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A gene regulatory network-aware graph learning method for cell identity annotation in single-cell RNA-seq data. 用于单细胞 RNA-seq 数据中细胞身份注释的基因调控网络感知图学习方法。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1101/gr.278439.123
Mengyuan Zhao, Jiawei Li, Xiaoyi Liu, Ke Ma, Jijun Tang, Fei Guo

Cell identity annotation for single-cell transcriptome data is a crucial process for constructing cell atlases, unraveling pathogenesis, and inspiring therapeutic approaches. Currently, the efficacy of existing methodologies is contingent upon specific data sets. Nevertheless, such data are often sourced from various batches, sequencing technologies, tissues, and even species. Notably, the gene regulatory relationship remains unaffected by the aforementioned factors, highlighting the extensive gene interactions within organisms. Therefore, we propose scHGR, an automated annotation tool designed to leverage gene regulatory relationships in constructing gene-mediated cell communication graphs for single-cell transcriptome data. This strategy helps reduce noise from diverse data sources while establishing distant cellular connections, yielding valuable biological insights. Experiments involving 22 scenarios demonstrate that scHGR precisely and consistently annotates cell identities, benchmarked against state-of-the-art methods. Crucially, scHGR uncovers novel subtypes within peripheral blood mononuclear cells, specifically from CD4+ T cells and cytotoxic T cells. Furthermore, by characterizing a cell atlas comprising 56 cell types for COVID-19 patients, scHGR identifies vital factors like IL1 and calcium ions, offering insights for targeted therapeutic interventions.

单细胞转录组数据的细胞身份注释是构建细胞图谱、揭示发病机制和启发治疗方法的关键过程。目前,现有方法的有效性取决于特定的数据集。然而,这些数据往往来自不同的批次、测序技术、组织甚至物种。值得注意的是,基因调控关系仍然不受上述因素的影响,这凸显了生物体内广泛的基因相互作用。因此,我们提出了 scHGR,这是一种自动注释工具,旨在利用基因调控关系为单细胞转录组数据构建基因介导的细胞通讯图谱。这种策略有助于减少来自不同数据源的噪声,同时建立遥远的细胞联系,从而获得有价值的生物学见解。涉及 22 种情况的实验表明,与最先进的方法相比,scHGR 能精确、一致地注释细胞身份。最重要的是,scHGR 发现了外周血单核细胞中的新型亚型,特别是 CD4+ T 细胞和细胞毒性 T 细胞。此外,通过对 COVID-19 患者的 56 种细胞类型组成的细胞图谱进行特征描述,scHGR 确定了 IL1 和钙离子等重要因子,为有针对性的治疗干预提供了启示。
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引用次数: 0
Widespread natural selection on metabolite levels in humans 人类代谢物水平的广泛自然选择
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1101/gr.278756.123
Yanina Timasheva, Kaido Lepik, Orsolya Liska, Balázs Papp, Zoltan Kutalik
Natural selection acts ubiquitously on complex human traits, predominantly constraining the occurrence of extreme phenotypes (stabilizing selection). These constraints propagate to DNA sequence variants associated with traits under selection. The genetic imprints of such evolutionary events can thus be detected via combining effect size estimates from genetic association studies and the corresponding allele frequencies. While this approach has been successfully applied to high-level traits, the prevalence and mode of selection acting on molecular traits remains poorly understood. Here, we estimate the action of natural selection on genetic variants associated with metabolite levels, an important layer of molecular traits. By leveraging summary statistics of published genome-wide association studies with large sample sizes, we find strong evidence of stabilizing selection for 15 out of 97 plasma metabolites. Mendelian randomization analysis revealed that metabolites under stronger stabilizing selection display larger effects on a range of clinically relevant complex traits, suggesting that maintaining a disease-free profile may be an important source of selective constraints on the metabolome. Metabolites under strong stabilizing selection in humans are also more conserved in their concentrations among diverse mammalian species, suggesting shared selective forces across micro and macroevolutionary time scales. Finally, we also found evidence for both disruptive and directional selection on specific lipid metabolites, potentially indicating ongoing evolutionary adaptation in humans. Overall, this study demonstrates that variation in metabolite levels among humans is frequently shaped by natural selection and this may act through their causal impact on disease susceptibility.
