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The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels
Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
Wellcome Sanger Inst, Cambridge CB10 1SA, England.
Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
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2018 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, no 5, p. 769-776Article in journal (Refereed) Published
Abstract [en]

Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene. By developing a simple, specific, PCR-based assay for DUP4, we show that the DUP4 variant reaches a frequency of 13% in the population of a malaria-endemic village in southeastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation and show that DUP4 is associated with a malarial-related phenotype in a longitudinally followed population.

Place, publisher, year, edition, pages
2018. Vol. 103, no 5, p. 769-776
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Medical Genetics
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URN: urn:nbn:se:uu:diva-369600DOI: 10.1016/j.ajhg.2018.10.008ISI: 000448942100011PubMedID: 30388403OAI: oai:DiVA.org:uu-369600DiVA, id: diva2:1272106
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Wellcome trust, WT098051Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2018-12-18Bibliographically approved

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