华西耳鼻喉前沿学术速递——文献导读（第54期）
学术前沿 |【Nature Genetics】2024年7-9月刊论文导读
整理人：张子妍 导师：赵宇
期刊介绍：
Nature Genetics创刊于1992年，由NATURE RESEARCH出版商出版，发表最高质量的遗传学研究。它包括对人类和植物性状以及其他模式生物的遗传和功能基因组研究。目前的重点是通过扰动实验研究常见和复杂疾病的遗传基础以及基因网络的功能机制、结构和进化。在行业领域中学术影响力很大，属于国际一流期刊，影响因子指数41.307。
Nature Genetics Volume 56 Issue 7, July 2024
在2024年7月，Nature Genetics共发表32篇文章，其中包括World View 1篇，Comment 1篇，Research Highlights 4篇，News & Views 3篇，Research Briefings 4篇，Perspectives 2篇，Review articles 1篇，Brief communications 1篇，Letters 2篇，Articles 12篇，Technical Reports 1篇。主要内容包括罕见编码变异、全基因组关联荟萃分析、单细胞多组学研究等内容。
1.Calibrated prediction intervals for polygenic scores across diverse contexts
针对不同情境下的多基因评分的校准预测区间
加州大学洛杉矶分校生物信息学跨系项目合作发表
Abstract：
Polygenic scores (PGS) have emerged as the tool of choice for genomic prediction in a wide range of fields. We show that PGS performance varies broadly across contexts and biobanks. Contexts such as age, sex and income can impact PGS accuracy with similar magnitudes as genetic ancestry. Here we introduce an approach (CalPred) that models all contexts jointly to produce prediction intervals that vary across contexts to achieve calibration (include the trait with 90% probability), whereas existing methods are miscalibrated. In analyses of 72 traits across large and diverse biobanks (All of Us and UK Biobank), we find that prediction intervals required adjustment by up to 80% for quantitative traits. For disease traits, PGS-based predictions were miscalibrated across socioeconomic contexts such as annual household income levels, further highlighting the need of accounting for context information in PGS-based prediction across diverse populations.
摘要：
多基因评分（PGS）已成为众多领域基因组预测的首选工具。该研究表明，PGS的性能在不同背景和生物样本库之间存在显著差异。年龄、性别和收入等背景因素对PGS准确性的影响程度与遗传祖先因素相当。在此，作者介绍了一种方法（CalPred），该方法联合建模所有背景因素，以产生随背景变化而变化的预测区间，从而实现校准（即以90%的概率包含性状），而现有方法则存在校准误差。在对大型且多样化的生物样本库（包括“All of Us”和英国生物银行）中的72个性状进行分析时，他们发现，对于定量性状，预测区间需要调整高达80%。对于疾病性状，基于PGS的预测在不同社会经济背景下（如家庭年收入水平）存在校准不当的问题，这进一步凸显了在对不同人群进行基于PGS的预测时考虑背景信息的必要性。
2.
Understanding the genetic complexity of puberty timing across the allele frequency spectrum
通过等位基因频谱了解青春期时间的遗传复杂性
英国剑桥大学生物医学校区代谢科学研究所，剑桥大学临床医学院MRC流行病学组
Abstract：
Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
摘要：
青春期发育时间存在很大差异，并与后期的健康状况相关。研究者对约80万名女性进行了多族群遗传分析，确定了1080个与初潮年龄相关的信号。这些信号共同解释了独立样本中11%的性状变异。在多基因风险最高和最低的1%的女性中，青春期延迟和早熟的风险分别高出约11倍和14倍。在约20万名女性中鉴定出了几个携带罕见功能缺失变异的基因，包括ZNF483中的变异，这些变异消除了多基因风险的影响。通过变异到基因的映射方法和小鼠促性腺激素释放激素神经元RNA测序，发现了665个基因，其中包括一个未表征的G蛋白偶联受体GPR83，该受体放大了关键营养感受器MC3R的信号。在与绝经时间相关的DNA损伤应答基因中发现的共同信号表明，卵巢储备可能向中枢发送信号以触发青春期发育。研究者还强调了依赖于或不依赖于体型的机制，这些机制可能将生殖时间与晚年疾病联系起来。
3.Exome sequence analysis identifies rare coding variants associated with a machine learning-based marker for coronary artery disease
外显子组序列分析确定了与基于机器学习的冠状动脉疾病标志物相关的罕见编码变异
美国纽约西奈山伊坎医学院查尔斯·布朗夫曼个性化医学研究所
Abstract:
Coronary artery disease (CAD) exists on a spectrum of disease represented by a combination of risk factors and pathogenic processes. An in silico score for CAD built using machine learning and clinical data in electronic health records captures disease progression, severity and underdiagnosis on this spectrum and could enhance genetic discovery efforts for CAD. Here we tested associations of rare and ultrarare coding variants with the in silico score for CAD in the UK Biobank, All of Us Research Program and BioMe Biobank. We identified associations in 17 genes; of these, 14 show at least moderate levels of prior genetic, biological and/or clinical support for CAD. We also observed an excess of ultrarare coding variants in 321 aggregated CAD genes, suggesting more ultrarare variant associations await discovery. These results expand our understanding of the genetic etiology of CAD and illustrate how digital markers can enhance genetic association investigations for complex diseases.
