ABO introgression from Eurasian hominins

One of the oldest group of loci investigated for variation in humans are the ABO antigen markers. There are several reasons for this. First, you can assay them with pre-DNA methods. Second, they vary a lot. Third, they’re very important for things like blood donation.

The fact that they vary a lot means that researchers in the early 20th century used these markers to try and figure out population history. This was not workable for two reasons. First, looking at a locus here and there is not really informative. Y and mtDNA have special characteristics, but even these markers are really informative in a broader context. Second, the ABO locus is subject to natural selection. More precisely, it looks like a lot of immunological markers the ABO locus is subject to balancing selection which keeps it quite diverse.

What does this mean? Basically, variation at any locus is going to turnover. All the polymorphism will “coalesce” back to a common ancestor. The date of coalescence is going to be conditional on parameters such as genetic drift, and selection. Strong sweeps mean all the variance is removed and the coalescence is shallow. Similarly, bottlenecks mean short lifetimes for lineages, since drift cranks away variation. Balancing selection results in the opposite effect. At immunological loci the coalescence is often deeper than the time between the separation of species. The reason is that frequency-dependent selection prevents rare alleles from going extinct (the fitness goes up the rarer the allele).

This is the context of a new preprint, ABO genetic variation in Neanderthals and Denisovans:

Variation at the ABO locus was one of the earliest sources of data in the study of human population identity and history, and to this day remains widely genotyped due to its importance in blood and tissue transfusions. As one of the first genetic markers, variation at the ABO gene has been studied for over 60 years, and yet there are some aspects of its evolution that remain mysterious. Here, we look at ABO blood type variants in our archaic relatives: Neanderthals and Denisovans. Our goal is to understand the genetic landscape of the ABO gene in archaic humans, and how it relates to modern human ABO variation. We analyze coding variation at the ABO locus from next-generation sequences in ~2,500 individuals from 28 populations, including three Neanderthal and one Denisovan individuals. We use the modern human haplotypes to impute ABO genotypes for the four archaic human genomes. We found that the Siberian Neanderthals, Altai and Chagyrskaya, are both homozygous for a derived Neanderthal variant of the O allele, while the European Neanderthal, Vindija, is a heterozygote for two derived Neanderthal variants, an O variant different from Altai and Chagyrskaya, and a rare cis-AB variant. The Denisovan individual is homozygous for an ancestral variant of the O allele, similar to variants found widely in modern humans. Perhaps more surprisingly, the derived O allele variant found in the Altai Neanderthal can be found at low frequencies in modern European and Southeast Asian individuals, and the derived O allele variant found in the Vindija Neanderthal is also found at very low frequency in East Asian individuals. Our genetic distance analyses suggests both alleles were introgressed through Neanderthal-human gene flow. In summary, our study identifies the genetic variation of the ABO gene in archaic humans, we find that ABO allele diversity in Neanderthals was likely high, and that some of these alleles still survive in modern humans due to inbreeding with Neanderthals.

The results are in alignment with theoretical expectations (which were probabilistic though). Alleles from these Eurasian hominins are probably beneficial in some way. Admixture with diverged lineages is a way to “rescue” diversity that may have been lost. The interesting point in the discussion though is that the Neanderthal population that the rare alleles were obtained had more variation than the small samples of European and Altai Neanderthals that we have now. This is not surprising, as it was probably a Near Eastern extension of European Neanderthals, and may even had have a larger long-term effective population than the groups further north.