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  1. Article ; Online: 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

    Cell Genomics, Vol 3, Iss 2, Pp 100248- (2023)

    2023  

    Abstract: 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 ... ...

    Abstract 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.
    Keywords ancient DNA ; immunity ; host defense ; natural selection ; local adaptation ; inflammatory disorders ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
    Subject code 930
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: IRF4 haploinsufficiency in a family with Whipple’s disease

    Antoine Guérin / Gaspard Kerner / Nico Marr / Janet G Markle / Florence Fenollar / Natalie Wong / Sabri Boughorbel / Danielle T Avery / Cindy S Ma / Salim Bougarn / Matthieu Bouaziz / Vivien Béziat / Erika Della Mina / Carmen Oleaga-Quintas / Tomi Lazarov / Lisa Worley / Tina Nguyen / Etienne Patin / Caroline Deswarte /
    Rubén Martinez-Barricarte / Soraya Boucherit / Xavier Ayral / Sophie Edouard / Stéphanie Boisson-Dupuis / Vimel Rattina / Benedetta Bigio / Guillaume Vogt / Frédéric Geissmann / Lluis Quintana-Murci / Damien Chaussabel / Stuart G Tangye / Didier Raoult / Laurent Abel / Jacinta Bustamante / Jean-Laurent Casanova

    eLife, Vol

    2018  Volume 7

    Abstract: Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing ... ...

    Abstract Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.
    Keywords Whipple's disease ; primary immunodeficiency ; IRF4 ; haploinsufficiency ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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