It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations.

35It is common to find considerable genetic variation in susceptibility to infection in natural 36 populations. We have investigated whether natural selection increases this variation by 37 testing whether host populations show more genetic variation in susceptibility to pathogens 38 that they naturally encounter than novel pathogens. In a large cross-infection experiment 39 involving four species of Drosophila and four host-specific viruses, we always found greater 40 genetic variation in susceptibility to viruses that had coevolved with their host. We went on 41 to examine the genetic architecture of resistance in one host species, finding that there are 42 more major-effect genetic variants in coevolved host-parasite interactions. We conclude 43 that selection by pathogens increases genetic variation in host susceptibility, and much of 44 this effect is caused by the occurrence of major-effect resistance polymorphisms within 45 populations.46 47 53 to infection. Insect populations, like those of other organisms, typically contain considerable 54 genetic variation in susceptibility to infection [2, 4, 9, 10], and provide a convenient 55 laboratory model in which to investigate basic questions about how this variation is 56 maintained [11]. Within vector species like mosquitoes, resistant genotypes are less likely to 57 transmit parasites, and this has the potential to reduce disease in vertebrate populations 58 [12]. Where pathogens are contributing the decline of beneficial species like pollinators, high 59 levels of genetic variation may allow populations to recover [13]. Understanding the origins 60 of genetic variation in susceptibility is therefore a fundamental question in infectious disease 61 biology. 63As pathogens are harmful, natural selection is expected to favour resistant host genotypes. 64Directional selection on standing genetic variation will drive alleles to fixation, removing 65 variants from the population [14-16]. However, as directional selection also increases the 66 frequency of mutations that change the trait in the direction of selection, at equilibrium it is 67 expected to have no effect on levels of standing genetic variation (relative to mutation-drift 68 balance; [17]). However, selection mediated by pathogens may be different. Coevolution 69 with pathogens can result in the maintenance of both resistant and susceptible alleles by 70 negative frequency dependent selection [18, 19]. Similarly, when infection prevalence 71 exhibits geographical or temporal variation, selection can maintain genetic variation,72 especially if pleiotropic costs to resistance provide an advantage to susceptible individuals 73 when infection is rare [20-22]. Even when there is simple directional selection on alleles that 74 increase resistance, the direction of selection by pathogens may frequently change so 75 populations may not be at equilibrium. If selection favours rare alleles -such as new 76 mutations -directional selection can transiently increase genetic variation during their 77 spread through t...

Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.

AbstractModern humans have substantially admixed with multiple archaic hominins. New Guineans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals, whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these events remain poorly understood. Here we investigate the function of archaic alleles of both Denisovan and Neanderthal ancestry characterised within a previously published set of 72 genomes from individuals of Papuan genetic ancestry living in the island of New Guinea. By comparing the distribution of archaic and modern human variants, we are able to assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We find that archaic alleles are often located within cis-regulatory elements and transcribed regions of the genome, suggesting that they are actively involved in a wide range of cellular regulatory processes. We identify 39,954 high-confidence Denisovan variants that fall within annotated cis-regulatory elements and have the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes in present-day humans. Additionally, we detect a consistent signal across Denisovan variants of strong involvement in immune-related processes. Lastly, we show how such regulatory effects might underlie some of the observed gene expression differences between multiple Indonesian populations carrying varying amount of Denisovan DNA. Together, these data provide support for the hypothesis that, despite their broadly deleterious nature, archaic alleles actively contribute to modern human phenotypic diversity and might have facilitated early adaptation to non-African environments.