摘要：
冠状动脉疾病（CAD）表现为由多种风险因素和致病过程共同作用的疾病谱。利用机器学习和电子健康记录中的临床数据构建的冠状动脉疾病的计算机评分，能够捕捉该疾病谱中的疾病进展过程、疾病严重程度和诊断不足的情况，并可能促进对冠状动脉疾病基因的发现。在此，研究者测试了英国生物银行（UK Biobank）、“我们所有人”研究项目（All of Us Research Program）和BioMe生物银行中罕见和超罕见编码变异与冠状动脉疾病计算机评分之间的关联性。我们确定了17个基因中的关联性；其中，14个基因至少显示出中度水平的先前遗传、生物和/或临床证据支持其与冠状动脉疾病的关联。此外，还在321个聚集性冠状动脉疾病基因中观察到超罕见编码变异的过量现象，这表明还有更多的超罕见变异关联有待发现。这些结果扩展了对冠状动脉疾病遗传病因的理解，并说明了数字标志物如何增强对复杂疾病的基因关联研究。
4.Saturation genome editing of BAP1 functionally classifies somatic and germline variants
BAP1的饱和基因组编辑功能分类体细胞和种系变异
英国欣克斯顿惠康桑格研究所
Abstract：
Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.
摘要：
从父母那里遗传或在体细胞中新获得的许多变异都是罕见的，这限制了将这些变异与疾病准确关联起来的精确度。研究者对BAP1基因进行了彻底的饱和基因组编辑（SGE），BAP1基因的破坏与肿瘤发生和神经发育改变有关。研究者实验性地鉴定了18,108个独特变异，其中6,196个被发现具有异常功能，然后利用这些数据来评估英国生物银行（UK Biobank）中的表型关联。此外，还鉴定了大量人群中确定的肿瘤样本集、癌症家系和ClinVar中的变异，并比较了与癌症相关的变异与与神经发育表型相关的变异的行为。分析表明，破坏性的BAP1生殖系变异与循环中促有丝分裂因子IGF-1水平升高显著相关，这提示了一种可能的病理机制和治疗靶点。此外，研究者构建了一个变异分类器，其敏感性和特异性均超过98%，并量化证据强度，以辅助精确变异解读。
5.Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation
非干细胞谱系作为炎症背景下肠道肿瘤发生的另一种来源
荷兰鹿特丹Erasmus大学医学中心病理学系和德国马尔堡大学药理学研究所联合发表
Abstract:
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
摘要：
传统观点认为，结肠癌起源于干细胞。然而，现已证实炎症是结肠癌的一个关键风险因素，能够抑制肠道干细胞。在本研究中，以潘氏细胞为模型，评估了在小鼠炎症环境中分化细胞系触发肿瘤发生的能力。在炎症条件下，潘氏细胞特异性的Apc突变导致了肠道肿瘤发生，这些肿瘤不仅类似于炎症性肠病患者产生的肿瘤，还类似于更大比例的人类散发性结肠癌。后者可能是西式饮食习惯（结肠癌的主要风险因素）造成的炎症后果。为了从患者来源的肿瘤样本中预测癌症起源细胞，研究者设计了机器学习方法，其结果证实，在相当一部分散发性病例中，结肠癌起源于分泌细胞系而非干细胞。
6.A single-cell transcriptome atlas of human euploid and aneuploid blastocysts
人类整倍体和非整倍体囊胚的单细胞转录组图谱
华大研究（杭州）和华大研究（深圳）和中国科学院大学生命科学学院
Abstract：
Aneuploidy is frequently detected in early human embryos as a major cause of early pregnancy failure. However, how aneuploidy affects cellular function remains elusive. Here, we profiled the transcriptomes of 14,908 single cells from 203 human euploid and aneuploid blastocysts involving autosomal and sex chromosomes. Nearly all of the blastocysts contained four lineages. In aneuploid chromosomes, 19.5% ± 1.2% of the expressed genes showed a dosage effect, and 90 dosage-sensitive domains were identified. Aneuploidy leads to prevalent genome-wide transcriptome alterations. Common effects, including apoptosis, were identified, especially in monosomies, partially explaining the lower cell numbers in autosomal monosomies. We further identified lineage-specific effects causing unstable epiblast development in aneuploidies, which was accompanied by the downregulation of TGF-β and FGF signaling, which resulted in insufficient trophectoderm maturation. Our work provides crucial insights into the molecular basis of human aneuploid blastocysts and may shed light on the cellular interaction during blastocyst development.
