Academic Journal
Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study
| العنوان: | Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study |
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| المؤلفون: | Oussalah, Abderrahim, Jeannesson-Thivisol, Elise, Chery, Céline, Perrin, Pascal, Rouyer, Pierre, Josse, Thomas, Cano, Aline, Barth, Magalie, Fouilhoux, Alain, Mention, Karine, Labarthe, François, Arnoux, Jean-Baptiste, Maillot, François, Lenaerts, Catherine, Dumesnil, Cécile, Wagner, Kathy, Terral, Daniel, Broue, Pierre, de Parscau, Loïc, Gay, Claire, Kuster, Alice, Bedu, Antoine, Besson, Gérard, Lamireau, Delphine, Odent, Sylvie, Masurel, Alice, Rodriguez-Guéant, Rosa-Maria, Feillet, François, Guéant, Jean-Louis, Namour, Fares |
| المساهمون: | Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Hôpital de la Timone CHU - APHM (TIMONE), Service de génétique Angers, Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud CHU - HCL (CHLS), Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Pédiatrie Générale CHU Clermont-Ferrand, CHU Estaing Clermont-Ferrand, CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne CHU Saint-Etienne (CHU ST-E), Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes), Service de Pédiatrie médicale - réanimation et néonatologie CHU Limoges, CHU Limoges, Centre Hospitalier Universitaire CHU Grenoble (CHUGA), Hôpital Pellegrin, CHU Bordeaux-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015) |
| المصدر: | ISSN: 2352-3964 ; EBioMedicine ; https://hal.univ-lorraine.fr/hal-02504210 ; EBioMedicine, 2020, 51, pp.102623. ⟨10.1016/j.ebiom.2019.102623⟩. |
| بيانات النشر: | HAL CCSD Elsevier |
| سنة النشر: | 2020 |
| المجموعة: | Université de Lorraine: HAL |
| مصطلحات موضوعية: | Population divergence, Balancing selection, Metabolic adaptation, Overdominance, Phenylketonuria, [SDV]Life Sciences [q-bio], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology |
| الوصف: | International audience ; Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients’ ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus.Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH.Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin_H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/31923802; hal-02504210; https://hal.univ-lorraine.fr/hal-02504210; https://hal.univ-lorraine.fr/hal-02504210/document; https://hal.univ-lorraine.fr/hal-02504210/file/2020_Oussalah_EBioMedicine_1.pdf; PRODINRA: 493067; PUBMED: 31923802; PUBMEDCENTRAL: PMC7000351 |
| DOI: | 10.1016/j.ebiom.2019.102623 |
| الاتاحة: | https://hal.univ-lorraine.fr/hal-02504210 https://hal.univ-lorraine.fr/hal-02504210/document https://hal.univ-lorraine.fr/hal-02504210/file/2020_Oussalah_EBioMedicine_1.pdf https://doi.org/10.1016/j.ebiom.2019.102623 |
| Rights: | http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.4C64DD36 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ebiom.2019.102623 |
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