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Studies Suggest Archaic Human Immune Sequences Particularly Persistent in Human Genome

NEW YORK (GenomeWeb) – A pair of studies published online today in the American Journal of Human Genetics suggest that mixing between modern humans and Neanderthals outside of Africa has contributed to immune features still found in the human genome.

For the first of these papers, researchers from France and the US searched through genome and/or exome sequence data generated for 1,092 individuals enrolled in the 1000 Genomes Project, looking at the signals of purifying selection found across some 1,553 innate immune response-related genes from nine main categories — selected with help from the Gene Ontology and InnateDB databases — relative to other parts of the genome.

Along with enhanced purifying selection for such genes in general, their analyses pointed to particularly pronounced selective pressure to resist change across genes such as STAT1 and TRAF3, which are involved in response to common bacteria and viruses. In addition, dozens of other innate immune genes showed signs of positive selection in particular human populations.

The team also noted that while Neanderthal sequences had been weeded out to a greater extent in modern human genomes, the levels of Neanderthal ancestry remained relatively high in regions coding for innate immune genes, especially TLR6, TLR1, and TLR10 genes coding for Toll-like receptors.

"These and other innate immunity genes present higher levels of Neanderthal ancestry than the remainder of the coding genome," senior author Lluis Quintana-Murci, an evolutionary genetics researcher affiliated with the Institut Pasteur and CNRS, said in a statement. "This highlights how important introgression events … may have been in the evolution of the innate immunity system in humans."

A team from the Max Planck Institute for Evolutionary Anthropology and the University of Leipzig saw similar Neanderthal and Denisovan contributions to innate immunity in a study that focused more generally on introgression in the human genome by archaic hominin sequences.

Since archaic hominins are believed to have lived in parts of Europe and West Asia for hundreds of thousands of years, the researchers reasoned that the Denisovans and Neanderthals likely acquired adaptations to such environments that would have benefited modern humans who migrated into these regions after leaving Africa.

With that in mind, the group scoured available human genome sequences for signs of archaic introgression, uncovering persistent Neanderthal haplotypes in a chromosome 4 region containing the TLR6, TLR1, and TLR10 genes. 

In particular, results from that study pointed to the presence of seven main haplotypes in the toll-like receptor-coding region, based on inferences made using 1000 Genomes Project data on more than 2,500 individuals from dozens of populations.

Three of the haplotypes that are mainly found outside of Africa resembled TLR regions in archaic humans, the researchers reported, and their subsequent analyses indicated that these sequences likely stemmed from introgression and local positive selection of the archaic sequences rather than incomplete lineage sorting or other processes.

The team noted that the archaic haplotypes appear to be linked to enhanced expression of TLR6, TLR1, and TLR10 in white blood cells, which has been implicated in enhanced resistance to some potential pathogens but an apparent jump in allergy risk.

"[I]nterbreeding with archaic humans does indeed have functional implications for modern humans, and [the] most obvious consequences have been in shaping our adaptation to our environment," that study's senior author Janet Kelso, an evolutionary genetics researcher at the Max Planck Institute for Evolutionary Anthropology, said in a statement.