Neanderthal introgression reintroduced thousands of ancestral alleles lost in the out of Africa bottleneck
Anatomically modern humans (AMHs) interbred with Neanderthals approximately 50,000 years ago, and as a result, ~1–3% of the genomes of modern Eurasians are derived from of DNA introgressed from Neanderthals. Recent studies have focused on identifying and testing the effects of Neanderthal-derived alleles in AMHs, and these introgressed haplotypes have been shown to influence diverse phenotypes in AMHs including risk for many immune, skin, and neuropsychiatric diseases. However, recent analysis of an introgressed Neanderthal haplotype at the OAS locus revealed that the variant responsible for changes in gene expression is a reintroduced ancestral human allele, rather than a Neanderthal-derived allele.
Motivated by this observation of the reintroduction of a functional ancestral allele that was lost in Eurasian populations in the out of Africa bottleneck, we performed a genome-wide search for other lost alleles on introgressed Neanderthal haplotypes in 1000 Genomes Phase 3 European (EUR), East Asian (EAS), and South Asian (SAS) individuals. In each super-population, we identified between ~47,000 and ~57,000 ancestral introgressed alleles. Consistent with the greater levels of Neanderthal DNA in Asian populations, these groups had more reintroduced ancestral alleles. Additionally, we found that nearly 66% of the reintroduced ancestral variants identified in EUR individuals are polymorphic in at least one non-admixed African sub-population (Yoruba, Esan, or Mende). These variants represent an extreme scenario where the ancestral allele was completely lost either before or during the out of Africa transition, and reintroduced by Neanderthal introgression.
Many introgressed haplotypes carry more lost ancestral alleles than Neanderthal-derived alleles. Thus, we hypothesized that these alleles might influence phenotypes in modern Eurasian populations. To explore the potential function of these reintroduced ancestral alleles, we performed a phenome-wide association analysis on the introgressed alleles over more than 20,000 European-ancestry individuals with electronic health record data in Vanderbilt’s BioVU databank. We identified and replicated several novel associations with clinical phenotypes that are likely driven by these reintroduced alleles.