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Schematic representation of interaction between modern humans and Neanderthals. The geographic range of modern humans appears in orange, that of Neanderthals is in blue, and the contact zone in the Levant is in purple. a Neanderthals and Moderns were separated for several hundred thousand years, with Moderns co-evolving with tropical pathogens in Africa and Neanderthals co-evolving with temperate pathogens in Eurasia. b As early as 180–120 kya, Moderns began migrating out of Africa into the Levant4–6. Their range remained restricted to this region for tens of thousands of years, during which they interacted intermittently with Neanderthals4,7–9. We propose that during this period, each species was exposed to novel pathogen packages carried by the other species and experienced disease burden. Note that the contact zone depicted here may have been larger, possibly including regions in the Arabian Peninsula³⁶. c Around 45–50 kya, the inter-species dynamics destabilized and Moderns began expanding further into Eurasia. Within several thousand years, Moderns replaced Neanderthals throughout Eurasia4,5,7,13,14
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Neanderthals and modern humans both occupied the Levant for tens of thousands of years prior to the spread of modern humans into the rest of Eurasia and their replacement of the Neanderthals. That the inter-species boundary remained geographically localized for so long is a puzzle, particularly in light of the rapidity of its subsequent movement. H...
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... (IV) Disease. It is possible that the Neanderthals were more susceptible to diseases carried by AMH [4]. This could have had a significant impact on their ability to survive and reproduce. ...
DNA viruses that produce persistent infections have been proposed as potential causes for the extinction of Neanderthals, and, therefore, the identification of viral genome remnants in Neanderthal sequence reads is an initial step to address this hypothesis. Here, as proof of concept, we searched for viral remnants in sequence reads of Neanderthal genome data by mapping to adenovirus, herpesvirus and papillomavirus, which are double-stranded DNA viruses that may establish lifelong latency and can produce persistent infections. The reconstructed ancient viral genomes of adenovirus, herpesvirus and papillomavirus revealed conserved segments, with nucleotide identity to extant viral genomes and variable regions in coding regions with substantial divergence to extant close relatives. Sequence reads mapped to extant viral genomes showed deamination patterns of ancient DNA, and these ancient viral genomes showed divergence consistent with the age of these samples (≈50,000 years) and viral evolutionary rates (10⁻⁵ to 10⁻⁸ substitutions/site/year). Analysis of random effects showed that the Neanderthal mapping to genomes of extant persistent viruses is above what is expected by random similarities of short reads. Also, negative control with a nonpersistent DNA virus does not yield statistically significant assemblies. This work demonstrates the feasibility of identifying viral genome remnants in archaeological samples with signal-to-noise assessment.
... An innovative approach highlighted the fact that Neanderthal genomes were already expressing regions of DNA associated with responses to infection, including tuberculosis [27]. Lower genetic diversity, linked to inbreeding, has been postulated to result in higher susceptibility of Neanderthals to newly virulent infectious diseases [28,29]. Sophisticated modelling of population dynamics concluded that, on exposure to novel disease, the very rapid demise of Neanderthals was highly predictable [30]. ...
... 54 kya Mandrin in France, [38]). Greenbaum et al. [39] invoke infectious diseases specific to Neanderthals and modern humans-caused by Eurasian and African pathogens, respectively-to account for the mutual inability to extend their ranges. They propose epidemic models that incorporate adaptive genetic introgression and argue that modern humans may have been able to overcome their disease load before the Neanderthals and hence commence an enduring out-of-Africa dispersal. ...
... We focus on diseases that may have had their origins in southern East Asia or Southeast Asia, noting that the majority of zoonotic diseases are currently found in low latitude regions of the world. Third, we propose and analyse a wave-of-advance/reaction-diffusion model that incorporates a simplified version of the single-timescale non-spatial epidemiological dynamics assumed by Greenbaum et al. [39]. By adding the diffusion (i.e. ...
... Genetic studies of extant pathogens have identified many that have been associated with hominins since the Palaeolithic. Greenbaum et al. [39] have argued that an inter-species boundary between Neanderthals and modern humans in the Levant was maintained for tens of thousands of years during the Middle Palaeolithic by a disease barrier. Here we apply this reasoning to Upper Palaeolithic East Asia to explain why the southward spread of microblades stalled at the Qinling-Huaihe Line. ...
An unsolved archaeological puzzle of the East Asian Upper Palaeolithic is why the southward expansion of an innovative lithic technology represented by microblades stalled at the Qinling–Huaihe Line. It has been suggested that the southward migration of foragers with microblades stopped there, which is consistent with ancient DNA studies showing that populations to the north and south of this line had differentiated genetically by 19 000 years ago. Many infectious pathogens are believed to have been associated with hominins since the Palaeolithic, and zoonotic pathogens in particular are prevalent at lower latitudes, which may have produced a disease barrier. We propose a mathematical model to argue that mortality due to infectious diseases may have arrested the wave-of-advance of the technologically advantaged foragers from the north.
... Furthermore, according to Greenbaum et al. (2019), considering a long-lasting contact zone between Neanderthals and modern humans, surviving disease transmission would have been a factor in their final fate, giving modern humans an advantage in their subsequent spread into Eurasia. * It has been stated (Siquijor 2020) that our species is facing a nodal point where technological developments will define our evolution as a species. ...
