【Nature Genetics】2025年6月刊论文导读
期刊介绍：
Nature Genetics创刊于1992年，由Springer Nature出版，涵盖人类和植物性状及其他模式生物的遗传学和功能基因组学研究。当前的研究重点是通过实验干预探究常见病和复杂疾病的遗传学基础，以及基因网络的功能机制、结构及进化。在行业领域中学术影响力很大，属于国际一流期刊，2024年期刊影响因子为29.0。
Volume 57 Issue 6, June 2025
在2025年6月，Nature Genetics共发表31篇文章，其中包括1篇Comment，4篇Research Highlights，2篇News & Views，2篇Research Briefings，1篇Perspectives，1篇Review Articles，2篇Brief Communications，1篇Letters，16篇Articles（13篇与人类相关），2篇Amendments & Corrections。
1.Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption
主要剪接体 U4 和 U5 小核 RNA 基因的显性变异通过剪接破坏引起神经发育障碍
法国索邦大学、南特大学、诺曼底大学
Abstract
The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5′ splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5′ splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.
主要剪接体包含五种对剪接至关重要的小核 RNA（snRNA;U1、U2、U4、U5 和 U6）。编码U4的RNU4-2变异会导致一种称为ReNU综合征的神经发育障碍。这项研究分析了23,649名罕见疾病患者的法国队列中50个snRNA编码基因的新发变异，并通过国际合作收集了更多病例。共确定了145个既往未报告的RNU4-2（可能）致病性变异先证者，以及21例携带RNU5B-1和RNU5A-1（编码 U5）中具有新发和/或复发性变异的个体。致病性变异通常是母源等位基因上的新发突变，并聚集在剪接关键区域。RNU4-2变异主要定位于两种结构，即茎环III和T环/准假结，它们负责U6 ACAGAGA 盒的定位以实现5’剪接位点识别，并与不同的表型严重程度相关。RNU4-2变异导致选择性5’剪接位点使用和甲基化模式（表观特征）的特征性缺陷，这些缺陷与变异位置和临床严重程度相关。研究确定RNU5B-1为神经发育障碍基因，提示RNU5A-1是一个强有力的候选基因，并强调了snRNA新发变异的作用。
2.Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
全基因组分析确定了30个与强迫症相关的位点
德国柏林洪堡大学、慕尼黑路德维希-马克西米利安大学
Abstract
Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.
强迫症（OCD）影响约1% 的儿童和成人，部分是由遗传因素引起。这项研究进行了一项全基因组关联研究（GWAS）荟萃分析，整合了53,660例OCD病例和2,044,417例对照，并确定了30个独立的全基因组显著位点。研究者使用基于基因的方法确定了249个OCD的潜在效应基因，其中25个被归类于最可能的致病候选基因，包括WDR6、DALRD3和CTNND1以及主要组织相容性复合体（MHC）区域中的多个基因。研究者估算约11,500 个遗传变异可解释 90% 的 OCD 遗传性。OCD 遗传风险与海马体和皮层中的兴奋性神经元，以及 D1和 D2 型多巴胺受体的中等棘神经元相关。OCD遗传风险与研究者检验的112种其他表型中的 65 种存在共享遗传风险，包括所有被分析的精神疾病，尤其是强迫症与焦虑、抑郁、神经性厌食症和妥瑞综合征呈正相关，而与炎症性肠病、受教育程度和体重指数呈负相关。
3.Genome-wide association study of long COVID
长期 COVID 的全基因组关联研究
芬兰分子医学研究所、加拿大麦吉尔大学、日本东京大学
Abstract
Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4’s role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.
感染可导致持续症状和继发疾病，例如水痘-带状疱疹感染后带状疱疹或链球菌感染后的风湿热。同样，严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）感染可导致新冠长期症状（long COVID），典型症状为疲劳、肺部症状和认知功能障碍。新冠长期症状背后的生物学机制仍不清楚。这项研究对新冠长期症状进行了一项全基因组关联研究，纳入来自16个国家/地区的24项研究的多达6,450例长新冠病例和1,093,995例人群对照。研究发现FOXP4与新冠长期症状的关联，独立于先前确定的其与重症 COVID-19 的关联。该关联性在9,500例具有新冠长期症状的病例和 798,835 例人群对照中得到验证。鉴于转录因子FOXP4在肺生理学和病理学中的作用，研究结果强调了肺功能在新冠长期症状的病理生理学中的重要性。
4.The contribution of gametic phase disequilibrium to the heritability of complex traits
配子期不平衡对复杂性状遗传力的贡献
澳大利亚昆士兰大学、美国麻省理工学院和哈佛大学博德研究所
Abstract
Nonrandom mating induces genome-wide correlations between unlinked genetic variants, known as gametic phase disequilibrium (GPD), whose contribution to heritability remains uncharacterized. Here we introduce the disequilibrium genome-based restricted maximum likelihood (DGREML) method to simultaneously quantify the additive contribution of SNPs to heritability and that of their directional covariances. We applied DGREML to 26 phenotypes of 550,000 individuals from diverse biobanks and found that cross-autosome GPD contributes 10–27% of the SNP-based heritability of height, educational attainment, intelligence, income, self-rated health status and sedentary behaviors. We observed a differential contribution of GPD to the heritability of height between the UK, Chinese and Japanese populations. Finally, bivariate DGREML analyses of educational attainment and height show that cross-autosome GPD contributes at least 32% of their genetic correlation. Altogether, our versatile and powerful method reveals understudied features of the genetic architecture of complex traits and informs potential mechanisms generating these features.
