeans.

"These data indicate that there is genetic continuity in the populations of central and western Eurasia," Lalueza-Fox said. "In fact, these data are consistent with the archeological remains," such as those found in other excavations in Europe and Russia, including Mal'ta, where anthropomorphic figures called Paleolithic Venus "have been recovered and they are very similar to each other."

Lalueza-Fox and his team then zoomed in on specific alleles that have been linked to recent adaptive evolution in humans, such as the abilities to digest starch and milk. La Braña 1 was unlikely to be able to digest either of those, they reported, as he has the ancestral lactose intolerance allele and a low number of the salivary amylase gene.

The 1,000 Genomes Project uncovered some 10 candidate non-synonymous variants found in modern humans of northern and western European ancestry, and the researchers examined whether this Mesolithic hunter-gather had those same variants.

Of those 10 variants, the hunter-gather was homozygous for the ancestral or non-selected alleles for three regions, one of which has an unknown function and two of which are linked to skin pigmentation. Those two variants are either absent or present at very low frequencies in modern Europeans.

Looking more broadly at known pigmentation-related genes, the researchers uncovered that La Braña 1 has ancestral alleles for three and derived alleles for the other three. This suggests, the researchers said, that the Mesolithic individual had dark skin and dark or brown hair.

Interestingly, La Braña 1 also has the HERC2 rs12913832*C SNP and related homozygous haplotype that spans the HERC2–OCA2 locus that is strongly associated with blue eyes, the researchers noted.

"The genotypic combination leading to a predicted phenotype of dark skin and non-brown eyes is unique and no longer present in contemporary European populations," the researchers said. "Our results indicate that the adaptive spread of light skin pigmentation alleles was not complete in some European populations by the Mesolithic and that the spread of alleles associated with light/blue eye color may have preceded changes in skin pigmentation."

For the other loci found in the 1,000 Genomes group, La Braña 1 had the derived alleles in five cases, including in three genes linked to immune system function.

Again, in a broader look at immune-related genes, the researchers found that La Braña 1 had the derived allele in some 24 genes, or about 60 percent. Those genes, the researchers noted, have a range of functions, from pattern recognition receptors to chemokines and chemokine receptors to intracellular modulators.

Then, by examining the La Braña 1 genome at all eQTL regions linked to positive selection in Europeans, the researchers found that eight immunity-related genes, including three Toll-like receptor genes, were likely overexpressed in La Braña 1.

"These observations suggest that the Neolithic transition did not drive all cases of adaptive innovation on immunity genes found in modern Europeans," the researchers said. "Several of the derived haplotypes seen at high frequency today in extant Europeans were already present during the Mesolithic as neutral standing variation or due to selection predating the Neolithic."

Still, La Braña 1 represents one Mesolithic hunter-gather genome, and the researchers noted that additional ancient genome sequences will be needed to determine whether the Braña 1 findings are generalizeable, and the lead author of the study, Iñigo Olalde, said that the team is working to sequence the La Braña 2 genome.

"Nevertheless," the researchers added, "this genome sequence provides the first insight as to how these hunter-gatherers are related to contemporary Europeans and other ancient peoples in both Europe and Asia, and shows how ancient DNA can shed light on the timing and nature of recent positive selection."