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. 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. 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.

中文翻译：

---

与疟疾有关的人类糖蛋白ABE区的结构变异。

大约5％的人类基因组显示出共同的结构变异，这种变异丰富了涉及免疫应答和细胞与细胞相互作用的基因。糖结构蛋白基因簇是公认的具有广泛结构变化的区域，其包括三个串联重复的区域，长度约120 kb，并携带高度同源的基因GYPA，GYPB和GYPE。糖蛋白A（由GYPA编码）和糖蛋白B（由GYPB编码）是在红细胞表面上高含量存在的糖蛋白，并且已被建议充当病毒病原体的诱饵受体。它们是恶性疟原虫（恶性疟原虫）入侵的受体。一种特殊的复杂结构变体，称为DUP4，可产生GYPB-GYPA融合基因，已知该基因可赋予对疟疾的抗性。糖蛋白基因簇中还存在许多其他结构变异，它们的特征仍然很差。在这里，我们分析了来自全球3234个二倍体基因组的序列，以分析糖蛋白基因座的结构变异，确认了1000个基因组计划队列中的15个变异体，发现了9个新变异体，并使用fibre-FISH和断点作图来表征这些变异体的选择在序列级别。我们确定了在西非人中以可预见的频率预测会产生新型融合基因和常见反向复制变异的变异。我们表明，几乎所有的变体都可以通过非等位基因同源重组以及将结构变体断点与重组热点图进行比较来解释，证实了特定减数分裂重组热点对该区域结构变异形成的重要性。我们确定并验证人类糖蛋白ABE基因簇中的大型结构变异，这可能与疟疾的不同临床方面有关。