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Reference-informed prediction of alternative splicing and splicing-altering mutations from sequences 从序列中预测替代剪接和剪接改变突变的参考信息
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1101/gr.279044.124
Chencheng Xu, Suying Bao, Ye Wang, Wenxing Li, Hao Chen, Yufeng Shen, Tao Jiang, Chaolin Zhang
Alternative splicing plays a crucial role in protein diversity and gene expression regulation in higher eukaryotes and mutations causing dysregulated splicing underlie a range of genetic diseases. Computational prediction of alternative splicing from genomic sequences not only provides insight into gene-regulatory mechanisms but also helps identify disease-causing mutations and drug targets. However, the current methods for the quantitative prediction of splice site usage still have limited accuracy. Here, we present DeltaSplice, a deep neural network model optimized to learn the impact of mutations on quantitative changes in alternative splicing from the comparative analysis of homologous genes. The model architecture enables DeltaSplice to perform "reference-informed prediction" by incorporating the known splice site usage of a reference gene sequence to improve its prediction on splicing-altering mutations. We benchmarked DeltaSplice and several other state-of-the-art methods on various prediction tasks, including evolutionary sequence divergence on lineage-specific splicing and splicing-altering mutations in human populations and neurodevelopmental disorders, and demonstrated that DeltaSplice outperformed consistently. DeltaSplice predicted ~15% of splicing quantitative trait loci (sQTLs) in the human brain as causal splicing-altering variants. It also predicted splicing-altering de novo mutations outside the splice sites in a subset of patients affected by autism and other neurodevelopmental disorders (NDD), including 19 genes with recurrent splicing-altering mutations. Integration of splicing-altering mutations with other types of denovo mutation burdens allowed prediction of eight novel NDD-risk genes. Our work expanded the capacity of in silico splicing models with potential applications in genetic diagnosis and the development of splicing-based precision medicine.
在高等真核生物中,替代剪接在蛋白质多样性和基因表达调控中起着至关重要的作用,而导致剪接失调的突变是一系列遗传疾病的根源。通过计算预测基因组序列中的替代剪接,不仅可以深入了解基因调控机制,还有助于确定致病突变和药物靶点。然而,目前对剪接位点使用情况进行定量预测的方法准确性仍然有限。在此,我们介绍一种深度神经网络模型 DeltaSplice,该模型经过优化,可从同源基因的比较分析中学习突变对替代剪接定量变化的影响。该模型的结构使DeltaSplice能够执行 "参考信息预测",即结合参考基因序列的已知剪接位点使用情况来改进其对剪接改变突变的预测。我们在各种预测任务上对 DeltaSplice 和其他几种最先进的方法进行了基准测试,包括人类群体和神经发育疾病中特定剪接和剪接改变突变的进化序列分歧,结果表明 DeltaSplice 的表现始终优于其他几种方法。DeltaSplice 预测了人脑中约 15% 的剪接定量性状位点 (sQTL),作为剪接改变变异的因果关系。它还预测了自闭症和其他神经发育障碍(NDD)患者子集中剪接位点外的剪接改变变异,其中包括 19 个具有复发性剪接改变变异的基因。将剪接改变突变与其他类型的非原发突变负担相结合,可以预测出 8 个新的 NDD 风险基因。我们的工作拓展了剪接硅学模型的能力,有望应用于基因诊断和基于剪接的精准医疗的开发。
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引用次数: 0
Parameter-efficient fine-tuning on large protein language models improves signal peptide prediction 对大型蛋白质语言模型进行参数高效微调可改进信号肽预测
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1101/gr.279132.124
Shuai Zeng, Duolin Wang, Lei Jiang, Dong Xu
Signal peptides (SP) play a crucial role in protein translocation in cells. The development of large protein language models (PLMs) and prompt-based learning provides a new opportunity for SP prediction, especially for the categories with limited annotated data. We present a parameter-efficient fine-tuning (PEFT) framework for SP prediction, PEFT-SP, to effectively utilize pretrained PLMs. We integrated low-rank adaptation (LoRA) into ESM-2 models to better leverage the protein sequence evolutionary knowledge of PLMs. Experiments show that PEFT-SP using LoRA enhances state-of-the-art results, leading to a maximum Matthews correlation coefficient (MCC) gain of 87.3% for SPs with small training samples and an overall MCC gain of 6.1%. Furthermore, we also employed two other PEFT methods, prompt tuning and adapter tuning, in ESM-2 for SP prediction. More elaborate experiments show that PEFT-SP using adapter tuning can also improve the state-of-the-art results by up to 28.1% MCC gain for SPs with small training samples and an overall MCC gain of 3.8%. LoRA requires fewer computing resources and less memory than the adapter during the training stage, making it possible to adapt larger and more powerful protein models for SP prediction.
