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

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journal contribution
posted on 29.04.2021, 10:32 by Sandra Louzada, Walid Algady, Eleanor Weyell, Luciana W Zuccherato, Paulina Brajer, Faisal Almalki, Marilia O Scliar, Michel S Naslavsky, Guilherme L Yamamoto, Yeda AO Duarte, Maria Rita Passos-Bueno, Mayana Zatz, Fengtang Yang, Edward J Hollox
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.

Funding

This work was funded by SACB PhD studentships to WA and FA and Wellcome Trust grant WT098051 (F.Y. and S.L.).

History

Citation

Louzada, S., Algady, W., Weyell, E. et al. Structural variation of the malaria-associated human glycophorin A-B-E region. BMC Genomics 21, 446 (2020). https://doi.org/10.1186/s12864-020-06849-8

Version

VoR (Version of Record)

Published in

BMC Genomics

Volume

21

Issue

1

Pagination

446

Publisher

BMC

issn

1471-2164

eissn

1471-2164

Acceptance date

18/06/2020

Copyright date

2020

Available date

29/04/2021

Spatial coverage

England

Language

English