Human Molecular Genetics Advance Access originally published online on August 2, 2006
Human Molecular Genetics 2006 15(17):2650-2658; doi:10.1093/hmg/ddl193
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Evolutionary insights into the high worldwide prevalence of MBL2 deficiency alleles
1 CNRS FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases and 2 Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France, 3 CNRS UMR 5145, Musée de l'Homme, 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 Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon, 7 Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, Paris 75015, France and 8 Unité d'Hématologie et Immunologie Pédiatriques, Hôpital Necker Enfants Malades, 75015 Paris, France
* To whom correspondence should be addressed at: CNRS FRE2849, Institut Pasteur, 25 rue Dr Roux, 75015 Paris, France. Tel: +33 145688920; Fax: +33 145688639; Email: quintana{at}pasteur.fr
Received May 24, 2006; Revised July 5, 2006; Accepted July 26, 2006
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 1166 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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