信号肽(SP)在细胞内的蛋白质转运中起着至关重要的作用。大型蛋白质语言模型(PLM)和基于提示的学习的发展为信号肽预测提供了新的机遇,尤其是对于注释数据有限的类别。我们提出了一种用于 SP 预测的参数高效微调(PEFT)框架 PEFT-SP,以有效利用预训练的 PLM。我们在 ESM-2 模型中集成了低阶适应(LoRA),以更好地利用 PLM 的蛋白质序列进化知识。实验表明,使用 LoRA 的 PEFT-SP 增强了最先进的结果,对于训练样本较少的 SP,马修斯相关系数 (MCC) 的最大增益为 87.3%,总体 MCC 增益为 6.1%。此外,我们还在 ESM-2 中采用了另外两种 PEFT 方法,即及时调整和适配器调整,用于 SP 预测。更详尽的实验表明,使用适配器调整的 PEFT-SP 也能改善最先进的结果,对训练样本较少的 SP 的 MCC 增益高达 28.1%,总体 MCC 增益为 3.8%。与适配器相比,LoRA 在训练阶段所需的计算资源和内存更少,因此可以为 SP 预测适配更大、更强大的蛋白质模型。
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引用次数: 0
Accurate assembly of circular RNAs with TERRACE 利用 TERRACE 精确装配环状 RNA
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1101/gr.279106.124
Tasfia Zahin, Qian Shi, Xiaofei Carl Zang, Mingfu Shao
Circular RNA (circRNA) is a class of RNA molecules that forms a closed loop with its 5' and 3' ends covalently bonded. circRNAs are known to be more stable than linear RNAs, admit distinct properties and functions, and have been proven to be promising biomarkers. Existing methods for assembling circRNAs heavily rely on the annotated transcriptomes, hence exhibiting unsatisfactory accuracy without a high-quality transcriptome. We present TERRACE, a new algorithm for full-length assembly of circRNAs from paired-end total RNA-seq data. TERRACE uses the splice graph as the underlying data structure that organizes the splicing and coverage information. We transform the problem of assembling circRNAs into finding paths that "bridge" the three fragments in the splice graph induced by back-spliced reads. We adopt a definition for optimal bridging paths and a dynamic programming algorithm to calculate such optimal paths. TERRACE features an efficient algorithm to detect back-spliced reads missed by RNA-seq aligners, contributing to its much improved sensitivity. It also incorporates a new machine-learning approach trained to assign a confidence score to each assembled circRNA, which is shown superior to using abundance for scoring. On both simulations and biological datasets TERRACE consistently outperforms existing methods by a large margin in sensitivity while maintaining better or comparable precision. In particular, when the annotations are not provided, TERRACE assembles 123%-413% more correct circRNAs than state-of-the-art methods. TERRACE presents a major leap on assembling full-length circRNAs from RNA-seq data, and we expect it to be widely used in the downstream research on circRNAs.
环状 RNA(circRNA)是一类 RNA 分子,它的 5' 端和 3' 端以共价键连接,形成一个闭合的环。众所周知,环状 RNA 比线性 RNA 更稳定,具有独特的性质和功能,而且已被证明是一种很有前景的生物标记物。现有的 circRNAs 组装方法严重依赖于已注释的转录组,因此在没有高质量转录组的情况下,其准确性不能令人满意。我们介绍了一种从成对总RNA-seq数据中全长组装circRNA的新算法TERRACE。TERRACE 使用剪接图作为组织剪接和覆盖信息的底层数据结构。我们将组装 circRNA 的问题转化为寻找路径,以 "桥接 "剪接图中由反向剪接读数引起的三个片段。我们采用最优桥接路径的定义和动态编程算法来计算这种最优路径。TERRACE 采用了一种高效算法来检测 RNA-seq 比对器遗漏的反向剪接读数,从而大大提高了灵敏度。它还采用了一种新的机器学习方法,经过训练后可为每个组装的 circRNA 指定一个置信度分数,这比使用丰度进行评分更有优势。在模拟和生物数据集上,TERRACE 的灵敏度一直远远超过现有方法,同时保持了更好或相当的精确度。特别是在不提供注释的情况下,TERRACE 组装出的 circRNA 比最先进的方法多出 123%-413% 的正确率。TERRACE 在从 RNA-seq 数据组装全长 circRNA 方面实现了重大飞跃,我们期待它在 circRNA 下游研究中得到广泛应用。
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引用次数: 0
Corrigendum: Centromere RNA is a key component for the assembly of nucleoproteins at the nucleolus and centromere. 更正:中心粒 RNA 是核蛋白在核仁和中心粒组装的关键组成部分。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.279693.124
Lee H Wong, Kate H Brettingham-Moore, Lyn Chan, Julie M Quach, Melissa A Anderson, Emma L Northrop, Ross Hannan, Richard Saffery, Margaret L Shaw, Evan Williams, K H Andy Choo
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引用次数: 0
Accurate estimation of pathway activity in single cells for clustering and differential analysis. 为聚类和差异分析准确估算单细胞中的通路活性。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278431.123
Daniel Davis, Avishai Wizel, Yotam Drier