摘要：
在人类早期胚胎中，非整倍体常被检测到，且其为导致早孕失败的主要原因。然而，非整倍体如何影响细胞功能仍不清楚。本文中研究者对203个包含常染色体和性染色体的人类整倍体和非整倍体囊胚中的14,908个单细胞进行了转录组分析。几乎所有囊胚都包含四种谱系。在非整倍体染色体中，有19.5% ± 1.2%的表达基因表现出剂量效应，并鉴定出90个剂量敏感区。非整倍体会导致普遍的全基因组转录组改变。研究者发现了包括凋亡在内的共同影响，这在单体细胞中尤为明显，部分解释了常染色体单体细胞中细胞数量较少的原因。其次，研究者还发现了导致非整倍体胚胎外胚层发育不稳定的谱系特异性效应，这伴随着转化生长因子β（TGF-β）和成纤维细胞生长因子（FGF）信号的下调，从而导致滋养层细胞成熟不足。该研究为理解人类非整倍体囊胚的分子基础提供了重要见解，并可能为囊胚发育过程中的细胞相互作用提供启示。
7.High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR–Cas9 editing
CRISPR-Cas9编辑诱导的染色体臂级截断的高分辨率全基因组图谱
Recursion（递归公司），位于美国犹他州盐湖城
Abstract：
Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) is a powerful tool for introducing targeted mutations in DNA, but recent studies have shown that it can have unintended effects such as structural changes. However, these studies have not yet looked genome wide or across data types. Here we performed a phenotypic CRISPR-Cas9 scan targeting 17,065 genes in primary human cells, revealing a 'proximity bias' in which CRISPR knockouts show unexpected similarities to unrelated genes on the same chromosome arm. This bias was found to be consistent across cell types, laboratories, Cas9 delivery methods and assay modalities, and the data suggest that it is caused by telomeric truncations of chromosome arms, with cell cycle and apoptotic pathways playing a mediating role. Additionally, a simple correction is demonstrated to mitigate this pervasive bias while preserving biological relationships. This previously uncharacterized effect has implications for functional genomic studies using CRISPR-Cas9, with applications in discovery biology, drug-target identification, cell therapies and genetic therapeutics.
摘要：
规律成簇间隔短回文重复序列（CRISPR）-CRISPR相关蛋白9（Cas9）是向DNA引入靶向突变的有力工具，但最近的研究表明，它可能会产生意外影响，如结构变化。然而，这些研究尚未在基因组范围内或跨数据类型进行。在此，研究者对人原代细胞中的17,065个基因进行了表型CRISPR-Cas9扫描，发现了一个“邻近偏差”，即CRISPR敲除基因与同一条染色体臂上的不相关基因表现出意外的相似性。这一偏差在不同细胞类型、实验室、Cas9递送方法和检测模式之间均保持一致，数据表明，该偏差是由染色体臂的端粒截断引起的，细胞周期和凋亡途径在其中起到了介导作用。此外，该研究还展示了一种简单的校正方法，可以在保留生物学关系的同时减轻这种普遍存在的偏差。这一先前未表征的效应对使用CRISPR-Cas9进行的功能基因组学研究具有重要影响，在生物学、药物靶点鉴定、细胞疗法和基因治疗等领域均有应用。
8.Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway
复合物-1增强哺乳动物听觉通路的超声神经传递
广州医科大学生命科学联合学院，粤港澳细胞命运调控与疾病联合实验室，广州国家实验室，广州，中国
Abstract：
Unlike megabats, which rely on well-developed vision, microbats use ultrasonic echolocation to navigate and locate prey. To study ultrasound perception, here we compared the auditory cortices of microbats and megabats by constructing reference genomes and single-nucleus atlases for four species. We found that parvalbumin (PV)+ neurons exhibited evident cross-species differences and could respond to ultrasound signals, whereas their silencing severely affected ultrasound perception in the mouse auditory cortex. Moreover, megabat PV+ neurons expressed low levels of complexins (CPLX1-CPLX4), which can facilitate neurotransmitter release, while microbat PV+ neurons highly expressed CPLX1, which improves neurotransmission efficiency. Further perturbation of Cplx1 in PV+ neurons impaired ultrasound perception in the mouse auditory cortex. In addition, CPLX1 functioned in other parts of the auditory pathway in microbats but not megabats and exhibited convergent evolution between echolocating microbats and whales. Altogether, we conclude that CPLX1 expression throughout the entire auditory pathway can enhance mammalian ultrasound neurotransmission.
摘要：
与依赖高度发达视觉的巨翼蝠不同，小蝠类利用超声回声定位进行导航和定位猎物。为了研究超声感知，研究者构建了四种物种的参考基因组和单核转录组图谱，通过比较小蝠类和巨翼蝠的听觉皮层来开展研究。研究者发现，小清蛋白（PV）+神经元在不同物种间存在显著差异，且能够对超声信号作出响应，而将其沉默会严重影响小鼠听觉皮层中的超声感知。此外，巨翼蝠的PV+神经元表达的突触囊泡蛋白（CPLX1-CPLX4）水平较低，这些蛋白可促进神经递质的释放；而小蝠类的PV+神经元则高度表达CPLX1，这有助于提高神经传递效率。进一步扰乱PV+神经元中的Cplx1会损害小鼠听觉皮层中的超声感知。此外，在小蝠类的听觉通路的其他部分而非巨翼蝠中，CPLX1也发挥作用，并表现出回声定位小蝠类与鲸类之间的趋同进化。综上所述，他们得出结论：在整个听觉通路中表达CPLX1可以增强哺乳动物的超声神经传递。
Volume 56 Issue 8, August 2024
在2024年8月，Nature Genetics共发表35篇文章，其中包括Comment 1篇，Research Highlights 4篇，News & Views 3篇，Research Briefings 4篇，Perspectives 2篇，Review articles 1篇，Letters 2篇，Articles 15篇，Amendments & Corrections 3篇。主要内容包括全基因组/外显子组关联分析、罕见编码变异分析、代谢基因功能发现平台、单细胞多组学研究等内容。
1.Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage
全基因组关联荟萃分析确定了五个与产后出血相关的基因座
丹麦哥本哈根大学Hvidovre医院妇产科
Abstract:
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.
