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Human Molecular Genetics Advance Access published online on August 2, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl193
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received May 24, 2006
Revised July 5, 2006
Accepted July 26, 2006

Article

Evolutionary Insights into the High Worldwide Prevalence of MBL2 Deficiency Alleles

Paul Verdu 1, Luis B. Barreiro 2, Etienne Patin 1, Antoine Gessain 3, Olivier Cassar 3, Judith R. Kidd 4, Kenneth K. Kidd 4, Doron M. Behar 5, Alain Froment 6, Evelyne Heyer 6, Lucas Sica 7, Jean-Laurent Casanova 8, Laurent Abel 9, and Lluís Quintana-Murci 10 *

1 CNRS FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases, Institut Pasteur, Paris, France; CNRS UMR 5145, Musée de l'Homme, Paris, France
2 CNRS FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases, Institut Pasteur, Paris, France
3 Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France
4 Yale University School of Medicine, New Haven, USA
5 Bruce Rappaport Faculty of Medicine and Research Institute, Technion and Rambam Medical Center, Haifa, Israel
6 CNRS UMR 5145, Musée de l'Homme, Paris, France
7 Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon
8 Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, Paris 75015, France; Unité d'Hématologie et Immunologie Pédiatriques, Hôpital Necker Enfants Malades, 75015 Paris, France
9 Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, Paris 75015, France
10 CNRS FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France

* To whom correspondence should be addressed.
Lluís Quintana-Murci, E-mail: Quintana{at}pasteur.fr


  Abstract

Human mannose-binding lectin (MBL) is a member of the collectin protein family that binds a broad range of microorganisms and activates the lectin-complement pathway of innate immunity. Common alleles of MBL2 disrupt the MBL protein or modulate the amount of protein produced, resulting in MBL deficiency. The clinical manifestations of MBL deficiency have been extensively studied but the actual role of this lectin in immunity to infection remains a matter of strong debate. MBL is commonly thought to play a key role in protective immunity, because MBL deficiency has been associated with an increase in susceptibility to infectious diseases. However, the high worldwide prevalence of multiple MBL2 deficiency or low-producing alleles suggests the converse, that MBL deficiency confers protection. To explore the underlying forces accounting for the high worldwide prevalence of MBL2 deficiency alleles, we characterized genetic diversity in and around the MBL2 genomic region in 1,166 chromosomes from 24 worldwide populations. Our results clearly demonstrate that the patterns of MBL2 variation are compatible with neutral evolution, as opposed to negative, positive, or balanced natural selection. The high worldwide frequencies of MBL2 alleles associated with the production of little or no protein therefore result exclusively from human migration and genetic drift. The evolutionary neutrality of MBL2 strongly supports the notion that MBL2 variation does not have strong effects on population fitness, suggesting therefore that this lectin is largely redundant in host human defences.


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