... Human movement is known to impact the epidemiology of pathogens (Balcan et al., 2009;Blackburn et al., 2019;Dougherty et al., 2018;Funk et al., 2010;Greenbaum et al., 2019;Meloni et al., 2011;Yang et al., 2011). Increased mobility (Findlater & Bogoch, 2018) and anthropogenic environmental change (Altizer et al., 2013;Gottdenker et al., 2014) have contributed to a rapid expansion (Albery et al., 2020;Carlson et al., 2021;Keim & Wagner, 2009;Lebarbenchon et al., 2008;Patz et al., 2004) and mixing of pathogens into new environments (Dallas et al., 2019;Poisot et al., 2014;K. ...
Human movement may be an important driver of transmission dynamics for enteric pathogens but has largely been underappreciated except for international 'travelers' diarrhea or cholera. Phylodynamic methods, which combine genomic and epidemiological data, are used to examine rates and dynamics of disease matching underlying evolutionary history and biogeographic distributions, but these methods often are not applied to enteric bacterial pathogens. We used phylodynamics to explore the phylogeographic and evolutionary patterns of diarrheagenic E. coli in northern Ecuador to investigate the role of human travel in the geographic distribution of strains across the country. Using whole genome sequences of diarrheagenic E. coli isolates, we built a core genome phylogeny, reconstructed discrete ancestral states across urban and rural sites, and estimated migration rates between E. coli populations. We found minimal structuring based on site locations, urban vs. rural locality, pathotype, or clinical status. Ancestral states of phylogenomic nodes and tips were inferred to have 51% urban ancestry and 49% rural ancestry. Lack of structuring by location or pathotype E. coli isolates imply highly connected communities and extensive sharing of genomic characteristics across isolates. Using an approximate structured coalescent model, we estimated rates of migration among circulating isolates were 6.7 times larger for urban towards rural populations compared to rural towards urban populations. This suggests increased inferred migration rates of diarrheagenic E. coli from urban populations toward rural populations. Our results indicate that investments in water and sanitation prevention in urban areas could limit the spread of enteric bacterial pathogens among rural populations. J o u r n a l P r e-p r o o f Journal Pre-proof
... For example, the Eurasian dispersal moved very rapidly eastward through Asia and down as far as Australia by 50 ka, following a familiar (warmer) savannah ecozone (75,87), despite the presence of multiple Denisovan and other ISEA hominin groups as well as significant marine barriers through ISEA (75,87). The contrasting delay before AMH groups successfully colonized Europe around 47 ka, following an apparently unsuccessful initial foray around 54 ka (76), has often been explained by the presence of Neandertal populations in the area (88,89). However, our data suggest that this delay may also have been associated with a distinct phase of genetic adaptation to the very cold northern environments, first seen as the set of sweeps in the Initial Upper Paleolithic individuals ( Fig. 4 and SI Appendix, Tables S2 and S9) who appear in Europe immediately after the extreme cold conditions of Heinrich Event 5 (48 to 47 ka). ...
... In comparison, the absence of ancient Eurasian sweep genes that are overtly involved in immune system functioning stands out, especially as introgressed archaic hominin immunogenetic variants appear to have been consistent targets of selection after Neandertal admixture ~54 to 51 ka (90)(91)(92). Indeed, recent epidemiological models predict that the successful expansion of AMH beyond the Levant likely required human migrants to adapt to the novel pathogen package carried by local Neandertal groups (89). While further testing is needed to reconcile this apparent discrepancy, these results align with recent research emphasizing the importance of genetic adaptation in facilitating range expansions into novel environments (93,94) and suggest that multiple modes of selection, including soft sweeps and polygenic selection that were not directly evaluated in the present study, were involved in the peopling of Eurasia. ...
The evolutionarily recent dispersal of anatomically modern humans (AMH) out of Africa (OoA) and across Eurasia provides a unique opportunity to examine the impacts of genetic selection as humans adapted to multiple new environments. Analysis of ancient Eurasian genomic datasets (~1,000 to 45,000 y old) reveals signatures of strong selection, including at least 57 hard sweeps after the initial AMH movement OoA, which have been obscured in modern populations by extensive admixture during the Holocene. The spatiotemporal patterns of these hard sweeps provide a means to reconstruct early AMH population dispersals OoA. We identify a previously unsuspected extended period of genetic adaptation lasting ~30,000 y, potentially in the Arabian Peninsula area, prior to a major Neandertal genetic introgression and subsequent rapid dispersal across Eurasia as far as Australia. Consistent functional targets of selection initiated during this period, which we term the Arabian Standstill, include loci involved in the regulation of fat storage, neural development, skin physiology, and cilia function. Similar adaptive signatures are also evident in introgressed archaic hominin loci and modern Arctic human groups, and we suggest that this signal represents selection for cold adaptation. Surprisingly, many of the candidate selected loci across these groups appear to directly interact and coordinately regulate biological processes, with a number associated with major modern diseases including the ciliopathies, metabolic syndrome, and neurodegenerative disorders. This expands the potential for ancestral human adaptation to directly impact modern diseases, providing a platform for evolutionary medicine.