摘要：
早孕出血和产后出血（PPH）均存在重大风险，前者与流产密切相关，后者是孕产妇死亡的首要原因，对母婴健康构成严重影响。研究者通过荟萃分析确定了五个与产后出血相关的遗传位点。功能注释分析指出，其中三个位点存在候选基因HAND2、TBX3和RAP2C/FRMD7，并显示在每个位点上，相关变异均位于孕激素受体结合位点内。这些位点与出生体重、妊娠时长和子宫肌瘤之间存在强烈的遗传相关性。孕早期出血未产生全基因组关联信号，但显示出与多种人类特征之间存在强烈的遗传相关性，这表明其病因可能很复杂且为多基因所致。结果表明，产后出血与孕激素信号传导失调有关，而孕早期出血则是一种与基础健康状况相关以及与社会经济地位可能相关的复杂特征，还可能包含尚未确定的遗传因素。
2.Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import
代谢基因功能发现平台GeneMAP鉴定出SLC25A48是线粒体胆碱输入所必需的
美国纽约洛克菲勒大学代谢调节与遗传学实验室
Abstract：
Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Association Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified solute carrier family 25 member 48 (SLC25A48) as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite betaine. Integrative rare variant and polygenic score analyses in UK Biobank provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter.
摘要：
生物体通过小分子转运体和酶的协同作用来维持代谢稳态。尽管许多代谢成分已得到明确，但仍有大量成分的生理底物尚未确定。为了弥补这一差距，研究者利用大规模血浆代谢组全基因组关联研究（GWAS）开发了一个多组学基因-代谢物关联预测（GeneMAP）发现平台。GeneMAP能够生成准确的预测结果，甚至可以精确定位与全基因组关联研究（GWAS）所涉及的变异相距甚远的基因。特别的是，研究者的分析确定了溶质载体家族25成员48（SLC25A48）是血浆胆碱水平的遗传决定因素。在机制上，SLC25A48缺失会严重损害线粒体胆碱的摄取及其下游代谢产物甜菜碱的合成。英国生物银行（UK Biobank）中的罕见变异和多基因评分综合分析提供了有力证据，表明SLC25A48对人类疾病的影响部分可能是通过胆碱的作用介导的。综上所述，本研究为代谢基因功能的发现提供了一个平台，并提出SLC25A48是一种线粒体胆碱转运体。
3.The correlation between CpG methylation and gene expression is driven by sequence variants
CpG甲基化与基因表达之间的相关性是由序列变异驱动的
冰岛deCODE genetics/Amgen公司
Abstract：
Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.3 million CpG units in 7,179 whole-blood genomes. We identified 189,178 methylation depleted sequences where three or more proximal CpGs were unmethylated on at least one haplotype. A total of 77,789 methylation depleted sequences (~41%) associated with 80,503 cis-acting sequence variants, which we termed allele-specific methylation quantitative trait loci (ASM-QTLs). RNA sequencing of 896 samples from the same blood draws used to perform nanopore sequencing showed that the ASM-QTL, that is, DNA sequence variability, drives most of the correlation found between gene expression and CpG methylation. ASM-QTLs were enriched 40.2-fold (95% confidence interval 32.2, 49.9) among sequence variants associating with hematological traits, demonstrating that ASM-QTLs are important functional units in the noncoding genome.