非随机交配会诱导全基因组范围内非连锁遗传变异之间的相关性，这种现象称为配子期不平衡 （GPD），其对遗传力的贡献仍未明确。这项研究介绍了基于不平衡基因组的限制最大似然方法（DGREML），能够同时量化单核苷酸多态性（SNP）对遗传力及其定向协方差的加性贡献。研究者将DGREML应用于来自不同生物库的 55万个个体的 26 种表型，发现跨常染色体GPD对身高、教育程度、智力、收入、自评健康状况和久坐行为的SNP估算遗传力贡献比例为10-27%。研究者还观察到英国、中国和日本人群中GPD对身高遗传力的贡献存在差异。最后，受教育程度和身高的双变量DGREML分析显示，跨常染色体GPD贡献了至少 32% 的遗传相关性。总而言之，这一多功能且强大的方法揭示了复杂性状遗传结构中尚未充分研究的特征，并为解析这些特征的潜在产生机制提供线索。
5.Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects
亨廷顿病中体细胞扩增和临床表型的遗传修饰因子突出了共同效应和组织特异性效应
美国麻省总医院、麻省理工学院和哈佛大学博德研究所、爱荷华大学卡佛医学院
Abstract
An inherited, expanded CAG repeat in HTT undergoes further somatic expansion to cause Huntington’s disease (HD). To gain insights into this molecular mechanism, we compared genome-wide association studies of somatic expansion in blood and somatic expansion-driven HD clinical phenotypes. Here, we show that somatic expansion is driven by a mismatch repair-related process whose genetic modification and consequences show unexpected complexity, including cell-type specificity. The HD clinical trajectory is further modified by non-DNA repair genes that differentially influence measures of cognitive and motor dysfunction. In addition to shared (DNA repair genes MSH3, PMS2 and FAN1) and distinct trans-modifiers, a synonymous CAG-adjacent variant in HTT dramatically hastens motor onset without increasing somatic expansion, while a cis-acting 5′-untranslated region variant promotes blood repeat expansion without influencing clinical HD. Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD pathogenic mechanisms beyond somatic expansion.
在HTT基因中，遗传获得的扩增CAG重复序列会进一步发生体细胞扩增，从而导致亨廷顿病 （HD）。为了深入了解这一分子机制，该研究比较了外周血中体细胞扩增的全基因组关联研究结果和由体细胞扩增驱动的HD临床表型的全基因组关联研究结果。研究表明，体细胞扩增由一个错配修复相关的过程驱动，其遗传调控及结果显示了出乎意料的复杂性，包括细胞类型特异性。HD的临床进程还受到非 DNA 修复基因的进一步影响，这些基因对认知和运动功能障碍指标具有不同的作用。除了共享的 （DNA 修复基因 MSH3、PMS2 和 FAN1） 和特异性的反式修饰因子外，HTT基因中的同义 CAG 相邻变异可显著加速运动症状发作，但不增加体细胞扩增，而一个位于5′非翻译区的顺式作用变异则可促进外周血中的重复序列扩增，却不影响HD临床表现。这些发现与DNA重复序列疾病的扩增抑制治疗直接相关，并为体细胞扩增之外的HD致病机制提供了新线索。
6.Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice
针对导致亨廷顿病和弗里德赖希共济失调的三核苷酸重复序列的碱基编辑，可减少患者细胞和小鼠中的体细胞重复扩增
美国哈佛大学和麻省理工学院博德研究所
Abstract
Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAG•CTG sequence is found in approximately one-third of pathogenic TNR loci, including the HTT gene that causes Huntington’s disease. Friedreich’s ataxia, the most prevalent hereditary ataxia, results from GAA repeat expansion at the FXN gene. Here we used cytosine and adenine base editing to reduce the repetitiveness of TNRs in patient cells and in mice. Base editors introduced G•C>A•T and A•T>G•C interruptions at CAG and GAA repeats, mimicking stable, nonpathogenic alleles that naturally occur in people. AAV9 delivery of optimized base editors in Htt.Q111 Huntington’s disease and YG8s Friedreich’s ataxia mice resulted in efficient editing in transduced tissues, and significantly reduced repeat expansion in the central nervous system. These findings demonstrate that introducing interruptions in pathogenic TNRs can mitigate a key neurological feature of TNR diseases in vivo.