Inferring which and how biological pathways and gene sets change is a key question in many studies that utilize single-cell RNA sequencing. Typically, these questions are addressed by quantifying the enrichment of known gene sets in lists of genes derived from global analysis. Here we offer SiPSiC, a new method to infer pathway activity in every single cell. This allows more sensitive differential analysis and utilization of pathway scores to cluster cells and compute UMAP or other similar projections. We apply our method to COVID-19, lung adenocarcinoma and glioma data sets, and demonstrate its utility. SiPSiC analysis results are consistent with findings reported in previous studies in many cases, but SiPSiC also reveals the differential activity of novel pathways, enabling us to suggest new mechanisms underlying the pathophysiology of these diseases and demonstrating SiPSiC's high accuracy and sensitivity in detecting biological function and traits. In addition, we demonstrate how it can be used to better classify cells based on activity of biological pathways instead of single genes and its ability to overcome patient-specific artifacts.

在许多利用单细胞 RNA 测序的研究中,推断哪些生物通路和基因组发生了变化以及如何发生变化是一个关键问题。通常,这些问题是通过量化全局分析得出的基因列表中已知基因集的富集程度来解决的。在这里,我们提供了 SiPSiC,一种推断每个单细胞中通路活性的新方法。这样就能进行更灵敏的差异分析,并利用通路得分对细胞进行聚类,计算 UMAP 或其他类似的预测。我们将这种方法应用于 COVID-19、肺腺癌和胶质瘤数据集,并证明了它的实用性。SiPSiC 分析结果在很多情况下与之前研究报告的结果一致,但 SiPSiC 也揭示了新通路的不同活动,使我们能够提出这些疾病病理生理学的新机制,并证明 SiPSiC 在检测生物功能和性状方面具有很高的准确性和灵敏度。此外,我们还展示了如何利用 SiPSiC 根据生物通路而不是单个基因的活性对细胞进行更好的分类,以及 SiPSiC 克服病人特异性伪影的能力。
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引用次数: 0
Simultaneous assessment of human genome and methylome data in a single experiment using limited deamination of methylated cytosine. 利用甲基化胞嘧啶的有限脱氨,在一次实验中同时评估人类基因组和甲基组数据。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278294.123
Bo Yan, Duan Wang, Laurence Ettwiller

Multiomics require concerted recording of independent information, ideally from a single experiment. In this study, we introduce RIMS-seq2, a high-throughput technique to simultaneously sequence genomes and overlay methylation information while requiring only a small modification of the experimental protocol for high-throughput DNA sequencing to include a controlled deamination step. Importantly, the rate of deamination of 5-methylcytosine is negligible and thus does not interfere with standard DNA sequencing and data processing. Thus, RIMS-seq2 libraries from whole- or targeted-genome sequencing show the same germline variation calling accuracy and sensitivity compared with standard DNA-seq. Additionally, regional methylation levels provide an accurate map of the human methylome.

