Structural variants are mapped that are correlated with a reduced risk of severe malaria. Pathogens select for genomic variants Large-scale deletions and duplications of genes, referred to as structural variants (SVs), are common within the human genome and have been linked to disease. Examining a genomic region that appears to confer a selective benefit, Leffler et al. used fine mapping to identify a specific SV that reduces the risk of severe malaria by an estimated 40% (see the Perspective by Winzeler). Data from African individuals revealed that populations harbor different SVs in this region. Furthermore, by dissecting a highly complex genomic region, the authors identified the likely causal element. This element encodes hybrid genes that affect glycophorin proteins, which are used by the malarial parasite in infection and are associated with resistance to severe disease. Science, this issue p. eaam6393; see also p. 1122 INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum, this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease. A structural variant creating hybrid glycophorin genes is associated with protection from severe malaria. The reference haplotype carries three glycophorin genes, two of which (GYPA and GYPB) are expressed as proteins on the red blood cell surface. The malaria-protective haplotype carries five glycophorin genes, including two hybrid genes that encode the Dantu blood group antigen and are composed of a GYPB extracellular domain and GYPA intracellular domain. These glycophorins serve as receptors for malaria-parasite ligands during red blood cell invasion. The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

中文翻译：

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通过红细胞侵袭受体的结构变异来抵抗疟疾

绘制了与严重疟疾风险降低相关的结构变体。病原体选择基因组变异 基因的大规模缺失和重复，称为结构变异 (SV)，在人类基因组中很常见，并且与疾病有关。Leffler 等人检查了似乎具有选择性益处的基因组区域。使用精细映射来识别特定的 SV，该 SV 可将严重疟疾的风险降低约 40%（参见 Winzeler 的观点）。来自非洲个体的数据显示，该地区的人群拥有不同的 SV。此外，通过剖析一个高度复杂的基因组区域，作者确定了可能的因果因素。该元件编码影响血型糖蛋白的杂合基因，它们被疟原虫用于感染，并与对严重疾病的抵抗力有关。科学，本期第 3 页。eaam6393; 另见第 1122 简介 疟原虫通过侵入和复制红细胞内部而引起人类疾病。就恶性疟原虫而言，这可能导致严重的疟疾，这是非洲儿童死亡的主要原因。这种寄生虫通过与决定多态性 MNS 血型系统的血型糖蛋白 GYPA 和 GYPB 等表面蛋白相互作用进入红细胞。在最近的一项全基因组关联研究中，我们在编码这些入侵受体的基因簇附近发现了与预防严重疟疾相关的等位基因。基本原理 由于相邻血型糖蛋白基因之间的高度序列相似性和相对缺乏捕获撒哈拉以南非洲遗传多样性的可用序列数据，对该基因座的遗传变异及其与严重疟疾的关系的研究具有挑战性。为了更好地评估血型糖蛋白基因的变异是否可以解释关联信号，我们从撒哈拉以南非洲人群中生成了额外的序列数据，并开发了一种分析方法来表征这个复杂基因座的结构变异。结果 使用来自 10 个非洲族群的 765 个新测序的人类基因组以及来自 1000 Genomes Project 的数据，我们生成了跨血型糖蛋白区域的单倍型参考面板。除了单核苷酸多态性和短插入缺失，我们使用测序读取深度分析了大拷贝数变体 (CNV)，并发现了广泛的结构多样性。通过从这个参考小组对来自三个非洲人群的 4579 例重症疟疾病例和 5310 例对照进行估算，我们发现一个复杂的 CNV，这里称为 DUP4，与对重症疟疾的抵抗力有关，并充分解释了先前报道的关联信号。在我们的样本中，DUP4 仅存在于东非，这种定位以及 DUP4 单倍型之间的相似程度表明它最近的频率有所增加，可能是由于疟疾的自然选择。为了评估这种结构变体的潜在功能后果，我们分析了来自多个个体的高覆盖度序列读取数据，以生成 DUP4 染色体结构模型。DUP4 单倍型包含五个血型糖蛋白基因，包括两个杂合基因，它们将 GYPB 的细胞外结构域与 GYPA 的跨膜和细胞内结构域并列。注意到这些预测的杂种是 MNS 血型系统中 Dantu 抗原的特征，我们对 Dantu 阳性个体进行了测序，并确认 DUP4 是 Dantu NE 血型变体的分子基础。结论 尽管 GYPA 和 GYPB 在寄生虫入侵中的作用是众所周知的，但血型糖蛋白多态性与临床对疟疾的易感性之间的直接联系一直难以捉摸。在这里，我们提供了 CNV 的系统目录，描述了可能在该位点具有功能重要性的结构多样性。我们的研究结果确定了一种编码杂化血型糖蛋白的特定变体，并且与预防严重疟疾有关。这一发现需要进一步的工作来确定这种特殊的分子重排如何影响寄生虫入侵和红细胞反应，并可能导致我们发现新的寄生虫脆弱性，这些脆弱性可用于未来对抗这种致命疾病的干预措施。产生混合血型糖蛋白基因的结构变体与对严重疟疾的保护有关。参考单倍型携带三个血型糖蛋白基因，其中两个（GYPA 和 GYPB）在红细胞表面以蛋白质形式表达​​。疟疾保护单倍型携带五个血型糖蛋白基因，包括两个编码丹兔血型抗原的杂交基因，由GYPB胞外域和GYPA胞内域组成。这些血型糖蛋白在红细胞入侵期间充当疟疾寄生虫配体的受体。疟原虫恶性疟原虫通过宿主和寄生虫表面蛋白之间的一系列相互作用侵入人体红细胞。通过分析来自人类群体的基因组序列数据，包括来自撒哈拉以南非洲的 1269 名个体，我们确定了影响宿主入侵受体基因 GYPA 和 GYPB 的各种大拷贝数变体。我们发现与严重疟疾的附近关联可以通过复杂的结构重排来解释，其中包括 GYPB 的丧失和两个 GYPB-A 杂合基因的获得，它编码一种血清学上不同的血型抗原，称为丹图。这种变体将严重疟疾的风险降低了 40%，并且最近在肯尼亚部分地区的频率有所增加，但西非似乎没有这种变体。这些发现将红细胞侵袭受体的结构变异与对严重疟疾的天然抗性联系起来。