Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe
Gaspard Kerner,
Anna-Lena Neehus,
Quentin Philippot,
Jonathan Bohlen,
Darawan Rinchai,
Nacim Kerrouche,
Anne Puel,
Shen-Ying Zhang,
Stéphanie Boisson-Dupuis,
Laurent Abel,
Jean-Laurent Casanova,
Etienne Patin,
Guillaume Laval,
Lluis Quintana-Murci
Affiliations
Gaspard Kerner
Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, 75015 Paris, France; Corresponding author
Anna-Lena Neehus
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France
Quentin Philippot
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France
Jonathan Bohlen
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France
Darawan Rinchai
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
Nacim Kerrouche
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
Anne Puel
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France
Shen-Ying Zhang
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
Stéphanie Boisson-Dupuis
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
Laurent Abel
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
Jean-Laurent Casanova
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University Paris Cité, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA; Department of Pediatrics, Necker Hospital for Sick Children, 75015 Paris, France
Etienne Patin
Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, 75015 Paris, France
Guillaume Laval
Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, 75015 Paris, France
Lluis Quintana-Murci
Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, 75015 Paris, France; Collège de France, Chair of Human Genomics and Evolution, 75005 Paris, France; Corresponding author
Summary: Ancient genomics can directly detect human genetic adaptation to environmental cues. However, it remains unclear how pathogens have exerted selective pressures on human genome diversity across different epochs and affected present-day inflammatory disease risk. Here, we use an ancestry-aware approximate Bayesian computation framework to estimate the nature, strength, and time of onset of selection acting on 2,879 ancient and modern European genomes from the last 10,000 years. We found that the bulk of genetic adaptation occurred after the start of the Bronze Age, <4,500 years ago, and was enriched in genes relating to host-pathogen interactions. Furthermore, we detected directional selection acting on specific leukocytic lineages and experimentally demonstrated that the strongest negatively selected candidate variant in immunity genes, lipopolysaccharide-binding protein (LBP) D283G, is hypomorphic. Finally, our analyses suggest that the risk of inflammatory disorders has increased in post-Neolithic Europeans, possibly because of antagonistic pleiotropy following genetic adaptation to pathogens.
