Journal Article

Structural variation of the malaria-associated human glycophorin A-B-E region

Zuccherato, Luciana W., Hollox, Edward J., Brajer, Paulina, Scliar, Marilia O., Duarte, Yeda A. O., Yamamoto, Guilherme L., Passos-Bueno, Maria Rita, Weyell, Eleanor, Algady, Walid, Yang, Fengtang, Almalki, Faisal, Louzada, Sandra, Naslavsky, Michel S., Zatz, Mayana

2020

Overview

Background Approximately 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. Results Here, 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. Conclusions We 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Biomedical and Life Sciences / Biotechnology / Blood groups / Breakpoints / Cell interactions / Chromosome Breakpoints / Chromosome Mapping / Clinical aspects / Copy number variation / Databases, Genetic / Diploids / Disease Resistance / E protein / E region / Erythrocytes / Fusion protein / Gene mapping / Genes / Genetic research / Genomes / Genomic Structural Variation / Genomics / Glycophorin / Glycophorin B / Glycophorins - genetics / Glycoproteins / GYPA / Homologous recombination / Homology / Human and rodent genomics / Humans / Immune response / In Situ Hybridization, Fluorescence / Inversion / Life Sciences / Ligands / Malaria / Malaria, Falciparum - genetics / Mapping / Meiosis / Microarrays / Microbial Genetics and Genomics / Parasites / Plant Genetics and Genomics / Plasmodium falciparum / Proteomics / Receptors / Recombination hot spots / Research Article / Sequence Alignment / Structural variation / Variation / Vector-borne diseases / Whole Genome Sequencing