多组学需要协同记录独立的信息,最好是来自一次实验。在本研究中,我们介绍了一种高通量技术 RIMS-seq2,它能同时对基因组进行测序并叠加甲基化信息,同时只需对高通量 DNA 测序的实验方案稍作修改,加入受控脱氨基步骤。重要的是,5mC 的脱氨率可以忽略不计,因此不会干扰标准 DNA 测序和数据处理。因此,与标准 DNA-seq 相比,来自全基因组或靶向基因组测序的 RIMS-seq2 文库显示出相同的种系变异调用准确性和灵敏度。此外,区域甲基化水平提供了准确的人类甲基组图谱。
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引用次数: 0
Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins. 对人类肠道微生物群中物种特异性孤儿基因的大规模调查阐明了它们的进化起源。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278977.124
Nikolaos Vakirlis, Anne Kupczok

Species-specific genes, also known as orphans, are ubiquitous across life's domains. In prokaryotes, species-specific orphan genes (SSOGs) are mostly thought to originate in external elements such as viruses followed by horizontal gene transfer, whereas the scenario of native origination, through rapid divergence or de novo, is mostly dismissed. However, quantitative evidence supporting either scenario is lacking. Here, we systematically analyzed genomes from 4644 human gut microbiome species and identified more than 600,000 unique SSOGs, representing an average of 2.6% of a given species' pangenome. These sequences are mostly rare within each species yet show signs of purifying selection. Overall, SSOGs use optimal codons less frequently, and their proteins are more disordered than those of conserved genes (i.e., non-SSOGs). Importantly, across species, the GC content of SSOGs closely matches that of conserved ones. In contrast, the ∼5% of SSOGs that share similarity to known viral sequences have distinct characteristics, including lower GC content. Thus, SSOGs with similarity to viruses differ from the remaining SSOGs, contrasting an external origination scenario for most of them. By examining the orthologous genomic region in closely related species, we show that a small subset of SSOGs likely evolved natively de novo and find that these genes also differ in their properties from the remaining SSOGs. Our results challenge the notion that external elements are the dominant source of prokaryotic genetic novelty and will enable future studies into the biological role and relevance of species-specific genes in the human gut.

物种特异性基因,又称孤儿基因,在生命领域无处不在。在原核生物中,物种特异性孤儿基因(SSOGs)大多被认为起源于病毒等外部因素,然后是水平基因转移,而通过快速分化或从头开始起源于本地的情况则大多被否定。然而,支持这两种情况的定量证据都很缺乏。在这里,我们系统分析了 4644 个人类肠道微生物组物种的基因组,发现了 60 多万个独特的 SSOG,平均占特定物种肠道微生物组的 2.6%。这些序列在每个物种中都很罕见,但却显示出纯化选择的迹象。总体而言,与保守基因(即非 SSOGs)相比,SSOGs 使用最佳密码子的频率较低,其蛋白质也更加无序。重要的是,在不同物种中,SSOG 的 GC 含量与保守基因的 GC 含量非常接近。相比之下,与已知病毒序列具有相似性的 ∼5% 的 SSOGs 具有独特的特征,包括较低的 GC 含量。因此,与病毒相似的 SSOG 与其余的 SSOG 不同,这与大多数 SSOG 起源于外部的情况形成鲜明对比。通过研究近缘物种的同源基因组区域,我们发现一小部分 SSOG 很可能是从头开始进化的,并发现这些基因的特性也与其余 SSOG 不同。我们的研究结果对外界元素是原核生物遗传新特性的主要来源这一观点提出了质疑,并将有助于今后对人类肠道中物种特异性基因的生物学作用和相关性进行研究。
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引用次数: 0
Accurate allocation of multimapped reads enables regulatory element analysis at repeats. 多映射读数的精确分配可对重复序列进行调控元件分析。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278638.123
Alexis Morrissey, Jeffrey Shi, Daniela Q James, Shaun Mahony

Transposable elements (TEs) and other repetitive regions have been shown to contain gene regulatory elements, including transcription factor binding sites. However, regulatory elements harbored by repeats have proven difficult to characterize using short-read sequencing assays such as ChIP-seq or ATAC-seq. Most regulatory genomics analysis pipelines discard "multimapped" reads that align equally well to multiple genomic locations. Because multimapped reads arise predominantly from repeats, current analysis pipelines fail to detect a substantial portion of regulatory events that occur in repetitive regions. To address this shortcoming, we developed Allo, a new approach to allocate multimapped reads in an efficient, accurate, and user-friendly manner. Allo combines probabilistic mapping of multimapped reads with a convolutional neural network that recognizes the read distribution features of potential peaks, offering enhanced accuracy in multimapping read assignment. Allo also provides read-level output in the form of a corrected alignment file, making it compatible with existing regulatory genomics analysis pipelines and downstream peak-finders. In a demonstration application on CTCF ChIP-seq data, we show that Allo results in the discovery of thousands of new CTCF peaks. Many of these peaks contain the expected cognate motif and/or serve as TAD boundaries. We additionally apply Allo to a diverse collection of ENCODE ChIP-seq data sets, resulting in multiple previously unidentified interactions between transcription factors and repetitive element families. Finally, we show that Allo may be particularly beneficial in identifying ChIP-seq peaks at centromeres, near segmentally duplicated genes, and in younger TEs, enabling new regulatory analyses in these regions.