摘要：
基因启动子和增强子序列被转录因子结合，并且缺乏甲基化的CpG位点（DNA中鸟嘌呤之前的胞嘧啶）。这些序列中甲基化CpG的缺失通常与基因表达的增加相关，表明甲基化具有调控基因表达的作用。研究者利用纳米孔测序技术，测定了7179个全血基因组中1530万个CpG单位的单倍型特异性甲基化率。研究者发现了189178个甲基化缺失序列，在这些序列中，至少在一个单倍型上，三个或更多邻近的CpG未发生甲基化。总共有77789个甲基化缺失序列（约41%）与80503个顺式作用序列变异相关，称之为等位基因特异性甲基化数量性状位点（ASM-QTL）。对用于纳米孔测序的同一批血液样本中的896个样本进行RNA测序显示，ASM-QTL（即DNA序列变异）驱动了基因表达与CpG甲基化之间的大部分相关性。与血液学特征相关的序列变异中，ASM-QTL富集了40.2倍（95%置信区间为32.2, 49.9），这表明ASM-QTL是非编码基因组中的重要功能单元。
4.Bayesian estimation of gene constraint from an evolutionary model with gene features
基于包含基因特征的进化模型对基因约束进行贝叶斯预测
斯坦福大学遗传学系
Abstract：
Measures of selective constraint on genes have been used for many applications, including clinical interpretation of rare coding variants, disease gene discovery and studies of genome evolution. However, widely used metrics are severely underpowered at detecting constraints for the shortest ~25% of genes, potentially causing important pathogenic mutations to be overlooked. Here we developed a framework combining a population genetics model with machine learning on gene features to enable accurate inference of an interpretable constraint metric, shet. Our estimates outperform existing metrics for prioritizing genes important for cell essentiality, human disease and other phenotypes, especially for short genes. Our estimates of selective constraint should have wide utility for characterizing genes relevant to human disease. Finally, our inference framework, GeneBayes, provides a flexible platform that can improve the estimation of many gene-level properties, such as rare variant burden or gene expression differences.
摘要：
基因选择约束的测量已被广泛应用于多个领域，包括罕见编码变异的临床解读、疾病基因的发现以及基因组进化的研究。然而，广泛使用的度量方法在检测最短约25%的基因约束时效力严重不足，可能会导致遗漏重要的致病突变。在此，研究者开发了一个框架，该框架结合了群体遗传学模型和基于基因特征的机器学习，能够准确推断出可解释的约束度量指标——shet。在确定对细胞本质、人类疾病和其他表型具有重要意义的基因的优先次序方面，研究者的估算结果优于现有指标，尤其是对短基因而言。研究者对选择性约束的估计值在描述与人类疾病相关的基因特征方面具有广泛的用途。最后，研究者的推断框架GeneBayes提供了一个灵活的平台，可以改进对许多基因水平特性的估计，如罕见变异负担或基因表达差异。
5.Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer
综合分析强调了三维基因组与转移性前列腺癌中DNA、RNA和表观基因组改变之间的相互作用
美国威斯康辛大学麦迪逊分校人类肿瘤学系
Abstract：
The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.
摘要：
人们已经认识到基因组三维结构变化所产生的影响，但目前针对实体癌组织的研究尚有限。本研究中，研究者对80例转移性去势抵抗性前列腺癌（mCRPC）患者的活检样本进行了综合深度Hi-C测序，并结合了匹配的全基因组测序、全基因组亚硫酸氢盐测序、5-羟甲基胞嘧啶（5hmC）测序和RNA测序。在A（开放型）和B（封闭型）染色质区室之间，基因表达、5-甲基胞嘧啶/5hmC甲基化以及结构变异与突变率方面存在显著差异。部分肿瘤在雄激素受体（AR）位点表现出区域染色质接触的减少，这与细胞外环状DNA（ecDNA）有关，且对雄激素受体信号传导抑制剂的反应更差。研究者还确定了与甲基化结构、基因表达和预后存在显著差异的拓扑亚型。数据表明，DNA相互作用可能使结构变异更易形成，TMPRSS2–ERG融合基因的反复出现就是一个例证。这项综合测序工作为临床肿瘤研究提供了独特的资源。
6.Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression
人类肾脏的单细胞多组学和空间图谱分析显示纤维化微环境与肾病进展有关
美国宾夕法尼亚州费城佩雷尔曼医学院宾夕法尼亚大学医学系肾脏、电解质和高血压科
Abstract：
Kidneys are intricate three-dimensional structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. We generated high-quality datasets for 81 samples, including single-cell, single-nuclear, spot-level (Visium) and single-cell resolution (CosMx) spatial-RNA expression and single-nuclear open chromatin, capturing cells from healthy, diabetic and hypertensive diseased human kidneys. Combining these data, we identify cell types and map them to their locations within the tissue. Unbiased deconvolution of the spatial data identifies the following four distinct microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex organization of microenvironments in health and disease and find that the fibrotic microenvironment is able to molecularly classify human kidneys and offers an improved prognosis compared to traditional histopathology. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
摘要：
人体中的肾脏有着复杂的三维结构，但肾脏健康和疾病的空间和分子机制尚未得到充分理解。研究者为81个样本生成了高质量的数据集，这些样本包括来自健康、糖尿病和高血压疾病人体肾脏的单细胞、单核、斑点水平（Visium）和单细胞分辨率（CosMx）空间RNA表达以及单核开放染色质数据。结合这些数据，研究者确定了细胞类型并将其定位到组织内的相应位置。对空间数据进行无偏反卷积分析，确定了以下四个独特的微环境：肾小球微环境、免疫微环境、肾小管微环境和纤维化微环境。研究者描述了健康和疾病状态下微环境的复杂组织，并发现纤维化微环境能够从分子层面对人体肾脏进行分类，且与传统组织病理学相比，能提供更准确的预后信息。研究者提供了人类肾脏和纤维化过程的空间分辨分子路线图，展示了空间转录组学的临床应用价值。
7.Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis
绘制人类和小鼠肺纤维化的空间分解转录组
瑞典哥德堡阿斯利康安全科学&临床药理学和安全科学&研发部
Abstract：
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.
