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Megavariate Methods Capture Complex Genotype-by-Environment Interactions. 巨变量方法捕捉复杂的基因型与环境的相互作用
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-04 DOI: 10.1093/genetics/iyae179
Alencar Xavier, Daniel Runcie, David Habier

Genomic prediction models that capture genotype-by-environment interaction are useful for predicting site-specific performance by leveraging information among related individuals and correlated environments, but implementing such models is computationally challenging. This study describes the algorithm of these scalable approaches, including two models with latent representations of genotype-by-environment interactions, namely MegaLMM and MegaSEM, and an efficient multivariate mixed model solver, namely PEGS, fitting different covariance structures (unstructured, XFA, HCS). Accuracy and runtime are benchmarked on simulated scenarios with varying numbers of genotypes and environments. MegaLMM and PEGS-based XFA and HCS models provided the highest accuracy under sparse testing with 100 testing environments. PEGS-based unstructured model was orders of magnitude faster than REML-based multivariate GBLUP while providing the same accuracy. MegaSEM provided the lowest runtime, fitting a model with 200 traits and 20,000 individuals in approximately 5 minutes, and a model with 2,000 traits and 2,000 individuals in less than 3 minutes. With the G2F data, the most accurate predictions were attained with the univariate model fitted across environments and by averaging environment-level GEBVs from models with HCS and XFA covariance structures.

捕捉基因型与环境交互作用的基因组预测模型有助于利用相关个体和相关环境之间的信息预测特定位点的表现,但实现这类模型在计算上具有挑战性。本研究介绍了这些可扩展方法的算法,包括两个具有基因型与环境相互作用潜在表征的模型,即 MegaLMM 和 MegaSEM,以及一个高效的多元混合模型求解器,即 PEGS,该求解器可拟合不同的协方差结构(非结构化、XFA、HCS)。在不同基因型和环境数量的模拟场景中,对准确性和运行时间进行了基准测试。在 100 个测试环境的稀疏测试中,MegaLMM 和基于 PEGS 的 XFA 和 HCS 模型的准确率最高。与基于 REML 的多元 GBLUP 相比,基于 PEGS 的非结构化模型在提供相同准确率的同时,速度快了几个数量级。MegaSEM 的运行时间最短,拟合一个有 200 个性状和 20,000 个个体的模型大约需要 5 分钟,拟合一个有 2,000 个性状和 2,000 个个体的模型不到 3 分钟。对于 G2F 数据,使用跨环境拟合的单变量模型以及通过 HCS 和 XFA 协方差结构模型得出的环境级 GEBV 平均值可以获得最准确的预测结果。
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引用次数: 0
Leveraging a new data resource to define the response of C. neoformans to environmental signals. 利用新的数据资源确定新变形杆菌对环境信号的反应。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-01 DOI: 10.1093/genetics/iyae178
Yu Sung Kang, Jeffery Jung, Holly Brown, Chase Mateusiak, Tamara L Doering, Michael R Brent

Cryptococcus neoformans is an opportunistic fungal pathogen with a polysaccharide capsule that becomes greatly enlarged in the mammalian host and during in vitro growth under host-like conditions. To understand how individual environmental signals affect capsule size and gene expression, we grew cells in all combinations of five signals implicated in capsule size and systematically measured cell and capsule sizes. We also sampled these cultures over time and performed RNA-Seq in quadruplicate, yielding 881 RNA-Seq samples. Analysis of the resulting data sets showed that capsule induction in tissue culture medium, typically used to represent host-like conditions, requires the presence of either CO2 or exogenous cyclic AMP (cAMP). Surprisingly, adding either of these pushes overall gene expression in the opposite direction from tissue culture media alone, even though both are required for capsule development. Another unexpected finding was that rich medium blocks capsule growth completely. Statistical analysis further revealed many genes whose expression is associated with capsule thickness; deletion of one of these significantly reduced capsule size. Beyond illuminating capsule induction, our massive, uniformly collected dataset will be a significant resource for the research community.