... (IV) Disease. It is possible that the Neanderthals were more susceptible to diseases carried by AMH [4]. This could have had a significant impact on their ability to survive and reproduce. ...
... Among DNA viruses causing persistent, or long-term, infections are Herpesviruses, Papillomaviruses and Adenoviruses. Herpesviruses, in particular, might have been a major cause for Neanderthal extinction as proposed in previous studies [4,6,17]. ...
DNA viruses that produce persistent infections have been proposed as potential causes for the extinction of Neanderthals. Here we searched for DNA viral genomes in sequencing reads of Neanderthal genome projects by mapping to references of Adenovirus, Herpesvirus and Papillomavirus, which are double stranded DNA viruses that establish lifelong latency. Reconstructed ancient viral genomes exhibited conserved segments with significant similarity to extant viral genomes. Variable positions were identified in coding regions and revealed substantial divergence to any extant closest relatives. Sequencing reads mapped to references showed typical deamination patterns of ancient DNA, suggesting that contamination with modern viral DNA is unlikely. These ancient viral genomes showed divergence corresponding with the age of these samples (approximately 50,000 years) and the viral evolutionary rates (10-5 to 10-8 substitutions/site/year). Variable regions reveal Neanderthal adaptive signatures, such as nonsynonymous substitutions in viral surface proteins that interact with receptors on host cells. Conserved regions here identified can be used as PCR targets for amplification of viral genomes from Neanderthal isolated DNA, in future experiments, that might close low coverage gaps in the assemblies for accurate reconstruction of these viral paleogenomes. Mapping Neanderthal and signatures of anatomically modern humans (AMH) in these viruses is essential to establish whether Neanderthals might have acquired these infections from invading modern human populations, as proposed to explain the extinction of Neanderthal upon contact with AMH.
... Therefore, individuals heterozygous at a given HLA locus may be able to defend against a greater pathogen diversity than homozygous individuals, or the benefit of specific alleles may fluctuate alongside pathogen incidence or load (Hughes and Nei 1988;Manczinger et al. 2019;Pierini and Lenz 2018;Takahata and Nei 1990). Throughout human evolution, these natural selective forces have led to the differentiation of HLA alleles among populations (Deng et al. 2021), the adaptive introgression of HLA alleles from ancient hominins (Abi-Rached et al. 2011;Greenbaum et al. 2019;Racimo et al. 2015), and ultimately the maintenance of diverse HLA alleles. ...
Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.
... Hypotheses of Neanderthal extinction have tracked general currents in paleontology and archaeology. Earlier models relied on competitive exclusion (Flores 1998;Banks et al. 2008), shifting to accounts emphasizing the role of environmental change (Staubwasser et al. 2018), catastrophic climatic events (Fitzsimmons et al. 2013;Cooper et al. 2021) or pathogen transmission (Houldcroft and Underdown 2016;Greenbaum et al. 2019). Recently, aligned with the 'demographic turn' in archaeology (Collard et al. 2016) and explanations emphasizing the relationship between demographic fluctuations and decreases in cultural complexity (Shennan 2001;Henrich 2004;Powell et al. 2009), paleoanthropologists argue that Neanderthal demography played a crucial role in their extinction (Kolodny and Feldman 2017;Vaesen et al. 2019Vaesen et al. , 2021Degioanni et al. 2019). ...
Neanderthal extinction is a matter of intense debate. It has been suggested that demography (as opposed to environment or competition) could alone provide a sufficient explanation for the phenomenon. We argue that demography cannot be a ‘stand-alone’ or ‘alternative’ explanation of token extinctions as demographic features are entangled with competitive and environmental factors, and further because demography should not be conflated with neutrality.
... Hypotheses of Neanderthal extinction have tracked general currents in paleontology and archaeology. Earlier models relied on competitive exclusion (Flores 1998;Banks et al. 2008), shifting to accounts emphasizing the role of environmental change (Staubwasser et al. 2018), catastrophic climatic events (Fitzsimmons et al. 2013;Cooper et al. 2021) or pathogen transmission (Houldcroft and Underdown 2016;Greenbaum et al. 2019). Recently, aligned with the 'demographic turn' in archaeology (Collard et al. 2016) and explanations emphasizing the relationship between demographic fluctuations and decreases in cultural complexity (Shennan 2001;Henrich 2004;Powell et al. 2009), paleoanthropologists argue that Neanderthal demography played a crucial role in their extinction (Kolodny and Feldman 2017;Vaesen et al. 2019Vaesen et al. , 2021Degioanni et al. 2019). ...
Published version available on RG or at this link: https://link.springer.com/article/10.1007/s10539-022-09881-y .
Neanderthal extinction is a matter of intense debate. It has been suggested that demography (as opposed to environment or competition) could alone provide a sufficient explanation for the phenomenon. We argue that demography cannot be a ‘stand-alone’ or ‘alternative’ explanation of token extinctions as demographic features are entangled with competitive and environmental factors, and further because demography should not be conflated with neutrality.
