Neanderthal Legacies in Today's Pandemics

The sequencing of the Neanderthal genome has revealed that between 1-4% of the DNA in present-day non-African populations is derived from interbreeding with Neanderthals approximately 50,000-60,000 years ago. Subsequent analyses demonstrated that a significant proportion of these introgressed alleles localize to genes involved in immune regulation and pathogen defense, suggesting that archaic admixture exerted selective pressure on host-pathogen interactions.

During the Covid-19 pandemic, the relevance of this legacy became clinically apparent. Zeberg and Pääbo (2020) identified a Neanderthal-derived haplotype on chromosome 3 that confers a substantially increased risk of severe outcomes. Carriers of this haplotype demonstrated an odds ratio of ~2.0 for ICU admission and mechanical ventilation, with the highest allele frequency observed in South Asian populations (up to 50%). Conversely, subsequent work by the same group (Zeberg & Pääbo, 2021) identified a protective Neanderthal haplotype on chromosome 12, associated with a 22% reduced risk of progression to severe disease.

These findings illustrate the dual nature of archaic introgression. Certain variants provided adaptive advantages to ancient humans encountering novel Eurasian pathogens, enhancing antiviral defenses via toll-like receptor pathways and interferon responses. However, in contemporary settings, the same alleles predispose carriers to maladaptive hyper-inflammatory states, increasing susceptibility to acute respiratory distress in viral infections such as Covid-19.

The clinical implications extend beyond SARS-CoV-2. Genome-wide association studies (GWAS) have linked Neanderthal-derived alleles to a spectrum of immune-mediated disorders, including systemic lupus erythematosus, Crohn's disease, and type 2 diabetes (Dannemann & Kelso, 2017). This highlights an evolutionary trade-off: alleles advantageous in pathogen-rich Pleistocene environments may contribute to autoimmune dysregulation in modern, relatively sanitized conditions.

For clinicians, these discoveries underscore the heterogeneity of patient responses to infection beyond comorbidities and demographics. Ancestral genomic background may constitute an underappreciated risk modifier for disease severity. Although not yet integrated into clinical practice, the growing field of archaic genomics suggests that precision medicine could eventually stratify infection risk and therapeutic response according to both modern and archaic genetic variants.

References

• Green RE, Krause J, Briggs AW, et al. (2010). A Draft Sequence of the Neandertal Genome. Science, 328(5979):710-722. 
• Zeberg H, Pääbo S. (2020). The major genetic risk factor for severe Covid-19 is inherited from Neanderthals. Nature, 587:610-612. 
• Zeberg H, Pääbo S. (2021). A genomic region associated with protection against severe Covid-19 is inherited from Neanderthals. PNAS, 118(9): e2026309118.
• Dannemann M, Prüfer K, Kelso J. (2016). Functional implications of Neandertal introgression in modern humans. Genome Biology, 17:90.
• Dannemann M, Kelso J. (2017). The contribution of Neanderthals to phenotypic variation in modern humans. Am J Hum Genet, 101(4):578-589.