新生隐球菌是一种机会性真菌病原体,其多糖囊在哺乳动物宿主体内和类似宿主条件的体外生长过程中会大大增大。为了了解个别环境信号如何影响胶囊大小和基因表达,我们在与胶囊大小有关的五种信号的所有组合中培养细胞,并系统地测量细胞和胶囊大小。我们还在一段时间内对这些培养物进行采样,并进行了四重 RNA-Seq,共获得 881 个 RNA-Seq 样本。对所得数据集的分析表明,在组织培养基(通常用来代表类似宿主的条件)中诱导蒴果需要二氧化碳或外源环磷酸腺苷(cAMP)的存在。令人惊讶的是,尽管蒴果的发育需要二氧化碳或外源环磷酸腺苷(cAMP),但加入这两种物质后,整体基因表达与单独加入组织培养基时相反。另一个意想不到的发现是,富培养基会完全阻止蒴果的生长。统计分析进一步揭示了许多基因的表达与蒴果厚度有关;删除其中一个基因会显著缩小蒴果大小。除了揭示蒴果的诱导过程,我们统一收集的大量数据集也将成为研究界的重要资源。
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引用次数: 0
Dominant myosin storage myopathy mutations disrupt striated muscles in Drosophila and the myosin tail-tail interactome of human cardiac thick filaments. 显性肌球蛋白贮积性肌病突变会破坏果蝇的横纹肌和人类心脏粗丝的肌球蛋白尾端相互作用组。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-01 DOI: 10.1093/genetics/iyae174
Meera C Viswanathan, Debabrata Dutta, William A Kronert, Kripa Chitre, Raul Padron, Roger Craig, Sanford I Bernstein, Anthony Cammarato

Myosin storage myopathy (MSM) is a rare skeletal muscle disorder caused by mutations in the slow muscle/β-cardiac myosin heavy chain (MHC) gene. MSM missense mutations frequently disrupt the tail's stabilizing heptad repeat motif. Disease hallmarks include subsarcolemmal hyaline-like β-MHC aggregates, muscle weakness and, occasionally, cardiomyopathy. We generated transgenic, heterozygous Drosophila to examine the dominant physiological and structural effects of the L1793P, R1845W, and E1883K MHC MSM mutations on diverse muscles. The MHC variants reduced lifespan and flight and jump abilities. Moreover, confocal and electron microscopy revealed that they provoked indirect flight muscle breaks and myofibrillar disarray/degeneration with filamentous inclusions. Incorporation of GFP-myosin enabled in situ determination of thick filament lengths, which were significantly reduced in all mutants. Semi-automated heartbeat analysis uncovered aberrant cardiac function, which worsened with age. Thus, our fly models phenocopied traits observed among MSM patients. We additionally mapped the mutations onto a recently-determined, 6Å resolution, cryo-EM structure of the human cardiac thick filament. The R1845W mutation replaces a basic arginine with a polar-neutral, bulkier tryptophan, while E1883K reverses charge at critical filament loci. Both would be expected to disrupt the core and the outer shell of the backbone structure. Replacing L1793 with a proline, a potent breaker of alpha-helices, could disturb the coiled-coil of the myosin rod and alter the tail-tail interactome. Hence, all mutations likely destabilize and weaken the filament backbone. This may trigger disease in humans, while potentially analogous perturbations are likely to yield the observed thick filament and muscle disruption in our fly models.

