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Interpretation of the models
Our results demonstrate that disease and introgression dynamics can explain the persistent stable phase of inter-species dynamics that preceded the replacement of Neanderthals by Moderns. They also suggest that such dynamics may have implications regarding the replacement phase.
In the two-time-scales model, the adaptive response is in the contact rate itself, which is akin to assuming conscious or unconscious behavioral or cultural modification of contact rates49,50; for example, a band of hunter–gatherers may decrease inter-species contact by not accepting, or not taking by force, individuals from bands of the other species. They may limit contact even further by avoiding other bands completely. However, reduction in contact rates in response to disease burden may also have occurred due to decreased population densities, and therefore this model may be viewed as one that implicitly incorporates the combined effect of both behavior and demography.
The model includes an implicit assumption regarding intra-species gene flow. Immune-related alleles are assumed to spread rapidly once introgressed; that is, introgression that relieves disease burden acts on each species as if it were a cohesive unit. Although this assumption may be inappropriate for large, geographically structured, populations, our model is concerned only with the peripheral region in which interaction occurs, and in which selection could have acted to favor beneficial immune-related genes.
Fig. 5
We also assume that genetic adaptation via de novo mutations is negligible compared to adaptive introgression in reducing disease burden. Under the scenario of Neanderthal–Modern interaction, this assumption amounts to assuming that introgression of pre-adapted alleles through interbreeding occurs more frequently than the appearance of novel mutations conveying resistance to a disease. We explore incorporation of regular adaptation into the models in Supplementary Note 2, with results qualitatively similar to those presented in Figs. 3–5, but with shorter stable phases.
In our alternative single-time-scale model, the adaptive response is a reduction in the level of disease-induced mortality, which is akin to assuming evolution of tolerance to the invading pathogen package. These exclusively demographic, rather than behavioral, dynamics can be readily interpreted in the context of an immunological or physiological response to assaults from novel pathogens. The model also assumes rapid within-species assimilation of acquired tolerance, similar to the assumption in the two-time-scales model. Modeling of regular adaptation in the single-time-scale model is addressed in Supplementary Note 2. Competition for resources between the species in the contact zone may have demographic consequences, but is not incorporated into the model; however, we have added competition to our model in Supplementary Note 3, and our analysis again yields similar results to those in Fig. 5, but with longer stable phases.
We have shown here that disease dynamics are sufficient to explain the long period in which the contact zone was confined to the Levant; however, we have not considered other factors that may have played a role. One such factor may be the species’ adaptation to their respective environments at the core of their geographical ranges7,34. Many such adaptations have been proposed, ranging from morphology supporting faster or slower heat loss37,51 to physiological traits that support different hunting methods39. Such adaptations could have limited migration of bands of one species into regions occupied by the other species, similarly to the effect of disease burden. However, local adaptation by itself would not explain the rapid destabilization of the interaction front. The period of 50–40 kya was not characterized by unprecedented environmental change that would have provided Moderns an advantage across the entirety of the Neanderthals' range52,53,54,55 (but see refs. 56,57 and the discussion in ref. 58). Similarly, no clear evidence has been found so far of a cultural shift among Moderns that would have provided them a sudden advantage over the Neanderthals59.
Fig. 4
Implications for the replacement of Neanderthals by modern humans
When the initial conditions are asymmetric, one species appears to acquire tolerance to novel diseases sooner than the other (Figs. 4 and 5d–f), permitting that species to expand its range earlier. A particularly plausible source of asymmetry in the case of modern humans and Neanderthals is the difference in pathogen complexes to which each of the species was adapted. Biotic diversity, on many taxonomic scales, is higher in the tropics60, including in human pathogens43,44. In the Levant, where climate was intermediate between the temperate and tropical zones61, many pathogens carried by both species would have been potential sources for diseases. It is therefore possible that Neanderthals would have had to adapt to a larger number of pathogens than did Moderns (P2(0) > P1(0) or α2(0) > α1(0) in our models, with species 1 representing Moderns and species 2 representing Neanderthals), leading to earlier Modern release from disease burden (Figs. 4 and 5e–g). Then, as modern humans recovered from disease burden and expanded further into Eurasia, they might have encountered bands of Neanderthals whose lineages had not interacted with Moderns, and who had been far enough from the long-standing front of interaction not to have benefited from immune-related adaptive introgressions. These bands would thus have been even more vulnerable than Neanderthals in the Levant to pathogens carried by Moderns.
The scenario is analogous to more recent events, such as when Europeans arrived in the Americas in the 15th and 16th centuries with a more potent pathogen package than that of the local inhabitants, not because of climatic diferences, but because of higher population densities and contact with domesticated animals48. The colonization of the Americas was followed by rapid replacement of Native Americans, facilitated by disease spread45,46,47,48.
