【Nature Genetics】2024年7月刊论文导读

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。

Volume 56 Issue 7, July 2024

在2024年7月，Nature Genetics共发表30篇文章，其中包括1篇World View，1篇Comment，4篇Research Highlights，1篇News & Views，4篇Research Briefings，2篇Perspectives，1篇Review Articles，1篇Brief Communications，2篇Letters，12篇Articles，1篇Technical Reports。

1. Calibrated prediction intervals for polygenic scores across diverse contexts

在不同背景下对多基因评分进行校准的预测区间

美国加州大学洛杉矶分校、德克萨斯大学

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） 已成为广泛领域基因组预测的首选工具。研究发现，PGS的表现在不同环境和生物样本库之间有很大差异。年龄、性别和收入等背景会影响PGS的准确性，其程度与遗传祖先相似。本研究介绍了一种方法（CalPred），该方法对所有上下文进行建模，以产生因上下文而异的预测区间，以实现校准（包括具有90%概率的特征），而现有方法被错误校准。在对大型和多样化生物样本库（All of Us 和 UK Biobank）的 72 个性状的分析中，发现数量性状的预测区间需要调整高达 80%。对于疾病性状，基于PGS的预测在社会经济背景（如家庭年收入水平）中被错误地校准，进一步凸显了在基于PGS的预测中对不同人群的背景信息进行考虑的必要性。

2. Understanding the genetic complexity of puberty timing across the allele frequency spectrum

了解等位基因频谱中青春期时间的遗传复杂性

英国剑桥大学、挪威卑尔根大学、瑞士洛桑大学等机构合作发表

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：

青春期时间差异很大，并且与以后的健康结果有关。本研究对 ~800,000 名女性进行了多血统遗传分析，确定了月经初潮时年龄的 1,080 个信号。总的来说，这些解释了独立样本中 11% 的性状变异。多基因风险最高和最低 1% 的女性分别表现出 ~11 倍和 ~14 倍的青春期延迟和性早熟风险。在 ~200,000 名女性中发现了几个携带罕见功能丧失变异的基因，包括 ZNF483 中的变异，这消除了多基因风险的影响。变异体-基因定位方法和小鼠促性腺激素释放激素神经元 RNA 测序涉及 665 个基因，包括一个未表征的 G 蛋白偶联受体 GPR83，它放大了 MC3R 的信号传导，MC3R 是一种关键的营养传感器。参与DNA损伤反应的基因与更年期时间的共同信号表明，卵巢储备可能发出中央信号以触发青春期。研究还强调了可能将生殖时间与晚年疾病联系起来的体型依赖性和独立机制。

3. Exome sequence analysis identifies rare coding variants associated with a machine learning-based marker for coronary artery disease

外显子组测序分析可识别与基于机器学习的冠状动脉疾病标记物相关的罕见编码变异

美国西奈山伊坎医学院、密歇根大学

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） 存在于一系列疾病中，以危险因素和致病过程的组合为代表。使用机器学习和电子健康记录中的临床数据构建的 CAD 计算机评分可以捕获该范围内的疾病进展、严重程度和诊断不足，并且可以增强 CAD 的基因发现工作。本研究测试了稀有和超稀有编码变体与UK Biobank、All of Us Research Program 和 BioMe Biobank 中 CAD 计算机评分的关联。确定了 17 个基因的关联；其中，14 个显示至少中等水平的先前遗传、生物学和/或临床对冠状动脉疾病的支持。还在 321 个聚集的 CAD 基因中观察到过量的超稀有编码变异，这表明更多的超稀有变异关联有待发现。这些结果扩展了对冠状动脉疾病遗传病因的理解，并说明了数字标记如何增强复杂疾病的遗传关联研究。

4. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

均聚物开关介导错配修复缺陷结直肠癌的适应性变异性

英国伦敦大学、威斯敏斯特大学、荷兰乌得勒支大学等机构合作发表

Abstract

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

摘要：

错配修复（MMR）缺陷癌症通过靶基因中编码均聚物的逐步侵蚀而进化。奇怪的是，MMR基因MutS同源物6（MSH6）和MutS同源物3（MSH3）也包含编码均聚物，这些是MMR缺陷癌症中常见的突变靶点。增量MMR突变对MMR缺陷癌症进化的影响尚不清楚。本研究展示了微卫星不稳定性通过随机移码切换来切换MSH6和MSH3中的超突变单核苷酸均聚物运行来调节DNA修复。自发突变和逆转调节亚克隆突变率、突变偏倚以及HLA和新抗原多样性。患者来源的类器官证实了这些观察结果，并表明在没有免疫选择的情况下，MMR均聚物序列会漂移回阅读框，这表明突变率升高的适应成本。实验和模拟研究的结合表明，亚克隆免疫选择有利于增量MMR突变。总体而言，研究数据表明，MMR 缺陷型结直肠癌通过适应亚克隆突变率和免疫选择的多样性来促进肿瘤内异质性。