三核苷酸重复序列（TNR）疾病是由扩增的基因组TNR引起的神经系统疾病，不稳定与重复长度相关。CAG•CTG序列存在于大约三分之一的致病性TNR位点中，包括导致亨廷顿病的HTT基因。弗里德赖希共济失调是最常见的遗传性共济失调，是FXN基因GAA重复扩增的结果。该研究使用胞嘧啶和腺嘌呤碱基编辑来减少患者细胞和小鼠中TNR的重复性。碱基编辑在CAG和GAA重复序列处引入了 G•C>A•T和A•T>G•C中断，模拟了人类中自然存在的稳定、非致病性等位基因。在Htt.Q111亨廷顿病和YG8弗里德赖希共济失调小鼠中，AAV9递送优化的碱基编辑器在转导组织中实现有效编辑，并显著减少中枢神经系统的重复扩增。这些发现表明，在致病性TNR中引入序列中断可以减轻体内TNR疾病的关键神经系统特征。
7.APOBEC3 mutagenesis drives therapy resistance in breast cancer
APOBEC3诱变导致乳腺癌的治疗耐药性
美国纪念斯隆凯特琳癌症、德克萨斯大学
Abstract
Acquired genetic alterations drive resistance to endocrine and targeted therapies in metastatic breast cancer; however, the underlying processes engendering these alterations are largely uncharacterized. To identify the underlying mutational processes, we utilized a clinically annotated cohort of 3,880 patient samples with tumor-normal sequencing. Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were prevalent and enriched in post-treatment hormone receptor-positive cancers. These signatures correlated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor therapy in hormone receptor-positive metastatic breast cancer. Whole-genome sequencing of breast cancer models and paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted therapy resistance through characteristic alterations such as RB1 loss. Evidence of APOBEC3 activity in pretreatment samples illustrated its pervasive role in breast cancer evolution. These studies reveal APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlight its potential as a biomarker and target for overcoming resistance.
获得性遗传改变导致转移性乳腺癌对内分泌和靶向治疗的耐药性，但产生这些改变的潜在过程尚不明确。为了确定潜在的突变过程，这项研究分析了一个包含 3,880名患者的肿瘤-正常组织测序数据的临床注释队列。与载脂蛋白 B mRNA 编辑酶催化多肽样3（APOBEC3）相关的突变特征在治疗后激素受体阳性癌症中普遍存在并富集。这些特征与激素受体阳性转移性乳腺癌患者接受抗雌激素联合 CDK4/6 抑制剂治疗的无进展生存期较短相关。乳腺癌模型和配对原发-转移样本的全基因组测序表明，APOBEC3的活跃突变通过RB1丢失等特征性改变促进治疗耐药性。治疗前样本中 APOBEC3 活性的证据揭示了它在乳腺癌演变中的普遍作用。这些研究表明APOBEC3突变是乳腺癌治疗耐药的常见介质，并强调了其作为生物标志物和克服耐药靶点的潜力。
8.KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage
KDM4C 抑制通过促进组织蛋白酶 L 介导的组蛋白 H3 裂解来阻断基底乳腺癌的肿瘤生长
美国Dana-Farber癌症研究所、布莱根妇女医院、哈佛医学院
Abstract
Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in KDM4C-amplified basal breast cancers, where KDM4C inhibition reshapes chromatin and transcriptomic landscapes without substantial alterations of its canonical substrates, trimethylated histone H3 lysine 9 (H3K9me3) and lysine 36 (H3K36me3). Rather, KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL), resulting in decreased glutamate–cysteine ligase expression and increased reactive oxygen species. CTSL is recruited to the chromatin by the grainyhead-like 2 (GRHL2) transcription factor that is methylated at lysine 453 following KDM4C inhibition, triggering CTSL histone clipping activity. Deletion of CTSL rescued KDM4-loss-mediated tumor suppression. Our study reveals a function for KDM4C that connects cellular redox regulation and chromatin remodeling.