自然选择对人类复杂性状的作用无处不在,主要是限制极端表型的出现(稳定选择)。这些制约因素会传播到与被选择性状相关的 DNA 序列变异中。因此,通过结合遗传关联研究的效应大小估计值和相应的等位基因频率,可以检测到此类进化事件的遗传印记。虽然这种方法已成功应用于高级性状,但人们对分子性状选择的普遍性和模式仍然知之甚少。在这里,我们估算了自然选择对与代谢物水平相关的遗传变异的作用,代谢物水平是分子性状的一个重要层面。通过利用已发表的大样本量全基因组关联研究的汇总统计,我们发现在 97 种血浆代谢物中,有 15 种存在稳定选择的有力证据。孟德尔随机化分析表明,处于较强稳定选择下的代谢物对一系列临床相关的复杂性状具有较大的影响,这表明保持无病特征可能是代谢组选择性限制的一个重要来源。在人类中处于强稳定选择下的代谢物在不同哺乳动物物种中的浓度也更加一致,这表明在微观和宏观进化时间尺度上存在共同的选择性力量。最后,我们还发现了对特定脂质代谢物进行破坏性选择和定向选择的证据,这可能表明人类正在进行进化适应。总之,这项研究表明,人类代谢物水平的变化经常受到自然选择的影响,这可能通过它们对疾病易感性的因果影响发挥作用。
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引用次数: 0
Colibactin leads to a bacteria-specific mutation pattern and self-inflicted DNA damage Colibactin 导致细菌特异性突变模式和自身造成的 DNA 损伤
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1101/gr.279517.124
Emily Lowry, Yiqing Wang, Tal Dagan, Amir Mitchell
Colibactin produced primarily by Escherichia coli strains of the B2 phylogroup crosslinks DNA and can promote colon cancer in human hosts. We investigated the toxin's impact on colibactin producers and on bacteria co-cultured with producing cells. Using genome-wide genetic screens and mutation accumulation experiments we uncovered the cellular pathways that mitigate colibactin damage and revealed the specific mutations it induces. We discovered that while colibactin targets A/T rich motifs, as observed in human colon cells, it induces a bacteria-unique mutation pattern. Based on this pattern, we predicted that long-term colibactin exposure will culminate in a genomic bias in trinucleotide composition. We tested this prediction by analyzing thousands of E. coli genomes and found that colibactin-producing strains indeed show the predicted skewness in trinucleotide composition. Our work revealed a bacteria-specific mutation pattern and suggests that the resistance protein encoded on the colibactin pathogenicity island is insufficient in preventing self-inflicted DNA damage.
大肠杆菌毒素主要由 B2 系统群的大肠杆菌菌株产生,可交联 DNA 并诱发人类宿主的结肠癌。我们研究了这种毒素对大肠杆菌生产者以及与生产者细胞共培养的细菌的影响。通过全基因组遗传筛选和突变累积实验,我们发现了减轻大肠杆菌毒素损伤的细胞通路,并揭示了其诱导的特定突变。我们发现,正如在人类结肠细胞中观察到的那样,虽然可乐菌素以富含 A/T 的基序为目标,但它会诱导一种细菌特有的突变模式。根据这种模式,我们预测长期暴露于 colibactin 将最终导致三核苷酸组成的基因组偏差。我们通过分析数以千计的大肠杆菌基因组验证了这一预测,发现产生可乐菌素的菌株确实在三核苷酸组成方面表现出预测的偏斜。我们的工作揭示了一种细菌特异性突变模式,并表明在可乐菌素致病性岛上编码的抗性蛋白不足以防止自身造成的 DNA 损伤。
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引用次数: 0
Allele specific transcription factor binding across human brain regions offers mechanistic insight into eQTLs 人脑各区域的等位基因特异性转录因子结合提供了对 eQTL 的机理认识
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1101/gr.278601.123
Ashlyn G Anderson, Belle A Moyers, Jacob M Loupe, Ivan Rodriguez-Nunez, Stephanie A Felker, James M.J. Lawlor, William E Bunney, Blynn G Bunney, Preston M Cartagena, Adolfo Sequeira, Stanley Watson, Huda Akil, Eric M Mendenhall, Gregory M Cooper, Richard M. Myers
Transcription Factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Since TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele specific binding (ASB) at heterozygous variants for 94 TFs in 9 brain regions from two donors. Leveraging graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signals between alleles at heterozygous variants within each brain region and identified thousands of variants exhibiting ASB for at least one TF. ASB reproducibility was measured by comparisons between independent experiments both within and between donors. We found that rarer alleles in the general population more frequently led to reduced TF binding, whereas common variation had an equal likelihood of increasing or decreasing binding. Motif analysis revealed TF-specific effects, with ASB variants for certain TFs displaying a greater incidence of motif alterations, as well as enrichments for variants under purifying selection. Notably, neuron-specific cis-regulatory elements (cCREs) showed depletion for ASB variants. We identified 2,670 ASB variants with prior evidence of allele-specific gene expression in the brain from GTEx data and observed increasing eQTL effect direction concordance as ASB significance increases. These results provide a valuable and unique resource for mechanistic analysis of cis-regulatory variation in human brain tissue.