5. Saturation genome editing of BAP1 functionally classifies somatic and germline variants

BAP1 的饱和基因组编辑对体细胞和种系变异进行功能性分类

英国威康桑格研究所、英国剑桥大学、荷兰莱顿大学等机构合作发表

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：

人们从父母那里遗传获得或在生殖细胞外新获得的（de novo）或体细胞获得的许多变异是罕见的，这限制了研究人员将它们与疾病联系起来的精确度。本研究对 BAP1 进行了详尽的饱和基因组编辑 （SGE），其破坏与肿瘤发生和神经发育改变有关。通过实验表征了 18,108 个独特变异，其中 6,196 个被发现具有异常功能，然后使用这些数据来评估UK Biobank的表型关联。本研究还在大量人群确定的肿瘤集合、癌症谱系和 ClinVar 中表征了变异，并探索了癌症相关变异与与神经发育表型相关的变异相比的行为。分析表明，破坏性种系 BAP1 变体与有丝分裂原 IGF-1 的较高循环水平显着相关，表明可能存在病理机制和治疗靶点。此外，构建了一个具有 >98% 敏感性和特异性的变体分类器，并量化证据强度以帮助精确解释变异。

6. Saturation genome editing maps the functional spectrum of pathogenic VHL alleles

饱和基因组编辑绘制致病性VHL等位基因的功能谱

英国弗朗西斯·克里克研究所、德国弗莱堡大学、加拿大多伦多病童医院等机构合作发表

Abstract

To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel–Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL’s coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype–phenotype relationships across complete genes.

摘要：

为了最大限度地发挥精准医疗方法的影响，识别疾病背后的遗传变异并准确量化其功能影响至关重要。一个体现变异解释挑战的基因是 von Hippel-Lindautumor 抑制因子（VHL）。VHL 编码一种 E3 泛素连接酶，可调节细胞对缺氧的反应。VHL 中的种系致病变异使患者易患肿瘤，包括透明细胞肾细胞癌 （ccRCC） 和嗜铬细胞瘤，并且在散发性肾癌中经常观察到体细胞 VHL 突变。本研究优化并应用饱和基因组编辑来检测VHL编码序列中几乎所有可能的单核苷酸变体（SNV）。为了描述机制，研究者量化了mRNA剂量效应，并比较了同基因细胞系中的功能效应。2,268个VHL SNV 的功能评分以完美的准确性确定了一组驱动 ccRCC 的核心致病等位基因，为肿瘤类型的不同风险提供信息，并揭示了变异影响功能的新机制。这些结果对于对临床遇到的VHL变异进行分类具有直接的实用性，并说明了精确的功能测量如何解决完整基因之间的多效性和剂量依赖性基因型-表型关系。

7. 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替代来源

荷兰鹿特丹伊拉斯谟大学、德国马尔堡大学、芬兰赫尔辛基大学等机构合作发表

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：

根据传统观点，结肠癌起源于干细胞。然而，炎症是结肠癌的一个关键危险因素，已被证明可以抑制肠道干性。本研究使用Paneth细胞作为模型来评估分化谱系在小鼠炎症背景下触发肿瘤发生的能力。炎症后，Paneth 细胞特异性 Apc 突变导致肠道肿瘤，不仅让人想起炎症性肠病患者中出现的肿瘤，而且也让人想起更大比例的人类散发性结肠癌。后者可能是因为西式饮食习惯的炎症后果，这是结肠癌的主要危险因素。旨在从患者来源的肿瘤样本中预测癌症起源的机器学习方法证实，在很大一部分散发病例中，结肠癌的起源存在于分泌谱系中，而不是干细胞中。

8. A single-cell transcriptome atlas of human euploid and aneuploid blastocysts

人整倍体和非整倍体囊胚的单细胞转录组图谱

中国华大基因研究院、中国科学院大学、中南大学等机构合作发表

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：

非整倍体在早期人类胚胎中经常被检测到，是早期妊娠失败的主要原因。然而，非整倍体如何影响细胞功能仍然难以捉摸。本研究分析了来自 203 个涉及常染色体和性染色体的人类整倍体和非整倍体囊胚的 14,908 个单细胞的转录组。几乎所有的囊胚都包含四个谱系。在非整倍体染色体中，19.5%±1.2%的表达基因显示出剂量效应，并鉴定出90个剂量敏感结构域。非整倍体导致普遍的全基因组转录组改变。确定了包括凋亡在内的常见影响，特别是在单体性中，部分解释了常染色体单体性中较低的细胞数量。研究进一步确定了导致非整倍体中不稳定的外胚层发育的谱系特异性效应，伴随着 TGF-β 和 FGF 信号传导的下调，导致滋养外胚层成熟不足。该工作为人类非整倍体囊胚的分子基础提供了重要的见解，并可能揭示囊胚发育过程中的细胞相互作用。