摘要：
特发性肺纤维化（IPF）是一种预后不良且治疗选择有限的进行性肺部疾病。由于人们对IPF发病机制的了解有限，且现有的临床前模型转化性差，寻找有效治疗方法的工作一直受到阻碍。为克服这些局限，研究者生成了人类IPF（n=4）和博来霉素诱导的小鼠肺纤维化（n=6）的空间分辨转录组图谱。研究者发现了IPF肺部独特的纤维化微环境，其特征是微环境中由转化生长因子β信号（如TP53和APOE）和预测调控因子主导的异常肺泡上皮细胞。此外，还发现，IPF纤维化微环境中的肺泡再生停滞与急性纤维化小鼠肺部活跃的组织修复之间存在明显差异。本研究深入探讨了IPF的转录组特征，并提出肺泡再生可能是治疗IPF的一种有前景的策略。
Volume 56 Issue 9, September 2024
在2024年9月，Nature Genetics共发表27篇文章，其中包括Research Highlights 4篇，News & Views 3篇，Perspectives 2篇，Brief communications 1篇，Letters 1篇，Articles 16篇。主要内容包括罕见变异、多组学分析、CRISPR基因编辑、花生的进化史和表型多样化等内容。
1.Rare coding variant analysis for human diseases across biobanks and ancestries
跨生物库和祖先的人类疾病罕见编码变异分析
美国麻省剑桥市麻省理工学院与哈佛大学博德研究所心血管疾病倡议项目
Abstract：
Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (βDeming = 0.7-1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease.
摘要：
大规模测序为人类表型变异中罕见编码变异的作用研究提供了前所未有的机遇。在此，研究者针对来自三大生物银行（包括“All of us”研究项目）的测序数据进行了跨祖先分析。利用混合效应模型，在748,879名个体（其中包括155,236名非欧洲血统个体）中针对601种疾病进行了基于基因的罕见变异检测。确定了363个显著相关性，这些相关性凸显了人类疾病表型的核心基因，并发现了潜在的新相关性，例如UBR3与心血管代谢疾病相关，YLPM1与精神疾病相关。跨祖先负担测试在多种数据集的发现中是一种包容且有用的方法，尽管研究者 也强调了在这种背景下进行特定祖先敏感性分析的重要性。最后，研究者发现，在欧洲血统相似样本和其他遗传血统样本中，罕见蛋白破坏变异的效应大小是一致的（βDeming = 0.7-1.0）。该研究结果对多祖先和跨生物银行在人类疾病测序关联研究中的应用具有启示意义。
2.Disease prediction with multi-omics and biomarkers empowers case–control genetic discoveries in the UK Biobank
在UKB中利用多组学和生物标志物进行疾病预测有助于病例对照基因的发现
英国剑桥阿斯利康生物制药研发中心&基因组学研究中心
Abstract:
The emergence of biobank-level datasets offers new opportunities to discover novel biomarkers and develop predictive algorithms for human disease. Here, we present an ensemble machine-learning framework (machine learning with phenotype associations, MILTON) utilizing a range of biomarkers to predict 3,213 diseases in the UK Biobank. Leveraging the UK Biobank's longitudinal health record data, MILTON predicts incident disease cases undiagnosed at time of recruitment, largely outperforming available polygenic risk scores. We further demonstrate the utility of MILTON in augmenting genetic association analyses in a phenome-wide association study of 484,230 genome-sequenced samples, along with 46,327 samples with matched plasma proteomics data. This resulted in improved signals for 88 known (P < 1 × 10-8) gene-disease relationships alongside 182 gene-disease relationships that did not achieve genome-wide significance in the nonaugmented baseline cohorts. We validated these discoveries in the FinnGen biobank alongside two orthogonal machine-learning methods built for gene-disease prioritization.