转录因子(TF)通过促进或破坏特定基因组位点转录启动机制的形成来调控基因表达。由于 TF 的占据部分是由 DNA 序列识别驱动的,因此遗传变异会影响 TF-DNA 关联和基因调控。为了确定影响人类脑组织中TF结合的变异,我们评估了两个供体9个脑区94个TF杂合变异的等位基因特异性结合(ASB)。利用分阶段基因组序列数据构建的图谱基因组,我们比较了每个脑区杂合变体等位基因之间的 ChIP-seq 信号,并确定了数千个至少对一种 TF 具有 ASB 的变体。ASB 的可重复性通过供体内部和供体之间独立实验的比较来衡量。我们发现,一般人群中较罕见的等位基因更经常导致 TF 结合力降低,而常见变异增加或减少结合力的可能性相同。基因组分析显示了TF的特异性效应,某些TF的ASB变体显示出更高的基因组改变发生率,以及纯化选择下变体的富集。值得注意的是,神经元特异性顺式调节元件(cCRE)显示出 ASB 变体的耗竭。我们从 GTEx 数据中发现了 2,670 个等位基因特异性基因在大脑中表达的 ASB 变异,并观察到随着 ASB 重要性的增加,eQTL 效应方向的一致性也在增加。这些结果为人类脑组织顺式调节变异的机理分析提供了宝贵而独特的资源。
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引用次数: 0
A simple method for finding related sequences by adding probabilities of alternative alignments 通过增加备选排列的概率寻找相关序列的简单方法
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1101/gr.279464.124
Martin C Frith
The main way of analyzing genetic sequences is by finding sequence regions that are related to each other. There are many methods to do that, usually based on this idea: find an alignment of two sequence regions, which would be unlikely to exist between unrelated sequences. Unfortunately, it is hard to tell if an alignment is likely to exist by chance. Also, the precise alignment of related regions is uncertain. One alignment does not hold all evidence that they are related. We should consider alternative alignments too. This is rarely done, because we lack a simple and fast method that fits easily into practical sequence-search software. Here is described a simplest-conceivable change to standard sequence alignment, which sums probabilities of alternative alignments. This makes it easier to tell if a similarity is likely to occur by chance. This approach is better than standard alignment at finding distant relationships, at least in a few tests. It can be used in practical sequence-search software, with minimal increase in implementation difficulty or run time. It generalizes to different kinds of alignment, e.g. DNA-versus-protein with frameshifts. Thus, it can widely contribute to finding subtle relationships between sequences.