Alternatively, a long-standing hypothesis argues that a genetic diversity difference upon contact could produce significant epidemics in the less-diverse population, due to immunological consequences of reduced diversity in that population’s MHC region46. According to this hypothesis, asymmetry in susceptibility to pathogens may also have been a result of differences between the species in genetic diversities. Ancient genomes suggest that Moderns’ genetic diversity exceeded that of Neanderthals’62,63, in which case modern human populations might have been less susceptible to Neanderthal diseases than Neanderthal populations were to modern human diseases. This asymmetry could then produce the same asymmetries in model parameters described above for pathogen diversities.
Analogously, in animals, severe asymmetric epidemics can be caused by contact between closely related species that have been separated for long periods64. For example, an ongoing epidemic of squirrelpox in Eurasian red squirrels in the UK and Ireland was most likely introduced by gray squirrels, which are native to North America but invasive in Europe65,66. Gray squirrels are largely tolerant to squirrelpox, having co-evolved with the virus in North America, but the disease is almost always fatal to red squirrels67. Consequently, red squirrel populations are currently in significant decline, and they are often replaced by gray squirrels65. In other examples of contact between closely related animal species, disease transmission may produce some of the elements of our scenario: reinforcement of a narrow contact zone, erosion of the contact zone, and promotion of hybridizations between the species64.
That diseases played an important role in the inter-species dynamics of modern humans and Neanderthals31,32,41,42 is suggested by studies that compare Neanderthal genomes with current-day Modern genomes, and that argue that genomic regions relating to disease immunity and tolerance are enriched in introgression of Neanderthal genes2,22,26,28,29,31. This result suggests that introgression was adaptive, and that diseases were a significant enough burden that natural selection in Moderns favored introgressed lineages that included immune-related genes. Interestingly, recent indications from analysis of European Neanderthal genomes suggest that gene flow was not symmetric between the species, and that more genes were introgressed from Neanderthals into Moderns than in the other direction63. This asymmetry is predicted by our two-time-scale model, which includes differential inter-species contact intensities (Fig. 4a, dashed curves); note, however, that the Neanderthals analyzed in producing this evidence of asymmetry were not sampled in the Levant63.
Nature Communications volume 10, Article number: 5003 (2019)
Our results demonstrate that disease and introgression dynamics can explain the persistent stable phase of inter-species dynamics that preceded the replacement of Neanderthals by Moderns. They also suggest that such dynamics may have implications regarding the replacement phase.
In the two-time-scales model, the adaptive response is in the contact rate itself, which is akin to assuming conscious or unconscious behavioral or cultural modification of contact rates49,50; for example, a band of hunter–gatherers may decrease inter-species contact by not accepting, or not taking by force, individuals from bands of the other species. They may limit contact even further by avoiding other bands completely. However, reduction in contact rates in response to disease burden may also have occurred due to decreased population densities, and therefore this model may be viewed as one that implicitly incorporates the combined effect of both behavior and demography.
The model includes an implicit assumption regarding intra-species gene flow. Immune-related alleles are assumed to spread rapidly once introgressed; that is, introgression that relieves disease burden acts on each species as if it were a cohesive unit. Although this assumption may be inappropriate for large, geographically structured, populations, our model is concerned only with the peripheral region in which interaction occurs, and in which selection could have acted to favor beneficial immune-related genes.
Fig. 5
We also assume that genetic adaptation via de novo mutations is negligible compared to adaptive introgression in reducing disease burden. Under the scenario of Neanderthal–Modern interaction, this assumption amounts to assuming that introgression of pre-adapted alleles through interbreeding occurs more frequently than the appearance of novel mutations conveying resistance to a disease. We explore incorporation of regular adaptation into the models in Supplementary Note 2, with results qualitatively similar to those presented in Figs. 3–5, but with shorter stable phases.
In our alternative single-time-scale model, the adaptive response is a reduction in the level of disease-induced mortality, which is akin to assuming evolution of tolerance to the invading pathogen package. These exclusively demographic, rather than behavioral, dynamics can be readily interpreted in the context of an immunological or physiological response to assaults from novel pathogens. The model also assumes rapid within-species assimilation of acquired tolerance, similar to the assumption in the two-time-scales model. Modeling of regular adaptation in the single-time-scale model is addressed in Supplementary Note 2. Competition for resources between the species in the contact zone may have demographic consequences, but is not incorporated into the model; however, we have added competition to our model in Supplementary Note 3, and our analysis again yields similar results to those in Fig. 5, but with longer stable phases.
