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An Evolutionary Medicine Perspective on Neandertal Extinction

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An Evolutionary Medicine Perspective on Neandertal Extinction Supplementary Information (Figures and Tables) for: An evolutionary medicine perspective on Neandertal extinction Alexis P. Sullivan1, Marc de Manuel3, Tomas Marques-Bonet3,4,5, & George H. Perry1,2 Departments of 1Biology and 2Anthropology, Pennsylvania State University, University Park, PA 16802, USA 3Institut de Biologia Evolutiva (CSIC/UPF), Parque de Investigación Biomédica de Barcelona (PRBB), Barcelona, Catalonia 08003, Spain 4CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain 5Catalan Institution of Research and Advanced Studies (ICREA), Passeig de Lluís Companys, 23, 08010, Barcelona, Spain Corresponding Author: George H. Perry E-mail: [email protected] Supplemental Figure 1: Innate immune system gene permutation analyses – 10,000 sets of 73 randomly selected genes containing nonsynonymous SNPs Supplemental Figure 2: Virus-interacting protein gene permutation analyses – 10,000 sets of 164 randomly selected genes containing nonsynonymous SNPs Supplemental Figure 3: MHC gene permutation analyses – 10,000 sets of 13 randomly selected genes containing nonsynonymous SNPs Supplemental Figure 4: Patterns of Neandertal and modern human nonsynonymous SNP diversity in MHC genes (n = 13) excluding the Altai Neandertal and one random modern human per population Supplemental Figure 5: Significantly enriched gene ontology categories (red) among top 1% ape diversity genes Supplemental Table 1: A comparison of genome-wide nonsynonymous SNPs versus total (nonsynonymous + synonymous) SNPs between Neandertal and modern human populations Supplemental Table 2: PolyPhen-2 predictions for genome-wide nonsynonymous SNPs – damaging versus not damaging – for Neandertal and modern human populations Supplemental Table 3: List of Innate immune system genes Supplemental Table 4: List of virus-interacting protein genes with known antiviral or broader immune activities Supplemental Table 5: List of MHC genes Supplemental Table 6: A comparison of nonsynonymous SNPs (benign + damaging) in innate immune system genes versus genome-wide genes (not including innate immune genes) between Neandertal and modern human populations Supplemental Table 7: A comparison of nonsynonymous SNPs (benign + damaging) in virus- interacting protein genes versus genome-wide genes (not including virus-interacting protein genes) between Neandertal and modern human populations Supplemental Table 8: A comparison of nonsynonymous SNPs (benign + damaging) in MHC genes versus genome-wide genes (not including MHC genes) between Neandertal and modern human populations Supplemental Table 9: Neandertal Minor Allele Frequency (MAF) comparison of nonsynonymous SNPs in MHC genes Supplemental Table 10: A comparison of nonsynonymous SNP (benign + damaging) Minor Allele Frequencies (MAFs) in MHC genes between Neandertal and modern human populations Supplemental Table 11: List of top 1% ape diversity genes Supplemental Table 12: Results of the top 1% ape diversity genes Gene Ontology enrichment analysis Supplemental Table 13: A comparison of nonsynonymous SNPs (benign + damaging) in top 1% ape diversity genes between Neandertal and modern human populations Supplemental Figure 1: Innate immune system gene permutation analyses - 10,000 sets of 73 randomly selected genes containing nonsynonymous SNPs Neandertal-European 800 Observed value 600 400 Probability that the observed ratio is 200 less than that expected by chance: Frequency of permutations P = 0.1944 0 0 0.5 1.0 1.5 2.0 2.5 Ratio Neandertal:European human nonsynonymous SNPs Neandertal-African Neandertal-Asian 800 800 Observed value Observed value 600 600 400 400 Probability that the Probability that the observed ratio is observed ratio is 200 200 less than that less than that expected by chance: expected by chance: Frequency of permutations P = 0.2789 Frequency of permutations P = 0.1400 0 0 0 0.5 1.0 1.5 2.0 2.5 0 0.5 1.0 1.5 2.0 2.5 Ratio Neandertal:African human Ratio Neandertal:Asian human nonsynonymous SNPs nonsynonymous SNPs Supplemental Figure 2: Virus-interacting protein gene permutation analyses - 10,000 sets of 164 randomly selected genes containing nonsynonymous SNPs Neandertal-European 700 Observed value 600 500 400 300 Probability that the observed ratio is 200 greater than that expected by chance: 100 Frequency of permutations P = 0.3547 0 0 0.5 1.0 1.5 Ratio Neandertal:European human nonsynonymous SNPs Neandertal-African Neandertal-Asian 700 700 Observed value Observed value 600 600 500 500 400 400 300 300 Probability that the Probability that the 200 observed ratio is 200 observed ratio is greater than that greater than that expected by chance: expected by chance: 100 