分析基因序列的主要方法是找到相互关联的序列区域。有很多方法可以做到这一点,通常基于以下想法:找到两个序列区域的比对,而这两个序列区域不太可能存在于不相关的序列之间。遗憾的是,很难说对齐是否可能是偶然存在的。而且,相关区域的精确排列也不确定。一次排列并不能证明它们之间存在关联。我们还应该考虑其他的排列方式。我们很少这样做,因为我们缺乏一种简单而快速的方法,可以很容易地应用到实用的序列搜索软件中。这里描述的是对标准序列比对的一个最简单的可想象的改变,即对备选比对的概率进行求和。这样就能更容易地判断相似性是否可能是偶然出现的。至少在一些测试中,这种方法比标准比对更能发现遥远的关系。这种方法可用于实际的序列搜索软件中,而且实施难度和运行时间的增加极少。它适用于不同类型的比对,如带有框架转换的 DNA 与蛋白质比对。因此,它可以广泛用于发现序列之间的微妙关系。
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引用次数: 0
A spatiotemporally resolved atlas of mRNA decay in the C. elegans embryo reveals differential regulation of mRNA stability across stages and cell types 优雅小鼠胚胎中 mRNA 衰减的时空分辨图谱揭示了不同阶段和细胞类型中 mRNA 稳定性的不同调控方式
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1101/gr.278980.124
Felicia Peng, C Erik Nordgren, John Isaac Murray
During embryonic development, cells undergo dynamic changes in gene expression that are required for appropriate cell fate specification. Although both transcription and mRNA degradation contribute to gene expression dynamics, patterns of mRNA decay are less well-understood. Here we directly measured spatiotemporally resolved mRNA decay rates transcriptome-wide throughout C. elegans embryogenesis by transcription inhibition followed by bulk and single-cell RNA sequencing. This allowed us to calculate mRNA half-lives within specific cell types and developmental stages and identify differentially regulated mRNA decay throughout embryonic development. We identified transcript features that are correlated with mRNA stability and found that mRNA decay rates are associated with distinct peaks in gene expression over time. Moreover, we provide evidence that, on average, mRNA is more stable in the germline compared to in the soma and in later embryonic stages compared to in earlier stages. This work suggests that differential mRNA decay across cell states and time helps to shape developmental gene expression, and it provides a valuable resource for studies of mRNA turnover regulatory mechanisms.
在胚胎发育过程中,细胞的基因表达会发生动态变化,而这种变化是适当的细胞命运分化所必需的。虽然转录和 mRNA 降解都有助于基因表达的动态变化,但人们对 mRNA 的衰变模式了解较少。在这里,我们通过抑制转录,然后进行大量和单细胞 RNA 测序,直接测量了整个秀丽隐杆线虫胚胎发生过程中转录组的时空分辨率 mRNA 降解率。这使我们能够计算特定细胞类型和发育阶段中的 mRNA 半衰期,并识别整个胚胎发育过程中受到不同调控的 mRNA 衰减。我们确定了与 mRNA 稳定性相关的转录本特征,并发现随着时间的推移,mRNA 的衰变率与基因表达的不同峰值相关。此外,我们还提供证据表明,平均而言,胚芽中的 mRNA 比胚体中的更稳定,胚胎晚期的 mRNA 比早期的更稳定。这项研究表明,不同细胞状态和不同时间的mRNA衰变有助于形成发育基因的表达,它为研究mRNA周转调控机制提供了宝贵的资源。
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引用次数: 0
The Chinese longsnout catfish genome provides novel insights into the feeding preference and corresponding metabolic strategy of carnivores 中国长口鲇基因组为了解食肉动物的摄食偏好和相应的代谢策略提供了新的视角
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1101/gr.278476.123
Yulong Liu, Gang Zhai, Jingzhi Su, Yulong Gong, Binyuan Yang, Qisheng Lu, Longwei Xi, Yutong Zheng, Jingyue Cao, Haokun Liu, Junyan Jin, Zhimin Zhang, Yunxia Yang, Xiaoming Zhu, Zhongwei Wang, Gaorui Gong, Jie Mei, Zhan Yin, Rodolphe E. Gozlan, Shouqi Xie, Dong Han
Fish show variation in feeding habits to adapt to complex environments. However, the genetic basis of feeding preference and the corresponding metabolic strategies that differentiate feeding habits remain elusive. Here, by comparing the whole genome of a typical carnivorous fish (Leiocassis longirostris Günther) with that of herbivorous fish, we identify 250 genes through both positive selection and rapid evolution, including taste receptor taste receptor type 1 member 3 (tas1r3) and trypsin. We demonstrate that tas1r3 is required for carnivore preference in tas1r3-deficient zebrafish and in a diet-shifted grass carp model. We confirm that trypsin correlates with the metabolic strategies of fish with distinct feeding habits. Furthermore, marked alterations in trypsin activity and metabolic profiles are accompanied by a transition of feeding preference in tas1r3-deficient zebrafish and diet-shifted grass carp. Our results reveal a conserved adaptation between feeding preference and corresponding metabolic strategies in fish, and provide novel insights into the adaptation of feeding habits over the evolution course.
