Interbreeding of anatomically modern Homo sapiens with Neanderthals (Homo neanderthalensis) around 40,000 years ago may have left humans with gene variants responsible for the immune response, according to two studies in the American Journal of Human Genetics. This inheritance may have also left some of us more prone to allergies.
Neanderthal. Image credit: Trustees of the Natural History Museum, London.
Earlier studies have shown that 1-6% of modern Eurasian genomes were inherited from ancient hominins, such as Neanderthal or Denisovans.
The two new studies highlight the functional importance of this inheritance on Toll-like receptor (TLR) genes – TLR1, TLR6, and TLR10, which are expressed on the cell surface, where they detect and respond to components of bacteria, fungi, and parasites. These immune receptors are essential for eliciting inflammatory and anti-microbial responses and for activating an adaptive immune response.
“We found that interbreeding with archaic humans has influenced the genetic diversity in present-day genomes at three innate immunity genes belonging to the human Toll-like-receptor family,” explained Dr Janet Kelso of the Max Planck Institute for Evolutionary Anthropology, lead author of one of the studies.
“These, and other, innate immunity genes present higher levels of Neanderthal ancestry than the remainder of the coding genome,” said Dr Lluis Quintana-Murci of the Institut Pasteur, lead author of another study. “This highlights how important introgression events may have been in the evolution of the innate immunity system in humans.”
Dr Quintana-Murci and co-author set out to explore the evolution of the innate immune system over time. They relied on data available from the 1000 Genomes Project together with the genome sequences of ancient hominins.
The scientists focused on a list of 1,500 genes known to play a role in the innate immune system. They then examined patterns of genetic variation and evolutionary change in those regions relative to the rest of the genome at an unprecedented level of detail.
Finally, they estimated the timing of the changes in innate immunity and the extent to which variation in those genes had been passed down from Neanderthals.
“These investigations revealed little change over long periods of time for some innate-immunity genes, providing evidence of strong constraints,” the scientists said.
“Other genes have undergone selective sweeps in which a new variant came along and quickly rose to prominence, perhaps because of a shift in the environment or as a result of a disease epidemic. Most adaptations in protein-coding genes occurred in the last 6,000 to 13,000 years, as human populations shifted from hunting and gathering to farming.”
But the biggest surprise for the team was to find that the TLR6-TLR1-TLR10 cluster is among the genes presenting the highest Neanderthal ancestry in both Europeans and Asians.
“We show that innate immunity genes present higher Neanderthal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neanderthal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans.”
Geographic distribution of the Neanderthal-like TLR haplotypes: world map showing the frequencies of Neanderthal-like core haplotypes in the 1000 Genomes dataset (upper image) and the Simons Genome Diversity Panel (lower image). On the second map, the size of each pie is proportional to the number of individuals within a population; core haplotypes (III – orange; IV – green; non-archaic core haplotypes V, VI, VIII, IX – blue) are colored. Image credit: Michael Dannemann et al.
Dr Kelso and co-authors came to the same conclusion.
They screened present-day human genomes for evidence of extended regions with high similarity to the Neanderthal and Denisovan genomes, then examined the prevalence of those regions in people from around the world. Those analyses led them to the same TLR6-TLR1-TLR10 cluster.
“We document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neanderthal genome, and the third haplotype is most similar to the Denisovan genome,” they said.
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Michael Dannemann et al. 2016. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors. American Journal of Human Genetics, vol. 98, no. 1, 22-33; doi: 10.1016/j.ajhg.2015.11.015
Matthieu Deschamps et al. 2016. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes. American Journal of Human Genetics, vol. 98, no. 1, 5-21; doi: 10.1016/j.ajhg.2015.11.014
