This page was produced as an assignment for an undergraduate course at Davidson College
Overview: Anatomically modern humans (AMH) appear to have overlapped in space and time with some archaic hominins based on fossil evidence. This would have allowed interbreeding to occur, specifically between ancient humans and Neandertals. Thus, some of the DNA found in AMH can be contributed to introgression from Neandertals. This paper investigates the impact of Neandertal DNA introgression on AMH phenotypes.
By incorporating data from the Electronic Medical Records and Genomics Network (eMERGE), the 1000 Genome Project (1KG), and an inferred map of Neandertal haplotypes, researchers discovered Neandertal alleles in AMH that explained a significant amount of phenotypic risk in those individuals. The Neandertal alleles had the most prominent effect on neurological and psychiatric phenotypes.
In my opinion, this paper introduced a novel way of analyzing AMH DNA for the residual effects of admixture. However, this analysis did not produce very many statistically significant replicable insights, which suggests that either this admixture is particularly difficult to detect or their methods need further refinement.
Figure 1: This figure demonstrates the researchers’ methodology for identifying phenotypes that are at least partially determined by Neandertal DNA in AMH. Generally, their procedure was as follows:
1. Gather genomic and phenotypic data on ~28,000 individuals from the eMERGE database (A).
2. Identify 1495 Neandertal specific alleles.
3. From the eMERGE data, all ~28,000 individuals were compared in a pair-wise fashion for each of the 1495 Neandertal loci (B, left stair step heat map). A second pair-wise comparison was conducted for each of the 46 high-prevalence phenotypes extracted from the eMERGE database (B inside dashed box).
4. Identify phenotypic traits of which a significant amount of variation can be explained by Neandertal genetic loci similarities (C).
5. Test identified allele-phenotype associations for robustness using a second data set, eMERGE E2. The results form one of these SNP-phenotype associations is shown in panel D.
6. Determine plausible mechanistic explanations for the phenotype produced by the identified SNP (E). The SNP from panel D is located near the SELP gene, which is responsible for producing a cell adhesion protein and therefore could contribute to hypercoagulation.
Table 1: Eight phenotypic traits were identified as owing a nominally significant (p < .1) proportion of variance in risk to Neandertal alleles after replication analysis.
Table 2: A list of all nominally significant Neadertal SNP-phenotype associations that were replicated by the eMERGE E2 dataset. For each of the SNPs in the table the researchers investigated their loci and found mechanistic explanations for the association with each phenotype. These associations usually were the result of close proximity to genes (flanking genes) known to be involved in pathways that could produce these phenotypes.
Figure 2: Neandertal SNPs are shown to significantly influence different classes of phenotypes. Particularly, Neandertal SNPs contributed to neurological phenotype changes significantly more often than would be expected based on Phenotype-Wide Association Study (PheWAS) data. Conversely, the Neandertal SNPs affected significantly fewer digestive phenotypes than expected.
Reference: Simonti, C. N., Vernot, B., Bastarache, L., Bottinger, E., Carrell, D. S., Chisholm, R. L., ... & Li, R. (2016). The phenotypic legacy of admixture between modern humans and Neandertals. Science, 351(6274), 737-741. || Original can be found here. All figures were taken from this paper and used solely in an academic and non-commercial capacity. Full permission is still pending.
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