鱼类的摄食习性各不相同,以适应复杂的环境。然而,鱼类摄食偏好的遗传基础以及区分摄食习性的相应代谢策略仍然难以捉摸。在这里,通过比较典型的肉食性鱼类(Leiocassis longirostris Günther)和草食性鱼类的全基因组,我们通过正向选择和快速进化发现了250个基因,包括味觉受体1型成员3(tas1r3)和胰蛋白酶。我们证明,在缺失 tas1r3 的斑马鱼和食谱改变的草鱼模型中,tas1r3 是食肉动物偏好所必需的。我们证实,胰蛋白酶与具有不同摄食习性的鱼类的代谢策略相关。此外,胰蛋白酶活性和新陈代谢特征的明显改变伴随着 tas1r3 缺陷斑马鱼和食性转换草鱼摄食偏好的转变。我们的研究结果揭示了鱼类摄食偏好与相应代谢策略之间的一致适应性,并对摄食习性在进化过程中的适应性提供了新的见解。
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引用次数: 0
Reconstructing extrachromosomal DNA structural heterogeneity from long-read sequencing data using Decoil 利用 Decoil 从长线程测序数据中重建染色体外 DNA 结构异质性
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-07 DOI: 10.1101/gr.279123.124
Madalina Giurgiu, Nadine Wittstruck, Elias Rodriguez-Fos, Rocio Chamorro Gonzalez, Lotte Brueckner, Annabell Krienelke-Szymansky, Konstantin Helmsauer, Anne Hartebrodt, Philipp Euskirchen, Richard P. Koche, Kerstin Haase, Knut Reinert, Anton G. Henssen
Circular extrachromosomal DNA (ecDNA) is a form of oncogene amplification found across cancer types and associated with poor outcome in patients. ecDNA can be structurally complex and contain rearranged DNA sequences derived from multiple chromosome locations. As the structure of ecDNA can impact oncogene regulation and may indicate mechanisms of its formation, disentangling it at high resolution from sequencing data is essential. Even though methods have been developed to identify and reconstruct ecDNA in cancer genome sequencing, it remains challenging to resolve complex ecDNA structures, in particular amplicons with shared genomic footprints. We here introduce Decoil, a computational method which combines a breakpoint-graph approach with regression to reconstruct complex ecDNA and deconvolve co-occurring ecDNA elements with overlapping genomic footprints from long-read nanopore sequencing. Decoil outperforms de novo assembly and alignment-based methods in simulated long-read sequencing data for both simple and complex ecDNAs. Applying Decoil on whole genome sequencing data uncovered different ecDNA topologies and explored ecDNA structure heterogeneity in neuroblastoma tumors and cell lines, indicating that this method may improve ecDNA structural analyzes in cancer.
环状染色体外 DNA(ecDNA)是癌基因扩增的一种形式,可在各种癌症类型中发现,并与患者的不良预后有关。ecDNA 结构复杂,包含来自多个染色体位置的重新排列 DNA 序列。由于 ecDNA 的结构会影响癌基因的调控,并可能显示其形成机制,因此从测序数据中高分辨率地将其分离出来至关重要。尽管已经开发出了在癌症基因组测序中识别和重建ecDNA的方法,但解析复杂的ecDNA结构,尤其是具有共享基因组足迹的扩增子,仍然是一项挑战。我们在此介绍一种计算方法 Decoil,它结合了断点图法和回归法,可重建复杂的 ecDNA,并从长线程纳米孔测序中解构具有重叠基因组足迹的共存 ecDNA 元素。在模拟长线程测序数据中,Decoil 在简单和复杂 ecDNA 方面的表现都优于从头组装和基于比对的方法。在全基因组测序数据中应用Decoil发现了不同的ecDNA拓扑结构,并探索了神经母细胞瘤肿瘤和细胞系中ecDNA结构的异质性,这表明该方法可以改善癌症中的ecDNA结构分析。
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引用次数: 0
Secure discovery of genetic relatives across large-scale and distributed genomic datasets 在大规模分布式基因组数据集上安全地发现基因亲缘关系
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-07 DOI: 10.1101/gr.279057.124
Matthew Man-Hou Hong, David Froelicher, Ricky Magner, Victoria Popic, Bonnie Berger, Hyunghoon Cho
Finding relatives within a study cohort is a necessary step in many genomic studies. However, when the cohort is distributed across multiple entities subject to data-sharing restrictions, performing this step often becomes infeasible. Developing a privacy-preserving solution for this task is challenging due to the burden of estimating kinship between all pairs of individuals across datasets. We introduce SF-Relate, a practical and secure federated algorithm for identifying genetic relatives across data silos. SF-Relate vastly reduces the number of individual pairs to compare while maintaining accurate detection through a novel locality-sensitive hashing (LSH) approach. We assign individuals who are likely to be related together into buckets and then test relationships only between individuals in matching buckets across parties. To this end, we construct an effective hash function that captures identity-by-descent (IBD) segments in genetic sequences, which, along with a new bucketing strategy, enable accurate and practical private relative detection. To guarantee privacy, we introduce an efficient algorithm based on multiparty homomorphic encryption (MHE) to allow data holders to cooperatively compute the relatedness coefficients between individuals, and to further classify their degrees of relatedness, all without sharing any private data. We demonstrate the accuracy and practical runtimes of SF-Relate on the UK Biobank and All of Us datasets. On a dataset of 200K individuals split between two parties, SF-Relate detects 97% of third-degree or closer relatives within 15 hours of runtime. Our work enables secure identification of relatives across large-scale genomic datasets.
