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Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

Genes & Immunity volume 5, pages 461–476 (2004)Cite this article

Abstract

Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total π=18.3 × 10−4). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3′ end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common ‘secretor haplotypes’ that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the ‘secretor haplotypes’ lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach.

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Acknowledgements

We thank A Hughes, V Kristensen, E Choi, E Tarazona, B Packer, S Savage and HC Erickson for discussion of the data; M Kiley, BJ Stewart, M Brown, A Crenshaw and D Kressley for their excellent technical assistance. TB was partially supported by a research traineeship-training grant of the Community Medicine program of the Ernst-Moritz-Arndt University Greifswald, Germany and the Alfried Krupp von Bohlen und Halbach foundation, Essen, Germany.

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Authors and Affiliations

  1. Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    T Bernig, J G Taylor & S J Chanock

  2. Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD, USA

    C B Foster

  3. Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, Bethesda, MD, USA

    B Staats, M Yeager & S J Chanock

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  1. T Bernig
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  2. J G Taylor
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  3. C B Foster
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  6. S J Chanock
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Corresponding author

Correspondence to S J Chanock.

Appendices

Appendix A

Details regarding MBL2 overlapping primers for PCR amplification are shown in Table A1.

Appendix B

Polymorphic sites at the MBL2 locus are listed in Table B1.

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Bernig, T., Taylor, J., Foster, C. et al. Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection. Genes Immun 5, 461–476 (2004). https://doi.org/10.1038/sj.gene.6364116

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