摘要：
生物银行级别数据集的涌现为发现新型生物标志物和开发人类疾病预测算法提供了新的机遇。在此，研究者介绍了一个集成机器学习框架（结合表型关联的机器学习，MILTON），该框架利用一系列生物标志物来预测英国生物银行中的3,213种疾病。借助英国生物银行的纵向健康记录数据，MILTON能够预测在招募时未被诊断的新发疾病病例，其性能大大优于现有的多基因风险评分。研究者进一步展示了MILTON在增强484,230个基因组测序样本（以及46,327个具有匹配血浆蛋白质组学数据的样本）的全表型遗传关联分析中的实用性。这导致88个已知基因-疾病关系（P < 1 × 10-8）的信号得到改善，同时发现了182个在非增强基线队列中未达到全基因组显著性水平的基因-疾病关系。在FinnGen生物银行中验证了这些发现，同时采用了两种为基因-疾病优先排序而构建的正交机器学习方法。所有提取的基因-疾病关联和新发疾病预测生物标志物均可公开获取（http://milton.public.cgr.astrazeneca.com）。
3.Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences
462,666 UK Biobank全基因组序列中端粒长度的遗传结构
英国剑桥阿斯利康生物制药研发中心&基因组学研究中心
Abstract：
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
摘要：
端粒可保护染色体末端免受损伤，其长度与人类疾病和衰老有关。研究者开发了一项联合端粒长度测量指标，该指标结合了来自462,666名英国生物银行参与者的定量聚合酶链反应（PCR）和全基因组测序测量结果。这一指标提高了单核苷酸多态性（SNP）的遗传力，表明它更能准确捕捉端粒长度的遗传调控。全外显子组罕见变异和基因水平折叠关联研究确定了64个变异和30个基因与端粒长度显著相关，其中包括ACD和RTEL1中的等位基因系列。值得注意的是，这些基因中有16%是克隆性造血（一种与髓系肿瘤和多种非恶性疾病相关的年龄相关体细胞嵌合体）的已知驱动因素。体细胞变异分析揭示了基因特异性与端粒长度的关系，包括SRSF2突变体克隆大的个体端粒变长，而由其他基因驱动的克隆扩张的个体端粒变短。总体而言，研究结果表明，罕见变异对端粒长度有影响，而在与克隆性造血相关的基因中，这种影响更为显著。
4.Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases
跨不同祖先的精细图谱推动了人类复杂性状和疾病的潜在因果变异的发现
美国马萨诸塞州波士顿总医院分析和转化遗传学部
Abstract：
Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries.
摘要：
人类复杂性状或疾病的全基因组关联研究（GWAS）通常涉及跨越数百或数千个遗传变异的遗传位点，其中许多变异具有相似的统计意义。尽管针对欧洲血统个体的统计精细定位已取得重要发现，但跨人群精细图谱有可能通过利用不同血统间的基因组多样性来提高统计效能和分辨率。在此，研究者提出了一种准确且计算高效的跨人群精细图谱绘制方法——SuSiEx。SuSiEx能够整合来自任意数量祖先的数据，明确模拟特定人群的等位基因频率和连锁不平衡模式，考虑基因组区域内的多个因果变异，并可应用于GWAS汇总统计。研究者通过模拟全面评估了SuSiEx的性能。此外，SuSiEx 改进了英国生物库和台湾生物库中一系列数量性状的精细图谱，并通过整合东亚和欧洲血统的GWAS改进了精神分裂症相关基因座的精细图谱。
5.Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology
对10,478个癌症基因组的分析确定了候选驱动基因和精确肿瘤学的机遇
英国伦敦癌症遗传与流行病学研究所
Abstract：
Tumor genomic profiling is increasingly seen as a prerequisite to guide the treatment of patients with cancer. To explore the value of whole-genome sequencing (WGS) in broadening the scope of cancers potentially amenable to a precision therapy, we analysed whole-genome sequencing data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 candidate driver genes, including 74 that are new to any cancer. We estimate that approximately 55% of patients studied harbor at least one clinically relevant mutation, predicting either sensitivity or resistance to certain treatments or clinical trial eligibility. By performing computational chemogenomic analysis of cancer mutations we identify additional targets for compounds that represent attractive candidates for future clinical trials. This study represents one of the most comprehensive efforts thus far to identify cancer driver genes in the real world setting and assess their impact on informing precision oncology.
摘要：
肿瘤基因组分析越来越被视为指导癌症患者治疗的先决条件。为了探索全基因组测序（WGS）在拓宽可能接受精准治疗癌症范围方面的价值，研究者分析了英国10万基因组项目中招募的涵盖35种癌症类型的10,478名患者的全基因组测序数据。研究者确定了330个候选驱动基因，其中包括74个在任何癌症中均为新发现的驱动基因。研究者估计，约55%的研究患者携带至少一种具有临床意义的突变，这些突变可预测对某些治疗的敏感性或耐药性，或预测临床试验的入组资格。通过对癌症突变进行计算化化学基因组学分析，研究者确定了未来临床试验中有吸引力的候选化合物的额外靶点。本研究是迄今为止在真实世界中识别癌症驱动基因并评估其对精准肿瘤学指导影响的最全面研究之一。
6.In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions
体内CRISPR筛选发现MEN1在调节肿瘤-微环境相互作用方面具有双重功能
加拿大安大略省多伦多大学医学生物物理系
Abstract：
Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.
摘要：
在二维细胞培养模型中进行的功能基因组筛选，在识别影响肿瘤微环境的治疗靶点方面存在局限性。通过比较二维培养中的靶向CRISPR-Cas9筛选与源自同一细胞系的异种移植模型，发现MEN1是体内外差异淘汰效应最强的靶点。在多种实体瘤类型中敲除MEN1，对体外细胞增殖无影响，但会分别显著促进或抑制免疫缺陷小鼠或免疫功能健全小鼠的肿瘤生长。从机制上讲，MEN1敲除会重新分配MLL1在染色质上的占有率，增加重复基因组区域的H3K4me3，激活双链RNA表达，并分别在免疫缺陷和免疫健全小鼠中增加中性粒细胞和CD8+ T细胞的浸润。通过药物抑制menin-MLL相互作用，可以以一种CD8+ T细胞依赖的方式减少肿瘤生长。这些发现揭示了MEN1依赖于肿瘤微环境的致癌和抑瘤功能，并为在实体瘤中靶向MEN1的治疗方式提供了理论依据。
7.Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells
表观遗传疗法可促进转座元件转录，从而在胶质母细胞瘤细胞中产生肿瘤富集抗原
华盛顿大学医学院遗传学系
Abstract:
Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy.