在研究队列中寻找亲属是许多基因组研究的必要步骤。然而,当队列分布在多个实体中并受到数据共享限制时,执行这一步骤往往变得不可行。为这项任务开发一个保护隐私的解决方案具有挑战性,因为要估计数据集中所有个体对之间的亲属关系。我们引入了 SF-Relate,这是一种实用、安全的联合算法,用于识别跨数据孤岛的遗传亲缘关系。SF-Relate 通过一种新颖的位置敏感哈希(LSH)方法,在保持准确检测的同时,大大减少了需要比较的个体配对数量。我们将很可能有亲属关系的个体分配到不同的桶中,然后只检测匹配桶中的个体之间的关系。为此,我们构建了一种有效的散列函数,它能捕捉基因序列中的后裔身份(IBD)片段,再加上一种新的分桶策略,就能实现准确而实用的私密亲属检测。为了保证隐私,我们引入了一种基于多方同态加密(MHE)的高效算法,允许数据持有者合作计算个体间的亲缘系数,并进一步对其亲缘程度进行分类,而无需共享任何私人数据。我们在英国生物库和 "我们所有人 "数据集上演示了 SF-Relate 的准确性和实际运行时间。在双方共享的 20 万个人数据集上,SF-Relate 在 15 小时的运行时间内检测到了 97% 的三级或更近的亲属。我们的工作实现了在大规模基因组数据集上安全识别亲属。
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引用次数: 0
Independent expansion, selection and hypervariability of the TBC1D3 gene family in humans 人类 TBC1D3 基因家族的独立扩展、选择和高变异性
IF 7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-06 DOI: 10.1101/gr.279299.124
Xavi Guitart, David Porubsky, DongAhn Yoo, Max L Dougherty, Philip Dishuck, Katherine M. Munson, Alexandra P. Lewis, Kendra Hoekzema, Jordan Knuth, Stephen Chang, Tomi Pastinen, Evan E. Eichler
TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 non-human primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ~1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL. These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.
TBC1D3 是一个灵长类特有的基因家族,它在人类血统中扩展,并与神经元祖细胞的增殖和额叶皮层的扩展有关。该基因家族及其表达一直是研究的难点,因为它包含在高同一性和高度可变的节段重复中。我们利用来自 34 个人类和 11 个非人灵长类物种的长线程测序数据对该基因家族进行了测序和组装。我们的分析表明,这个特殊的基因家族在至少五个灵长类物种中发生了独立的重复,重复的基因位点富集在 17 号染色体上大规模染色体重排的位置。我们发现,人类所有的拷贝数变异都映射到位于染色体 17q12 的两个不同群组上,而且人类在该基因座上的结构变异很大,根据单倍型的不同,拷贝数相差多达 20 个,长度相差约 1 Mbp。我们还显示了正选择的证据,以及预测的人类 TBC1D3 蛋白序列的显著变化。最后,我们发现,尽管存在多个重复,但人类 TBC1D3 的表达仅限于一部分拷贝,而且最明显的是,只来自一个旁系组:TBC1D3-CDKL。这些观察结果可能有助于解释为什么一个可能对大脑皮层发育很重要的基因在人类群体中会如此多变。
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引用次数: 0
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