肌球蛋白贮积性肌病(MSM)是一种罕见的骨骼肌疾病,由慢肌/β-心肌肌球蛋白重链(MHC)基因突变引起。MSM 的错义突变经常会破坏尾部的稳定七联重复基序。该病的特征包括浆膜下透明样β-MHC聚集、肌无力,偶尔还会出现心肌病。我们培育了转基因杂合果蝇,以研究 L1793P、R1845W 和 E1883K MHC MSM 突变对不同肌肉的显性生理和结构影响。这些MHC变异降低了果蝇的寿命以及飞行和跳跃能力。此外,共聚焦显微镜和电子显微镜显示,它们会导致间接的飞行肌肉断裂和肌纤维混乱/变性,并伴有丝状内含物。GFP-肌球蛋白的加入使原位测定粗丝长度成为可能,所有突变体的粗丝长度都显著减少。半自动心跳分析发现了异常的心脏功能,这种功能随着年龄的增长而恶化。因此,我们的苍蝇模型表征了在MSM患者中观察到的特征。我们还将突变绘制到了最近确定的人类心脏粗丝的 6 Å 分辨率低温电子显微镜结构图上。R1845W 突变用极性中性、体积更大的色氨酸取代了碱性精氨酸,而 E1883K 则在关键的粗丝位置反转了电荷。预计这两种突变都会破坏骨架结构的核心和外壳。脯氨酸是α-螺旋的强力破坏者,用脯氨酸取代 L1793 可能会扰乱肌球蛋白杆的线圈,并改变尾部的相互作用组。因此,所有突变都可能破坏和削弱肌丝骨架的稳定性。这可能会引发人类疾病,而潜在的类似扰动可能会导致我们的苍蝇模型中观察到的粗丝和肌肉破坏。
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引用次数: 0
Parental-effect gene-drive elements under partial selfing, or why do Caenorhabditis genomes have hyperdivergent regions? 部分自交条件下的亲本效应基因驱动元素,或为什么 Caenorhabditis 基因组具有超分化区域?
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-30 DOI: 10.1093/genetics/iyae175
Matthew V Rockman

Self-fertile Caenorhabditis nematodes carry a surprising number of Medea elements, alleles that act in heterozygous mothers and cause death or developmental delay in offspring that don't inherit them. At some loci, both alleles in a cross operate as independent Medeas, affecting all the homozygous progeny of a selfing heterozygote. The genomic coincidence of Medea elements and ancient, deeply coalescing haplotypes, which pepper the otherwise homogeneous genomes of these animals, raises questions about how these apparent gene-drive elements persist for long periods of time. Here I investigate how mating system affects the evolution of Medeas, and their paternal-effect counterparts, peels. Despite an intuition that antagonistic alleles should induce balancing selection by killing homozygotes, models show that, under partial selfing, antagonistic elements experience positive frequency dependence: the common allele drives the rare one extinct, even if the rare one is more penetrant. Analytical results for the threshold frequency required for one allele to invade a population show that a very weakly penetrant allele, one whose effects would escape laboratory detection, could nevertheless prevent a much more penetrant allele from invading under high rates of selfing. Ubiquitous weak antagonistic Medeas and peels could then act as localized barriers to gene flow between populations, generating genomic islands of deep coalescence. Analysis of gene expression data, however, suggest that this cannot be the whole story. A complementary explanation is that ordinary ecological balancing selection generates ancient haplotypes on which Medeas can evolve, while high homozygosity in these selfers minimizes the role of gene drive in their evolution.

自交不育的 Caenorhabditis 线虫携带着数量惊人的美狄亚因子,这些等位基因作用于杂合母本,导致没有遗传到这些等位基因的后代死亡或发育迟缓。在某些位点,杂交中的两个等位基因都是独立的美狄亚,会影响自交杂合子的所有同源后代。美狄亚基因与古老的、深度凝聚的单倍型在基因组上的重合,使这些动物原本同质的基因组变得更加丰富,这就提出了一个问题:这些明显的基因驱动基因是如何长期存在的?在这里,我研究了交配系统如何影响鳉鱼及其父系效应对应物鳞皮的进化。尽管根据直觉,拮抗等位基因应该通过杀死同源基因来诱导平衡选择,但模型显示,在部分自交的情况下,拮抗基因会出现正的频率依赖性:普通等位基因会促使稀有等位基因灭绝,即使稀有等位基因的穿透力更强。对一个等位基因入侵一个种群所需的阈值频率的分析结果表明,一个穿透力很弱的等位基因,其影响会逃过实验室的检测,但在自交率很高的情况下,可以阻止一个穿透力更强的等位基因入侵。这样,无处不在的弱拮抗梅迪亚种和等位基因就会成为种群间基因流动的局部障碍,产生深度聚合的基因组孤岛。然而,对基因表达数据的分析表明,这并不是故事的全部。一种补充解释是,普通的生态平衡选择产生了古老的单倍型,Medeas 可以在这些单倍型上进化,而这些自体中的高同源性将基因驱动在其进化中的作用降至最低。
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引用次数: 0
MegaLMM improves genomic predictions in new environments using environmental covariates. MegaLMM 利用环境协变量改进了新环境中的基因组预测。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-29 DOI: 10.1093/genetics/iyae171
Haixiao Hu, Renaud Rincent, Daniel E Runcie