9. 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

美国盐湖城Recursion生物科技公司

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：

成簇的规则间隔短回文重复序列（CRISPR）–CRISPR相关蛋白9（Cas9）是在DNA中引入靶向突变的有力工具，但最近的研究表明，它可能会产生意想不到的影响，例如结构变化。然而，这些研究尚未在全球范围内或跨数据类型进行研究。在这里，我们进行了针对原代人类细胞中17,065个基因的表型CRISPR-Cas9扫描，揭示了“邻近偏差”，其中CRISPR敲除显示出与同一染色体臂上不相关的基因的意外相似性。研究发现，这种偏倚在细胞类型、实验室、Cas9递送方法和检测方式之间是一致的，数据表明，这是由染色体臂的端粒截短引起的，细胞周期和凋亡途径起着介导作用。此外，还展示了一个简单的校正可以减轻这种普遍存在的偏见，同时保留生物学关系。这种以前未表征的效应对使用CRISPR-Cas9的功能基因组研究具有重要意义，在发现生物学、药物靶点鉴定、细胞疗法和基因疗法中都有应用。

10. LINE-1 transcription activates long-range gene expression

LINE-1 转录激活长程基因表达

中国清华大学-北京大学生命科学联合中心

Abstract

Long interspersed nuclear element-1 (LINE-1 or L1) is a retrotransposon group that constitutes 17% of the human genome and shows variable expression across cell types. However, the control of L1 expression and its function in gene regulation are incompletely understood. Here we show that L1 transcription activates long-range gene expression. Genome-wide CRISPR–Cas9 screening using a reporter driven by the L1 5′ UTR in human cells identifies functionally diverse genes affecting L1 expression. Unexpectedly, altering L1 expression by knockout of regulatory genes impacts distant gene expression. L1s can physically contact their distal target genes, with these interactions becoming stronger upon L1 activation and weaker when L1 is silenced. Remarkably, L1s contact and activate genes essential for zygotic genome activation (ZGA), and L1 knockdown impairs ZGA, leading to developmental arrest in mouse embryos. These results characterize the regulation and function of L1 in long-range gene activation and reveal its importance in mammalian ZGA.

摘要：

长散布核元件-1（LINE-1 或 L1）是一种逆转录转座子基团，占人类基因组的 17%，在细胞类型中表现出不同的表达。然而，对L1表达的控制及其在基因调控中的功能尚不清楚。本研究表明L1转录激活了长程基因表达。在人类细胞中使用由 L1 5′ UTR 驱动的报告基因进行全基因组 CRISPR-Cas9 筛选，可识别影响 L1 表达的功能多样性基因。出乎意料的是，通过敲除调节基因来改变 L1 表达会影响远处基因的表达。L1 可以物理接触它们的远端靶基因，这些相互作用在 L1 激活时变得更强，而当 L1 沉默时，这些相互作用会变弱。值得注意的是，L1 接触并激活合子基因组激活 （ZGA） 所必需的基因，而 L1 敲低会损害 ZGA，导致小鼠胚胎发育停滞。这些结果表征了L1在长程基因激活中的调控和功能，并揭示了其在哺乳动物ZGA中的重要性。

11. Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway

Complexin-1 增强哺乳动物听觉通路中的超声神经传递

中国广州GMU-GIBH联合生命科学学院、Bioland实验室、华东师范大学、北京师范大学等机构合作发表

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：

与依赖于发达视力的巨型蝙蝠不同，微型蝙蝠使用超声波回声定位来导航和定位猎物。为了研究超声感知，本研究通过构建四个物种的参考基因组和单核图谱来比较微蝠和巨型蝙蝠的听觉皮层。研究发现小白蛋白（PV）+神经元表现出明显的跨物种差异，并且可以对超声信号做出反应，而它们的沉默严重影响了小鼠听觉皮层的超声感知。此外，megabat PV+神经元表达低水平的复合蛋白（CPLX1-CPLX4），可以促进神经递质的释放，而微蝙蝠PV+神经元高度表达CPLX1，可以提高神经传递效率。PV+ 神经元中 Cplx1 的进一步扰动损害了小鼠听觉皮层中的超声感知。此外，CPLX1在微蝙蝠的听觉通路的其他部分起作用，但在巨型蝙蝠中没有起作用，并且在回声定位微蝙蝠和鲸鱼之间表现出趋同进化。总而言之，本研究得出结论，CPLX1在整个听觉通路中的表达可以增强哺乳动物的超声神经传递。

汇报人：张宇阳

导师：赵宇

审核：张子妍、任建君