Abstract
BackgroundApproximately 5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120 kb in length and carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A (encoded by GYPA) and glycophorin B (encoded by GYPB) are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They are receptors for the invasion of the protist parasite Plasmodium falciparum, a causative agent of malaria. A particular complex structural variant, called DUP4, creates a GYPB-GYPA fusion gene known to confer resistance to malaria. Many other structural variants exist across the glycophorin gene cluster, and they remain poorly characterised.ResultsHere, we analyse sequences from 3234 diploid genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection of these variants using fibre-FISH and breakpoint mapping at the sequence level. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by non-allelic homologous recombination and by comparing the structural variant breakpoints with recombination hotspot maps, confirm the importance of a particular meiotic recombination hotspot on structural variant formation in this region.ConclusionsWe identify and validate large structural variants in the human glycophorin A-B-E gene cluster which may be associated with different clinical aspects of malaria.
Highlights
5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions
Structural variation using sequence read depth analysis Previous work by us and others has shown that unbalanced structural variation - that is, variation that causes a copy number change - can be effectively discovered by measuring the relative depth of sequence reads across the glycophorin region [11, 12]
We identified a new duplication variant, termed DUP29, that had not been identified previously in that cohort
Summary
5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. Like the glycophorin locus, are prone to genomic rearrangements, and the DUP4 variant is a complex variant that generates a GYPBGYPA fusion gene, with potential somatic variation in fusion gene copy number [11, 12]. This fusion gene is expressed and can be detected on the cell surface as the Dantu blood group [11], and erythrocytes carrying this blood group are known to be resistant to infection by Plasmodium falciparum in cell culture [16]
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