Multi-environment trials (METs) are crucial for identifying varieties that perform well across a target population of environments (TPE). However, METs are typically too small to sufficiently represent all relevant environment-types, and face challenges from changing environment-types due to climate change. Statistical methods that enable prediction of variety performance for new environments beyond the METs are needed. We recently developed MegaLMM, a statistical model that can leverage hundreds of trials to significantly improve genetic value prediction accuracy within METs. Here, we extend MegaLMM to enable genomic prediction in new environments by learning regressions of latent factor loadings on Environmental Covariates (ECs) across trials. We evaluated the extended MegaLMM using the maize Genome-To-Fields dataset, consisting of 4402 varieties cultivated in 195 trials with 87.1% of phenotypic values missing, and demonstrated its high accuracy in genomic prediction under various breeding scenarios. Furthermore, we showcased MegaLMM's superiority over univariate GBLUP in predicting trait performance of experimental genotypes in new environments. Finally, we explored the use of higher-dimensional quantitative ECs and discussed when and how detailed environmental data can be leveraged for genomic prediction from METs. We propose that MegaLMM can be applied to plant breeding of diverse crops and different fields of genetics where large-scale linear mixed models are utilized.

多环境试验(MET)对于确定在目标环境(TPE)中表现良好的品种至关重要。然而,多环境试验通常规模太小,无法充分代表所有相关的环境类型,而且还面临着气候变化导致环境类型不断变化的挑战。我们需要能预测 METs 以外新环境中品种表现的统计方法。我们最近开发了 MegaLMM,这是一种统计模型,可利用数百次试验,显著提高 METs 内遗传值预测的准确性。在此,我们对 MegaLMM 进行了扩展,通过学习各试验中环境协变量(ECs)的潜在因子载荷回归,实现了新环境下的基因组预测。我们使用玉米 "基因组-田间 "数据集对扩展的MegaLMM进行了评估,该数据集由195个试验中的4402个品种组成,表型值缺失率为87.1%。此外,在预测新环境中试验基因型的性状表现方面,我们展示了 MegaLMM 优于单变量 GBLUP 的优势。最后,我们探讨了高维定量EC的使用,并讨论了何时以及如何利用详细的环境数据通过MET进行基因组预测。我们建议将 MegaLMM 应用于不同作物的植物育种和使用大规模线性混合模型的不同遗传学领域。
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引用次数: 0
Drosophila ring chromosomes interact with sisters and homologs to produce anaphase bridges in mitosis. 果蝇环状染色体与姐妹染色单体和同源染色体相互作用,在有丝分裂过程中产生无丝分裂桥。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-25 DOI: 10.1093/genetics/iyae169
Ho-Chen Lin, Mary M Golic, Hunter J Hill, Katherine F Lemons, Truc T Vuong, Madison Smith, Forrest Golic, Kent G Golic

Ring chromosomes are known in many eukaryotic organisms, including humans. They are typically associated with a variety of maladies, including abnormal development and lethality. Underlying these phenotypes are anaphase chromatin bridges that can lead to chromosome loss, nondisjunction and breakage. By cytological examination of ring chromosomes in Drosophila melanogaster we identified five causes for anaphase bridges produced by ring chromosomes. Catenation of sister chromatids appears to be the most common cause and these bridges frequently resolve during anaphase, presumably by the action of topoisomerase II. Sister chromatid exchange and chromosome breakage followed by sister chromatid union also produce anaphase bridges. Mitotic recombination with the homolog was rare, but was another route to generation of anaphase bridges. Most surprising, was the discovery of homolog capture, where the ring chromosome was connected to its linear homolog in anaphase. We hypothesize that this is a remnant of mitotic pairing and that the linear chromosome is connected to the ring by multiple wraps produced through the action of topoisomerase II during establishment of homolog pairing. In support, we showed that in a ring/ring homozygote the two rings are frequently catenated in mitotic metaphase, a configuration that requires breaking and rejoining of at least one chromosome.