摘要：
抑制表观遗传调节因子可以在转录水平上重新激活可转座元件（TE）。这些TE转录本通常会生成独特的肽，这些肽可以作为免疫治疗的免疫原性抗原。本文旨在探讨表观遗传疗法激活的可转座元件是否能显著增加胶质母细胞瘤（一种低突变率和新抗原负荷高的侵袭性脑癌）的抗原库。采用表观遗传药物对患者来源的原代胶质母细胞瘤干细胞系、星形胶质细胞系和原代成纤维细胞系进行处理，并鉴定出由治疗诱导、来源于TE且优先在癌细胞中表达的转录本。研究者通过液相色谱串联质谱下拉实验验证了这些转录本能够产生人类白细胞抗原I类呈递的抗原。重要的是，在表观遗传疗法后，即使在增殖的非肿瘤细胞系中，许多TE也被转录，这表明像CRISPR介导的激活这样的靶向策略可以最大限度地减少激活非目标基因组区域可能带来的副作用。这些结果既强调了在使用治疗诱导的TE衍生抗原进行靶向免疫治疗时需要谨慎，也展现了未来转化研究的潜力。
8.Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules
小分子致病性终止密码子解读的基因组尺度定量与预测
西班牙巴塞罗那巴塞罗那科学技术研究所（BIST）生物医学研究所（IRB Barcelona）
Abstract：
Premature termination codons (PTCs) cause ~10-20% of inherited diseases and are a major mechanism of tumor suppressor gene inactivation in cancer. A general strategy to alleviate the effects of PTCs would be to promote translational readthrough. Nonsense suppression by small molecules has proven effective in diverse disease models, but translation into the clinic is hampered by ineffective readthrough of many PTCs. Here we directly tackle the challenge of defining drug efficacy by quantifying the readthrough of ~5,800 human pathogenic stop codons by eight drugs. We find that different drugs promote the readthrough of complementary subsets of PTCs defined by local sequence context. This allows us to build interpretable models that accurately predict drug-induced readthrough genome-wide, and we validate these models by quantifying endogenous stop codon readthrough. Accurate readthrough quantification and prediction will empower clinical trial design and the development of personalized nonsense suppression therapies.
摘要：
提前终止密码子（PTC）是导致约10-20%遗传性疾病的诱因，也是癌症中抑癌基因失活的主要机制。缓解PTC影响的一种通用策略是促进翻译通读。小分子介导的无义抑制已在多种疾病模型中被证明有效，但许多PTC的无效通读阻碍了其向临床的转化。本研究中，通过量化8种药物对约5800个人类致病性终止密码子的通读作用，直接解决了确定药物疗效的挑战。研究者发现，不同药物可促进由局部序列环境定义的互补PTC子集的通读。这使研究者能够构建可解释模型，准确预测药物诱导的全基因组通读，并通过量化内源性终止密码子的通读来验证这些模型。准确的通读量化和预测将助力临床试验设计和个性化无义抑制疗法的开发。
9.An integrated single-cell reference atlas of the human endometrium
人类子宫内膜单细胞参考图谱
英国剑桥威康桑格研究所
Abstact：
The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal–epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.
摘要：
人类子宫内膜的细胞组成复杂且动态多变，目前对其了解仍不够深入。以往的子宫内膜单细胞图谱分析涵盖的供体数量有限，且在定义细胞类型方面缺乏共识。本文推出了人类子宫内膜细胞图谱（HECA），这是一个高分辨率的单细胞参考图谱（包含313,527个细胞），结合了63名患有子宫内膜异位症与未患子宫内膜异位症女性的已发表和新生成的子宫内膜单细胞转录组的数据集。HECA通过共识分类法确定了细胞类型，并发现了之前未报告的细胞类型。这些细胞类型通过空间转录组学进行原位定位，并使用一个新的独立单细胞核数据集（包含312,246个细胞核，来自63名供体）进行了验证。在功能学中，确定了转化生长因子β（TGFβ）信号通路介导的复杂基质细胞-上皮细胞协同作用。在基底层中，研究者确定了成纤维细胞与表达祖细胞标志物的上皮细胞群之间的信号传递。将HECA与大规模子宫内膜异位症全基因组关联研究数据相结合，发现蜕膜化基质细胞和巨噬细胞在子宫内膜异位症中最可能发生功能失调。HECA是研究子宫内膜生理和疾病以及指导微观生理学体外系统开发的宝贵资源。
汇报人：张子妍
导师：赵宇
审核：胥飞宇、任建君
