The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels

Algady, WalidUniv Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England (författare)

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.

Louzada, SandraWellcome Sanger Inst, Cambridge CB10 1SA, England (författare)
Carpenter, DanielleUniv Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England (författare)
Brajer, PaulinaUniv Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England (författare)
Farnert, AnnaKarolinska Institutet (författare)
Rooth, IngegerdNatl Inst Med Res, Nyamisati Malaria Res, Dar Es Salaam, Tanzania (författare)
Ngasala, BillyUppsala universitet,Internationell barnhälsa och nutrition,Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania(Swepub:uu)bilng827 (författare)
Yang, FengtangWellcome Sanger Inst, Cambridge CB10 1SA, England (författare)
Shaw, Marie-AnneUniv Leeds, Leeds Inst Med Res St Jamess, Leeds LS9 7TF, W Yorkshire, England (författare)
Hollox, Edward J.Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England (författare)
Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, EnglandWellcome Sanger Inst, Cambridge CB10 1SA, England (creator_code:org_t)

Ingår i:American Journal of Human Genetics: Elsevier BV103:5, s. 769-7760002-92971537-6605

Av författaren/redakt...: Algady, Walid; Louzada, Sandra; Carpenter, Danie ...; Brajer, Paulina; Farnert, Anna; Rooth, Ingegerd; visa fler...; Ngasala, Billy; Yang, Fengtang; Shaw, Marie-Anne; Hollox, Edward J ...; visa färre...

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