包括人类在内的许多真核生物都存在环状染色体。环状染色体通常与多种疾病相关,包括发育异常和致死。这些表型的基础是可导致染色体缺失、非连接和断裂的无丝分裂染色质桥。通过对黑腹果蝇的环状染色体进行细胞学检查,我们确定了环状染色体产生无丝期桥的五种原因。姐妹染色单体的同源化似乎是最常见的原因,这些桥经常在无丝分裂过程中消失,可能是在拓扑异构酶 II 的作用下消失的。姐妹染色单体交换和染色体断裂后姐妹染色单体结合也会产生无丝分裂桥。同源染色体的有丝分裂重组很少见,但这是产生无丝分裂桥的另一个途径。最令人惊讶的是同源物捕获的发现,即环状染色体在无丝分裂期与其线性同源物相连。我们假设这是有丝分裂配对的残留物,在同源染色体配对建立过程中,通过拓扑异构酶 II 的作用产生的多条缠绕将线性染色体连接到环上。作为佐证,我们发现在环/环同源基因中,两个环经常在有丝分裂分裂相中结合,这种构型需要至少一条染色体的断裂和重合。
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引用次数: 0
Higher-order epistasis within Pol II trigger loop haplotypes. Pol II 触发环单倍型中的高阶表观遗传。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-24 DOI: 10.1093/genetics/iyae172
Bingbing Duan, Chenxi Qiu, Steve W Lockless, Sing-Hoi Sze, Craig D Kaplan

RNA polymerase II (Pol II) has a highly conserved domain, the trigger loop (TL), that controls transcription fidelity and speed. We previously probed pairwise genetic interactions between residues within and surrounding the TL for the purpose of understand functional interactions between residues and to understand how individual mutants might alter TL function. We identified widespread incompatibility between TLs of different species when placed in the Saccharomyces cerevisiae Pol II context, indicating species-specific interactions between otherwise highly conserved TLs and its surroundings. These interactions represent epistasis between TL residues and the rest of Pol II. We sought to understand why certain TL sequences are incompatible with S. cerevisiae Pol II and to dissect the nature of genetic interactions within multiply substituted TLs as a window on higher order epistasis in this system. We identified both positive and negative higher-order residue interactions within example TL haplotypes. Intricate higher-order epistasis formed by TL residues was sometimes only apparent from analysis of intermediate genotypes, emphasizing complexity of epistatic interactions. Furthermore, we distinguished TL substitutions with distinct classes of epistatic patterns, suggesting specific TL residues that potentially influence TL evolution. Our examples of complex residue interactions suggest possible pathways for epistasis to facilitate Pol II evolution.

RNA 聚合酶 II(Pol II)有一个高度保守的结构域,即触发环(TL),它控制着转录的保真度和速度。我们以前曾探究过 TL 内部和周围残基之间的成对遗传相互作用,目的是了解残基之间的功能性相互作用,并了解单个突变体可能如何改变 TL 的功能。我们发现,当把不同物种的 TL 放在酿酒酵母 Pol II 上下文中时,它们之间普遍存在不相容性,这表明原本高度保守的 TL 与其周围环境之间存在物种特异性相互作用。这些相互作用代表了 TL 残基与 Pol II 其他部分之间的外显性。我们试图了解某些 TL 序列与 S. cerevisiae Pol II 不兼容的原因,并剖析多重置换 TL 内遗传相互作用的性质,以此作为了解该系统中高阶表观性的窗口。我们在示例 TL 单倍型中发现了正向和负向的高阶残基相互作用。由 TL 残基形成的错综复杂的高阶表观性有时只能从中间基因型的分析中看出,这强调了表观相互作用的复杂性。此外,我们还区分了具有不同表观模式类别的 TL 替代,这表明特定的 TL 残基可能会影响 TL 的进化。我们列举的复杂残基相互作用的例子表明了表观作用促进 Pol II 进化的可能途径。
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引用次数: 0
Genomic prediction of cereal crop architectural traits using models informed by gene regulatory circuitries from maize. 利用玉米基因调控回路模型对谷类作物结构特征进行基因组预测。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1093/genetics/iyae162
Edoardo Bertolini, Mohith Manjunath, Weihao Ge, Matthew D Murphy, Mirai Inaoka, Christina Fliege, Andrea L Eveland, Alexander E Lipka