100 Frequency of permutations P = 0.0647 Frequency of permutations P = 0.2618 0 0 0 0.5 1.0 1.5 0 0.5 1.0 1.5 Ratio Neandertal:African human Ratio Neandertal:Asian human nonsynonymous SNPs nonsynonymous SNPs Supplemental Figure 3: MHC gene permutation analyses - 10,000 sets of 13 randomly selected genes containing nonsynonymous SNPs Neandertal-European 2000 Observed value 1500 1000 Probability that the observed ratio is 500 greater than that expected by chance: Frequency of permutations P = 0.1556 0 0 2.0 4.0 6.0 8.0 Ratio Neandertal:European human nonsynonymous SNPs Neandertal-African Neandertal-Asian 2000 2000 Observed value Observed value 1500 1500 1000 1000 Probability that the Probability that the observed ratio is observed ratio is 500 greater than that 500 greater than that expected by chance: expected by chance: Frequency of permutations P = 0.0222 Frequency of permutations P = 0.0759 0 0 0 2.0 4.0 6.0 8.0 0 2.0 4.0 6.0 8.0 Ratio Neandertal:African human Ratio Neandertal:Asian human nonsynonymous SNPs nonsynonymous SNPs Supplemental Figure 4: Patterns of Neandertal and modern human nonsynonymous SNP diversity in MHC genes (n = 13) excluding the Altai Neandertal and one random modern human per popula- tion A 20 Predicted damaging 15 Predicted benign 10 5 Number of nonsyn. SNPs 0 Neandertal African European Asian Population B 1.0 MAF = 2 0.8 MAF = 1 0.6 0.4 0.2 Proportion of nonsyn. SNPs 0.0 Neandertal African European Asian Population Supplemental Figure 5: Significantly enriched gene ontology categories (red) among top 1% ape diversity genes Supplemental Table 1: A comparison of genome-wide nonsynonymous SNPs versus total (nonsynonymous + synonymous) SNPs between Neandertal and modern human populations Population Neandertal African European Asian Total Nonsynonymous SNPs 2469 6445 4561 4654 Total Synonymous SNPs 2472 8195 5692 5652 Total Nonsyn/Synon SNPs 4941 14640 10253 10306 Proportion Nonsyn:Total SNPs 0.4997 0.4402 0.4448 0.4516 Proportion Neandertal Nonsyn. - 0.383 0.541 0.531 SNPs to Modern Human Population Fisher's Exact Test P-value - 4.52E-13 2.29E-10 2.59E-08 Supplemental Table 2: PolyPhen-2 predictions for genome-wide nonsynonymous SNPs - damaging versus not damaging - for Neandertal and modern human populations Population Neandertal African European Asian Total Damaging Nonsyn. SNPs 1073 1878 1331 1380 Total Not-Damaging Nonsyn. SNPs 1396 4567 3230 3274 Total Nonsynonymous SNPs 2469 6445 4561 4654 Proportion Damaging SNPs:Total Nonsyn. SNPs 0.4346 0.2914 0.2918 0.2965 Fisher's Exact Test P-value - 2.20E-16 2.20E-16 2.20E-16 Supplemental Table 3: List of innate immune system genes Gene ID Description NLRP1 NOD-like receptors NLRP2 NOD-like receptors NLRP3 NOD-like receptors *See note NLRP4 NOD-like receptors NLRP5 NOD-like receptors NLRP6 NOD-like receptors NLRP7 NOD-like receptors NLRP8 NOD-like receptors NLRP9 NOD-like receptors NLRP10 NOD-like receptors NLRP11 NOD-like receptors NLRP12 NOD-like receptors NLRP13 NOD-like receptors NLRP14 NOD-like receptors NOD1 NOD-like receptors NOD2 NOD-like receptors NLRC3 NOD-like receptors NLRC4 NOD-like receptors NLRC5 NOD-like receptors *See note NLRX1 NOD-like receptors *See note CIITA NOD-like receptors *See note NAIP NOD-like receptors RIG-1 RIG-I-like receptors IFIH1 RIG-I-like receptors *See note LGP2 RIG-I-like receptors TLR1 Toll-Like receptors TLR2 Toll-Like receptors *See note TLR3 Toll-Like receptors *See note TLR4 Toll-Like receptors *See note TLR5 Toll-Like receptors TLR6 Toll-Like receptors TLR7 Toll-Like receptors TLR8 Toll-Like receptors TLR9 Toll-Like receptors TLR10 Toll-Like receptors CLEC7A C-type lectins CD209 C-type lectins CARD9 C-type lectins CLECL1 C-type lectins MR C-type lectins CD206 C-type lectins MRC1 C-type lectins CLEC16A C-type lectins IFI16 Cytosololic DNA sensors MNDA Cytosololic DNA sensors IFIX Cytosololic DNA sensors AIM2 Cytosololic DNA sensors MYD88 adaptors TRIF adaptors MAL adaptors TRAM adaptors IRAK4 adaptors IRAK1 adaptors C3 alternative pathway;classical pathways, Lectin pathway *See note C5 alternative pathway;classical pathways, Lectin pathway C6 alternative pathway;classical pathways, Lectin pathway C7 alternative pathway;classical pathways, Lectin pathway C8A alternative pathway;classical pathways, Lectin pathway C9 alternative pathway;classical pathways, Lectin pathway *See note CFB alternative pathway CFD alternative pathway CFP alternative pathway C2 classical pathways, Lectin pathway C1QA classical pathway C1QB classical pathway C1QC classical pathway C1R classical pathway *See note C1S classical pathway C4A classical pathways, Lectin pathway C4B classical pathways, Lectin pathway MASP1 Lectin pathway MASP2 Lectin pathway MBL2 Lectin pathway *Overlap with virus-interacting protein gene list Supplemental Table 4: List of virus-interacting protein
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