An evolutionary medicine perspective on Neandertal extinction

Abstract

The Eurasian sympatry of Neandertals and anatomically modern humans -beginning at least 45,000 years ago and lasting for more than 5,000 years -has long sparked anthropological interest into the factors that potentially contributed to Neandertal extinction. Among many different hypotheses, the "differential pathogen resistance" extinction model posits that Neandertals were disproportionately affected by exposure to novel infectious diseases that were transmitted during the period of spatiotemporal sympatry with modern humans. Comparisons of new archaic hominin paleogenome sequences with modern human genomes have confirmed a history of genetic admixture -and thus direct contact -between humans and Neandertals. Analyses of these data have also shown that Neandertal nuclear genome genetic diversity was likely considerably lower than that of the Eurasian anatomically modern humans with whom they came into contact, perhaps leaving Neandertal innate immune systems relatively more susceptible to novel pathogens. In this study, we compared levels of genetic diversity in genes for which genetic variation is hypothesized to benefit pathogen defense among Neandertals and African, European, and Asian modern humans, using available exome sequencing data (six chromosomes per population). We observed that Neandertals had only 31-39% as many nonsynonymous (amino acid changing) polymorphisms across 73 innate immune system genes compared to modern human populations. We also found that Neandertal genetic diversity was relatively low in an unbiased set of balancing selection candidate genes for primates -genes with the highest 1% genetic diversity genome-wide in non-human apes. In contrast, Neandertals had similar to higher levels of genetic diversity than humans in 13 major histocompatibility complex (MHC) genes. Thus, while Neandertals may have been relatively more susceptible to some novel pathogens and differential pathogen resistance could be considered as one potential contributing factor in their extinction, this model does have limitations.

Immune gene diversity in archaic and present-day humans

“…Our results are consistent with previous studies that have reported lower genetic diversity in archaic humans than in present-day humans, both genome-wide and in protein-coding regions (Castellano et al 2014;Meyer et al 2012;Prufer et al 2017;Prufer et al 2014). In a recent study, lower protein-coding diversity observed in a set of 73 innate immunity genes (Sullivan et al 2017) was interpreted as suggesting that Neandertals may have lacked the functional immune diversity necessary to survive new pathogen infections (Houldcroft and Underdown 2016;Sullivan et al 2017;Wolff and Greenwood 2010). Here, we re-evaluated this hypothesis by studying the diversity of a set of 1,548 innate immune genes, and by explicitly comparing them to all autosomal protein-coding genes.…”

“…It has been suggested that lack of functional variation in immune-related genesespecially in genes related to the innate immune system which is known to serve as a first defence mechanism against pathogen detection -, some of which are targets of long-term balancing selection (Bitarello et al 2018;Key et al 2014b;Meyer and Thomson 2001), could have contributed to Neandertal extinction (Houldcroft and Underdown 2016;Sullivan et al 2017;Wolff and Greenwood 2010). This is known as the differential pathogen resistance hypothesis (DPRH), and (Sullivan et al 2017) recently presented evidence both for and against this hypothesis.…”

“…It has been suggested that lack of functional variation in immune-related genesespecially in genes related to the innate immune system which is known to serve as a first defence mechanism against pathogen detection -, some of which are targets of long-term balancing selection (Bitarello et al 2018;Key et al 2014b;Meyer and Thomson 2001), could have contributed to Neandertal extinction (Houldcroft and Underdown 2016;Sullivan et al 2017;Wolff and Greenwood 2010). This is known as the differential pathogen resistance hypothesis (DPRH), and (Sullivan et al 2017) recently presented evidence both for and against this hypothesis. Using the exome data (Castellano et al 2014), they found that Neandertals had substantially lower numbers of non-synonymous single nucleotide polymorphisms (SNPs) than present-day humans in 73 innate immune-related genes, 12 genes of the Major Histocompatibility Complex (MHC), 164 virus-interacting protein genes, and 73 loci with high diversity in chimpanzee (which might be enriched for targets of balancing selection).…”

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

“…Moreover, OAS1 is among the most diverse genes in both humans and non-human primates. Indeed, a recent analysis of genome-wide sequence data from a total of 55 individuals from four non-human ape species, chimpanzee (Pan troglodytes ellioti), bonobo (Pan paniscus), gorilla (Gorilla gorilla gorilla), and orangutan (Pongo abelii), identified OAS1 as in the top 1% of genes showing the largest levels of nucleotide diversity among ape species [43], consistent with a scenario of long-term balancing selection (OAS2 and OAS3 are ranked in the 60th and 36th percentile of the genome-wide distribution, respectively) or, as previous research has suggested, rapid evolution across the primate order [44]. Further supporting the idea of balancing selection on the introgressed haplotype, our functional data suggest that the Neandertal haplotype contributes a range of gene expression responses in a cell-type and stimulusspecific manner.…”

Paleomedicine and the use of plant secondary compounds in the Paleolithic and Early Neolithic

“…In the case of surgical interventions, plants with analgesic properties may also have been used. Sullivan et al suggested that novel pathogens and differential pathogenetic resistance may have contributed to the extinction of Neanderthals. A recent example of the devastating effects that pathogens can have was the decimation of the indigenous people of the American continent, where around 90% of the population died from a range of infectious diseases against which they had no natural resistance.…”