Plant architecture is a major determinant of planting density, which enhances productivity potential for crops per unit area. Genomic prediction is well positioned to expedite genetic gain of plant architectural traits since they are typically highly heritable. Additionally, the adaptation of genomic prediction models to query predictive abilities of markers tagging certain genomic regions could shed light on the genetic architecture of these traits. Here, we leveraged transcriptional networks from a prior study that contextually described developmental progression during tassel and leaf organogenesis in maize (Zea mays) to inform genomic prediction models for architectural traits. Since these developmental processes underlie tassel branching and leaf angle, 2 important agronomic architectural traits, we tested whether genes prioritized from these networks quantitatively contribute to the genetic architecture of these traits. We used genomic prediction models to evaluate the ability of markers in the vicinity of prioritized network genes to predict breeding values of tassel branching and leaf angle traits for 2 diversity panels in maize and diversity panels from sorghum (Sorghum bicolor) and rice (Oryza sativa). Predictive abilities of markers near these prioritized network genes were similar to those using whole-genome marker sets. Notably, markers near highly connected transcription factors from core network motifs in maize yielded predictive abilities that were significantly greater than expected by chance in not only maize but also closely related sorghum. We expect that these highly connected regulators are key drivers of architectural variation that are conserved across closely related cereal crop species.

植物结构是种植密度的主要决定因素,而种植密度可提高作物单位面积的生产潜力。由于植物结构特性通常具有高度遗传性,因此基因组预测完全有能力加快植物结构特性的遗传增益。此外,调整基因组预测模型以查询标记某些基因组区域的标记物的预测能力,可以揭示这些性状的遗传结构。在这里,我们利用先前一项研究中的转录网络(该研究结合上下文描述了玉米(Zea mays)穗和叶器官发生过程中的发育进程)来为结构性状的基因组预测模型提供信息。由于这些发育过程是穗分枝和叶片角度这两个重要农艺结构性状的基础,我们测试了从这些网络中优先排序的基因是否对这些性状的遗传结构有定量贡献。我们使用基因组预测模型评估了优先网络基因附近的标记预测玉米两个多样性面板以及高粱(Sorghum bicolor)和水稻(Oryza sativa)多样性面板的抽穗分枝和叶片角度性状育种价值的能力。这些优先网络基因附近标记的预测能力与使用全基因组标记集的预测能力相似。值得注意的是,在玉米和与玉米密切相关的高粱中,玉米核心网络基序中高度连接的转录因子附近标记的预测能力明显高于偶然的预期。我们预计,这些高度连接的调控因子是结构变异的关键驱动因素,它们在近缘谷类作物物种中是保守的。
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引用次数: 0
Set2 and H3K36 regulate the Drosophila male X chromosome in a context-specific manner, independent from MSL complex spreading. Set2和H3K36以一种独立于MSL复合体扩散的特异性方式调控果蝇雄性X染色体。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-17 DOI: 10.1093/genetics/iyae168
Harmony R Salzler, Vasudha Vandadi, Julia R Sallean, A Gregory Matera

Dosage compensation in Drosophila involves upregulating male X-genes two-fold. This process is carried out by the MSL (male-specific lethal) complex, which binds high-affinity sites and spreads to surrounding genes. Current models of MSL spreading focus on interactions betwen MSL3 (male-specific lethal 3) and Set2-dependent histone marks like trimethylated H3 lysine-36 (H3K36me3). However, Set2 could affect DC via another target, or there could be redundancy between canonical H3.2 and variant H3.3 histones. Furthermore, it is important to parse male-specific effects from those that are X-specific. To discriminate among these possibilities, we employed genomic approaches in H3K36 'residue' and Set2 'writer' mutants. The results confirm a role for Set2 in X-gene regulation, but show that expression trends in males are often mirrored in females. Instead of global, male-specific reduction of X-genes in Set2 or H3K36 mutants, we observe heterogeneous effects. Interestingly, we identified groups of differentially expressed genes (DEGs) whose changes were in opposite directions following loss of H3K36 or Set2, suggesting that H3K36me states have reciprocal functions. In contrast to H4K16R controls, differential expression analysis of combined H3.2K36R/H3.3K36R mutants showed neither consistent reduction in X-gene expression, nor correlation with MSL3 binding. Motif analysis of the DEGs implicated BEAF-32 and other insulator proteins in Set2/H3K36-dependent regulation. Overall, the data are inconsistent with the prevailing model wherein H3K36me3 is essential for spreading the MSL complex to genes along the male X. Rather, we propose that Set2 and H3K36 support DC indirectly, via processes that are utilized by MSL but common to both sexes.