转座元件(TE)和其他重复区域已被证明含有基因调控元件,包括转录因子结合位点。然而,事实证明,使用 ChIP-seq 或 ATAC-seq 等短读数测序方法很难鉴定重复区所包含的调控元件。大多数调控基因组学分析管道都会丢弃与多个基因组位置对齐度相同的 "多映射 "读数。由于多映射读数主要来自重复区,目前的分析管道无法检测到发生在重复区的大部分调控事件。为了解决这一缺陷,我们开发了 Allo,这是一种以高效、准确和用户友好的方式分配多映射读数的新方法。Allo 将多映射读数的概率映射与卷积神经网络相结合,后者能识别潜在峰的读数分布特征,从而提高多映射读数分配的准确性。Allo 还以校正比对文件的形式提供读数级输出,使其与现有的调控基因组学分析管道和下游峰值查找器兼容。在 CTCF ChIP-seq 数据的演示应用中,我们发现 Allo 能发现数千个新的 CTCF 峰。其中许多峰包含预期的同源主题和/或作为 TAD 边界。此外,我们还将 Allo 应用于各种 ENCODE ChIP-seq 数据集,结果发现了转录因子和重复性元件家族之间多种以前未发现的相互作用。最后,我们证明了 Allo 对识别中心粒、节段重复基因附近和年轻 TE 中的 ChIP-seq 峰特别有用,可以对这些区域进行新的调控分析。
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引用次数: 0
DEAD box RNA helicases are pervasive protein kinase interactors and activators. DEAD box RNA 螺旋酶是一种普遍存在的蛋白激酶相互作用体和激活剂。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278264.123
Alexander Hirth, Edoardo Fatti, Eugen Netz, Sergio P Acebron, Dimitris Papageorgiou, Andrea Švorinić, Cristina-Maria Cruciat, Emil Karaulanov, Alexandr Gopanenko, Tianheng Zhu, Irmgard Sinning, Jeroen Krijgsveld, Oliver Kohlbacher, Christof Niehrs

DEAD box (DDX) RNA helicases are a large family of ATPases, many of which have unknown functions. There is emerging evidence that besides their role in RNA biology, DDX proteins may stimulate protein kinases. To investigate if protein kinase-DDX interaction is a more widespread phenomenon, we conducted three orthogonal large-scale screens, including proteomics analysis with 32 RNA helicases, protein array profiling, and kinome-wide in vitro kinase assays. We retrieved Ser/Thr protein kinases as prominent interactors of RNA helicases and report hundreds of binary interactions. We identified members of ten protein kinase families, which bind to, and are stimulated by, DDX proteins, including CDK, CK1, CK2, DYRK, MARK, NEK, PRKC, SRPK, STE7/MAP2K, and STE20/PAK family members. We identified MARK1 in all screens and validated that DDX proteins accelerate the MARK1 catalytic rate. These findings indicate pervasive interactions between protein kinases and DEAD box RNA helicases, and provide a rich resource to explore their regulatory relationships.