We have shown here that disease dynamics are sufficient to explain the long period in which the contact zone was confined to the Levant; however, we have not considered other factors that may have played a role. One such factor may be the species’ adaptation to their respective environments at the core of their geographical ranges7,34. Many such adaptations have been proposed, ranging from morphology supporting faster or slower heat loss37,51 to physiological traits that support different hunting methods39. Such adaptations could have limited migration of bands of one species into regions occupied by the other species, similarly to the effect of disease burden. However, local adaptation by itself would not explain the rapid destabilization of the interaction front. The period of 50–40 kya was not characterized by unprecedented environmental change that would have provided Moderns an advantage across the entirety of the Neanderthals' range52,53,54,55 (but see refs. 56,57 and the discussion in ref. 58). Similarly, no clear evidence has been found so far of a cultural shift among Moderns that would have provided them a sudden advantage over the Neanderthals59.
Fig. 4
Implications for the replacement of Neanderthals by modern humans
When the initial conditions are asymmetric, one species appears to acquire tolerance to novel diseases sooner than the other (Figs. 4 and 5d–f), permitting that species to expand its range earlier. A particularly plausible source of asymmetry in the case of modern humans and Neanderthals is the difference in pathogen complexes to which each of the species was adapted. Biotic diversity, on many taxonomic scales, is higher in the tropics60, including in human pathogens43,44. In the Levant, where climate was intermediate between the temperate and tropical zones61, many pathogens carried by both species would have been potential sources for diseases. It is therefore possible that Neanderthals would have had to adapt to a larger number of pathogens than did Moderns (P2(0) > P1(0) or α2(0) > α1(0) in our models, with species 1 representing Moderns and species 2 representing Neanderthals), leading to earlier Modern release from disease burden (Figs. 4 and 5e–g). Then, as modern humans recovered from disease burden and expanded further into Eurasia, they might have encountered bands of Neanderthals whose lineages had not interacted with Moderns, and who had been far enough from the long-standing front of interaction not to have benefited from immune-related adaptive introgressions. These bands would thus have been even more vulnerable than Neanderthals in the Levant to pathogens carried by Moderns.
The scenario is analogous to more recent events, such as when Europeans arrived in the Americas in the 15th and 16th centuries with a more potent pathogen package than that of the local inhabitants, not because of climatic diferences, but because of higher population densities and contact with domesticated animals48. The colonization of the Americas was followed by rapid replacement of Native Americans, facilitated by disease spread45,46,47,48.
Alternatively, a long-standing hypothesis argues that a genetic diversity difference upon contact could produce significant epidemics in the less-diverse population, due to immunological consequences of reduced diversity in that population’s MHC region46. According to this hypothesis, asymmetry in susceptibility to pathogens may also have been a result of differences between the species in genetic diversities. Ancient genomes suggest that Moderns’ genetic diversity exceeded that of Neanderthals’62,63, in which case modern human populations might have been less susceptible to Neanderthal diseases than Neanderthal populations were to modern human diseases. This asymmetry could then produce the same asymmetries in model parameters described above for pathogen diversities.
Analogously, in animals, severe asymmetric epidemics can be caused by contact between closely related species that have been separated for long periods64. For example, an ongoing epidemic of squirrelpox in Eurasian red squirrels in the UK and Ireland was most likely introduced by gray squirrels, which are native to North America but invasive in Europe65,66. Gray squirrels are largely tolerant to squirrelpox, having co-evolved with the virus in North America, but the disease is almost always fatal to red squirrels67. Consequently, red squirrel populations are currently in significant decline, and they are often replaced by gray squirrels65. In other examples of contact between closely related animal species, disease transmission may produce some of the elements of our scenario: reinforcement of a narrow contact zone, erosion of the contact zone, and promotion of hybridizations between the species64.
That diseases played an important role in the inter-species dynamics of modern humans and Neanderthals31,32,41,42 is suggested by studies that compare Neanderthal genomes with current-day Modern genomes, and that argue that genomic regions relating to disease immunity and tolerance are enriched in introgression of Neanderthal genes2,22,26,28,29,31. This result suggests that introgression was adaptive, and that diseases were a significant enough burden that natural selection in Moderns favored introgressed lineages that included immune-related genes. Interestingly, recent indications from analysis of European Neanderthal genomes suggest that gene flow was not symmetric between the species, and that more genes were introgressed from Neanderthals into Moderns than in the other direction63. This asymmetry is predicted by our two-time-scale model, which includes differential inter-species contact intensities (Fig. 4a, dashed curves); note, however, that the Neanderthals analyzed in producing this evidence of asymmetry were not sampled in the Levant63.
Nature Communications volume 10, Article number: 5003 (2019)