Zijun Zhou,1,2,5 Sigrid M.A Swagemakers,3 Mirthe S. Lourens,1,5 Narissara Suratannon,1,4 Peter J. van der Spek,3 Virgil A.S.H. Dalm,1,2,5 Willem A. Dik,1,5 Hanna IJspeert,1,5 P. Martin van Hagen1,2,4,5

1 Erasmus MC, University Medical Center Rotterdam, Laboratory Medical Immunology, department of Immunology, the Netherlands
2 Erasmus MC, University Medical Center Rotterdam, department of Internal Medicine, Division of Clinical Immunology, the Netherlands
3 Erasmus MC, University Medical Center Rotterdam, department of Pathology, Division of Clinical Bioinformatics, the Netherlands
4 Center of Excellence for Allergy and Clinical Immunology, Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
5 Erasmus MC, University Medical Center Rotterdam, Academic Center for Rare Immunological Diseases (RIDC), the Netherlands

Abstract

Background: Neanderthals were a species of archaic humans that became extinct around 40,000 years ago. Modern humans have inherited 1-6% of Neanderthal DNA as a result of interbreeding. These inherited Neanderthal genes have paradoxical influences, while some can provide protection to viral infections, some others are associated with autoimmune/auto-inflammatory diseases.
Objective: We aim to investigate whether genetic variants with strong detrimental effects on the function of the immune system could have potentially contributed to the extinction of the Neanderthal population.
Methods: We used the publically available genome information from an Altai Neanderthal and filtered for potentially damaging variants present in genes associated with inborn errors of immunity (IEI) and checked whether these variants were present in the genomes of the Denisovan, Vindija and Chagyrskaya Neanderthals.
Results: We identified 24 homozygous variants and 15 heterozygous variants in IEI-related genes in the Altai Neanderthal. Two homozygous variants in the UNC13D gene and one variant in the MOGS gene were present in all archaic genomes. Defects in the UNC13D gene are known to cause a severe and often fatal disease called hemophagocytic lymphohistiocystosis (HLH). One of these variants p.(N943S) has been reported in patients with HLH. Variants in MOGS are associated with glycosylation defects in the immune system affecting the susceptibility for infections.
Conclusion: Although the exact functional impact of these three variants needs further elucidation, we speculate that they could have resulted in an increased susceptibility to severe diseases and may have contributed to the extinction of Neanderthals after exposure to specific infections.
Key words: Neanderthals, Denisovan, inborn errors of immunity (IEI), innate immunity, Hemophagocytic
Lymphohistiocystosis (HLH), HLA, MOGS, UNC13D, MHC I presentation, glycosylation, cytotoxicity, viral infection, SARS-Cov2