死亡盒(DDX)RNA 螺旋酶是一个庞大的 ATP 酶家族,其中许多功能尚不清楚。有新证据表明,DDX 蛋白除了在 RNA 生物学中发挥作用外,还可能刺激蛋白激酶。为了研究蛋白激酶-DDX 相互作用是否是一种更普遍的现象,我们进行了三次正交大规模筛选,包括对 32 种 RNA 螺旋酶进行蛋白质组学分析、蛋白质阵列分析和全激酶组体外激酶测定。我们发现 Ser/Thr 蛋白激酶是 RNA 螺旋酶的主要相互作用者,并报告了数百种二元相互作用。我们发现了与 DDX 蛋白结合并受其刺激的十个蛋白激酶家族成员,包括 CDK、CK1、CK2、DYRK、MARK、NEK、PRKC、SRPK、STE7/MAP2K 和 STE20/PAK 家族成员。我们在所有筛选中都发现了 MARK1,并验证了 DDX 蛋白会加快 MARK1 的催化速度。这些发现表明蛋白激酶与 DEAD 盒 RNA 螺旋酶之间普遍存在相互作用,并为探索它们之间的调控关系提供了丰富的资源。
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引用次数: 0
Comparative genomics of Cryptosporidium parvum reveals the emergence of an outbreak-associated population in Europe and its spread to the United States. 副猪隐孢子虫的比较基因组学揭示了欧洲出现的爆发相关种群及其向美国的传播。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-23 DOI: 10.1101/gr.278830.123
Greta Bellinzona, Tiago Nardi, Michele Castelli, Gherard Batisti Biffignandi, Karim Adjou, Martha Betson, Yannick Blanchard, Ioana Bujila, Rachel Chalmers, Rebecca Davidson, Nicoletta D'Avino, Tuulia Enbom, Jacinto Gomes, Gregory Karadjian, Christian Klotz, Emma Östlund, Judith Plutzer, Ruska Rimhanen-Finne, Guy Robinson, Anna Rosa Sannella, Jacek Sroka, Christen Rune Stensvold, Karin Troell, Paolo Vatta, Barbora Zalewska, Claudio Bandi, Davide Sassera, Simone M Cacciò

The zoonotic parasite Cryptosporidium parvum is a global cause of gastrointestinal disease in humans and ruminants. Sequence analysis of the highly polymorphic gp60 gene enabled the classification of C. parvum isolates into multiple groups (e.g., IIa, IIc, Id) and a large number of subtypes. In Europe, subtype IIaA15G2R1 is largely predominant and has been associated with many water- and food-borne outbreaks. In this study, we generated new whole-genome sequence (WGS) data from 123 human- and ruminant-derived isolates collected in 13 European countries and included other available WGS data from Europe, Egypt, China, and the United States (n = 72) in the largest comparative genomics study to date. We applied rigorous filters to exclude mixed infections and analyzed a data set from 141 isolates from the zoonotic groups IIa (n = 119) and IId (n = 22). Based on 28,047 high-quality, biallelic genomic SNPs, we identified three distinct and strongly supported populations: Isolates from China (IId) and Egypt (IIa and IId) formed population 1; a minority of European isolates (IIa and IId) formed population 2; and the majority of European (IIa, including all IIaA15G2R1 isolates) and all isolates from the United States (IIa) clustered in population 3. Based on analyses of the population structure, population genetics, and recombination, we show that population 3 has recently emerged and expanded throughout Europe to then, possibly from the United Kingdom, reach the United States, where it also expanded. The reason(s) for the successful spread of population 3 remain elusive, although genes under selective pressure uniquely in this population were identified.

人畜共患病寄生虫副隐孢子虫是导致人类和反刍动物胃肠道疾病的全球性原因。通过对高度多态的 gp60 基因进行序列分析,可将副猪隐孢子虫分离株分为多个组别(如 IIa、IIc、Id)和大量亚型。在欧洲,亚型 IIaA15G2R1 在很大程度上占主导地位,并与许多水源和食源性疾病的爆发有关。在这项研究中,我们从 13 个欧洲国家收集到的 123 个来源于人类和反刍动物的分离物中生成了新的全基因组序列(WGS)数据,并将来自欧洲、埃及、中国和美国(n = 72)的其他可用 WGS 数据纳入了迄今为止最大规模的比较基因组学研究中。我们采用了严格的筛选方法来排除混合感染,并分析了来自人畜共患病 IIa 组(n = 119)和 IId 组(n = 22)的 141 个分离株的数据集。根据 28,047 个高质量的双偶联基因组 SNPs,我们确定了三个不同的、得到强烈支持的种群:来自中国(IId)和埃及(IIa 和 IId)的分离株形成了种群 1;少数欧洲分离株(IIa 和 IId)形成了种群 2;大多数欧洲分离株(IIa,包括所有 IIaA15G2R1 分离株)和所有来自美国的分离株(IIa)聚集在种群 3 中。根据对种群结构、种群遗传学和重组的分析,我们发现种群 3 是最近出现并扩展到整个欧洲的,然后可能从英国扩展到美国。种群 3 成功扩散的原因仍然难以捉摸,尽管在该种群中发现了独特的受到选择性压力的基因。
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