基底样乳腺癌是一种预后不良的亚型，需要更有效的治疗方法。这项研究描述了KDM4C组蛋白赖氨酸去甲基化酶在KDM4C扩增的基底样乳腺癌中的独特作用，其中KDM4C抑制可重塑染色质和转录组景观，而不显著改变其经典底物三甲基化组蛋白H3赖氨酸 9（H3K9me3）和赖氨酸 36（H3K36me3）。相反，KDM4C缺失会通过组织蛋白酶L（CTSL）介导的组蛋白H3的蛋白水解裂解，导致谷氨酸-半胱氨酸连接酶表达降低和活性氧增加。KDM4C抑制使转录因子GRHL2的453位赖氨酸甲基化，进而招募CTSL至染色质并激活其组蛋白剪切活性。CTSL缺失逆转 KDM4 缺失介导的肿瘤抑制效应。研究揭示了KDM4C连接细胞氧化还原调节和染色质重塑的功能。
9.Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
染色体裂解相关的 21 号染色体扩增通过靶向过表达 DYRK1A 协调向急变期 MPN 的转化
英国牛津大学、美国纪念斯隆凯特琳癌症中心
Abstract
Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
染色体碎裂，即染色体的混乱破碎和修复，在癌症中普遍存在。染色体碎裂是否产生可作的治疗靶点仍不明确。在64名骨髓增生性肿瘤急变期（BP-MPN）的患者队列中，发现了25%的病例存在21号染色体区域（'chr. 21amp'）的反复扩增，其中三分之一的病例由染色体碎裂驱动。Chr. 21amp BP-MPN具有特别侵袭性和治疗耐药的表型。DYRK1A是一种丝氨酸苏氨酸激酶，是2.7兆碱基对最小扩增区域中唯一表现表达量和染色质可及性均高于非chr.21am对照。DYRK1A是BP-MPN发育所需的多个关键细胞功能枢纽的中心节点，对BP-MPN细胞体外和体内增殖至关重要，并构成可药物干预的靶点。总的来说，这些发现确立了chr. 21amp作为BP-MPN的预后生物标志物的价值，并将染色体碎裂与治疗靶点联系起来。
10.Genomic landscape of multiple myeloma and its precursor conditions
多发性骨髓瘤的基因组景观及其前体条件
美国Dana-Farber 癌症研究所、哈佛医学院
Abstract
Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. We assembled a comprehensive collection of MM genomic data comprising 1,030 patients (218 with precursor conditions) that we used to identify recurrent coding and non-coding candidate drivers as well as significant hotspots of structural variation. We used those drivers to define and validate a simple ‘MM-like’ score, which we could use to place patients’ tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides insights into the time of initiation and cell-of-origin of the disease, order of acquisition of genomic alterations and mutational processes found across the stages of transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.
目前仍缺乏可靠的策略来识别从多发性骨髓瘤（MM）癌前阶段进展为显性疾病的高风险患者。该研究收集了1,030名患者（218名患有前体疾病）的 MM 基因组数据，鉴定出频发性编码和非编码候选驱动因素以及结构变异的重要热点。基于这些驱动因素，开发并验证了一个简单的“MM样”评分系统，可将患者的肿瘤置于向活动性疾病进展的连续轴上。MM癌前基因组图谱提供了对疾病的起始时间、细胞起源、基因组改变的获取顺序以及在转化阶段发现的突变过程的见解。综上所述，这项研究强调了基因组测序可更好地为MM癌前状况的风险评估和监测提供信息。
11.Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination
纵向和多位点采样揭示了转移播散过程中肿瘤的突变和拷贝数演变
美国纪念斯隆凯特琳癌症中心、威尔康奈尔医学院
Abstract
To understand genetic evolution in cancer during metastasis, we analyzed genomic profiles of 3,732 cancer patients in whom several tumor sites were longitudinally biopsied. During distant metastasis, tumors were observed to accumulate copy number alterations (CNAs) to a much greater degree than mutations. In particular, the development of whole genome duplication was a common event during metastasis, emerging de novo in 28% of patients. Loss of 9p (including CDKN2A) developed during metastasis in 11% of patients. To a lesser degree, mutations and allelic loss in human leukocyte antigen class I and other genes associated with antigen presentation also emerged. Increasing CNA, but not increasing mutational load, was associated with immune evasion in patients treated with immunotherapy. Taken together, these data suggest that CNA, rather than mutational accumulation, is enriched during cancer metastasis, perhaps due to a more favorable balance of enhanced cellular fitness versus immunogenicity.
为了解癌症转移过程中的遗传进化，这项研究分析了3,732名癌症患者的基因组图谱，其中几个肿瘤部位进行了纵向活检。在远处转移期间，肿瘤拷贝数变异（CNA）的积累程度远大于基因突变。全基因组复制的发展是转移过程中的常见事件，在28%的患者中新发出现。11%的患者在转移期间出现9p （包括 CDKN2A基因） 丢失。人类白细胞抗原I类和其他与抗原呈递相关的基因的突变和等位基因丢失发生频率较低。在免疫治疗患者中，CNA增加（而非突变负荷增加）与免疫逃逸相关。综上所述，这些数据表明在癌症转移过程中，CNA 而不是突变积累富集，可能源于细胞适应性增强与免疫原性之间更有利的平衡。
12.High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer
结直肠癌免疫细胞群的高清空间转录组学
美国10x Genomics
Abstract
A comprehensive understanding of cellular behavior and response to the tumor microenvironment (TME) in colorectal cancer (CRC) remains elusive. Here, we introduce the high-definition Visium spatial transcriptomic technology (Visium HD) and investigate formalin-fixed paraffin-embedded human CRC samples (n = 5). We demonstrate the high sensitivity, single-cell-scale resolution and spatial accuracy of Visium HD, generating a highly refined whole-transcriptome spatial profile of CRC samples. We identify transcriptomically distinct macrophage subpopulations in different spatial niches with potential pro-tumor and anti-tumor functions via interactions with tumor and T cells. In situ gene expression analysis validates our findings and localizes a clonally expanded T cell population close to macrophages with anti-tumor features. Our study demonstrates the power of high-resolution spatial technologies to understand cellular interactions in the TME and paves the way for larger studies that will unravel mechanisms and biomarkers of CRC biology, improving diagnosis and disease management strategies.
目前对结直肠癌（CRC）中细胞行为和对肿瘤微环境（TME）的反应的全面认知仍然存在空白。这项研究引入了高清 Visium 空间转录组学技术（Visium HD）并研究了5例福尔马林固定石蜡包埋的人CRC样本，展示了Visium HD的高灵敏度、单细胞规模分辨率和准确的空间定位能力，生成CRC样本的高度精细的全转录组空间图谱。通过该技术，在不同空间微环境中鉴定出具有潜在促瘤和抗瘤功能的转录组异质性巨噬细胞亚群。原位基因表达分析验证了上述发现，并定位到一组克隆性扩增的T细胞群邻近具有抗瘤特征的巨噬细胞。该研究彰显了高分辨率空间技术在解析肿瘤微环境细胞相互作用中的强大能力，为开展更大规模研究以揭示结直肠癌生物学机制及生物标志物奠定了基础，有望推动诊断及疾病管理策略的优化。
13.Conservation of regulatory elements with highly diverged sequences across large evolutionary distances
跨长进化距离高度分化序列调控元件的保守性
德国柏林夏里特医学院、马克斯·普朗克分子遗传学研究所
Abstract
Developmental gene expression is a remarkably conserved process, yet most cis-regulatory elements (CREs) lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that CREs at the same genomic position remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. Here, we profiled the regulatory genome in mouse and chicken embryonic hearts at equivalent developmental stages and found that most CREs lack sequence conservation. To identify positionally conserved CREs, we introduced the synteny-based algorithm interspecies point projection, which identifies up to fivefold more orthologs than alignment-based approaches. We termed positionally conserved orthologs ‘indirectly conserved’ and showed that they exhibited chromatin signatures and sequence composition similar to sequence-conserved CREs but greater shuffling of transcription factor binding sites between orthologs. Finally, we validated indirectly conserved chicken enhancers using in vivo reporter assays in mouse. By overcoming alignment-based limitations, we revealed widespread functional conservation of sequence-divergent CREs.
发育相关基因表达具有高度保守性，但大多数顺式调控元件（CRE）缺乏序列保守性，在远缘物种间尤为显著。一些证据表明，位于相同基因组位置的 CREs 在功能上保持保守，与序列保守无关，但这种位置保守性的普遍程度仍不清楚。这项研究分析了处于等效发育阶段的小鼠和鸡胚胎心脏中的调节基因组，发现大多数CRE缺乏序列保守性。为了识别位置保守的CRE，开发了基于共线性的算法——种间点投影，它基于序列比对的方法可多识别5倍的直系同源对。将这些位置保守的直系同源物称为“间接保守元件”，并证明其表现出与序列保守CREs相似的染色质特征和序列组成，但转录因子结合位点在直系同源物间存在更显著的重排。最后，通过小鼠体内报告实验验证了鸡间接保守增强子的功能。该研究通过克服基于序列比对的局限性，揭示了序列分化CRE广泛存在的功能保守性。
汇报人：肖瑶
导师：赵宇
审核：程丹妮、任建君