果蝇的剂量补偿包括将雄性 X 基因上调两倍。这一过程由 MSL(雄性特异性致死)复合体完成,它结合高亲和力位点并扩散到周围的基因。目前的 MSL 扩散模型主要关注 MSL3(雄性特异性致死基因 3)与 Set2 依赖性组蛋白标记(如三甲基化 H3 赖氨酸-36(H3K36me3))之间的相互作用。然而,Set2可能通过另一个靶点影响DC,或者典型的H3.2和变异的H3.3组蛋白之间可能存在冗余。此外,将男性特异性效应与 X 特异性效应区分开来也很重要。为了区分这些可能性,我们在 H3K36 "残基 "和 Set2 "作者 "突变体中采用了基因组学方法。结果证实了 Set2 在 X 基因调控中的作用,但也表明雄性基因的表达趋势往往反映在雌性基因中。在Set2或H3K36突变体中,X基因的表达量并没有出现全面的、男性特异性的减少,而是出现了异质性的影响。有趣的是,我们发现了几组差异表达基因(DEGs),它们在 H3K36 或 Set2 缺失后的变化方向相反,这表明 H3K36me 状态具有互作功能。与 H4K16R 对照组不同的是,H3.2K36R/H3.3K36R 组合突变体的差异表达分析既没有显示 X 基因表达的一致减少,也没有显示与 MSL3 结合的相关性。对 DEGs 的动因分析表明,BEAF-32 和其他绝缘体蛋白参与了 Set2/H3K36 依赖性调控。总体而言,这些数据与目前流行的模型不一致,在该模型中,H3K36me3 是将 MSL 复合物扩散到雄性 X 基因的关键。相反,我们认为 Set2 和 H3K36 通过 MSL 所利用的、但两性共同的过程间接支持 DC。
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引用次数: 0
A maternal germline mutator phenotype in a family affected by heritable colorectal cancer. 一个受遗传性结直肠癌影响的家族中的母系生殖突变表型。
IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-15 DOI: 10.1093/genetics/iyae166
Candice L Young, Annabel C Beichman, David Mas-Ponte, Shelby L Hemker, Luke Zhu, Jacob O Kitzman, Brian H Shirts, Kelley Harris

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.

DNA 修复基因的变异会提高致癌突变率,从而增加患癌风险。众所周知,MUTYH 基因缺陷会以孟德尔隐性遗传的方式增加结直肠癌的发病率。最近的证据还表明,MUTYH 与影响正常体细胞和女性生殖细胞的突变表型有关。在这里,我们利用全基因组测序技术测量了一个大家族的生殖系从头突变率,这个大家族的母亲和父亲都受到致病性 MUTYH 变异的影响。通过开发使用兄弟姐妹作为 "代理父母 "来识别从头突变的新方法,我们得以纳入几个其父母无法进行测序的孩子的突变数据。在受致病 MUTYH 基因型 p.Y179C/V234M 影响的母亲所生的孩子中,我们发现 C>A 突变率的升高弱于之前报道的其他致病 MUTYH 基因型引起的突变效应,这表明正常组织中的突变率可能有助于按照严重程度的连续性对癌症相关变异进行分类。令人惊讶的是,我们发现父亲具有相同 MUTYH 基因型的孩子,其 C>A 突变率并没有明显升高,而且我们同样发现,小鼠同源物 Mutyh 的突变效应似乎只作用于胚胎发育,而不是精母细胞。我们的研究结果表明,母体MUTYH变体可通过减弱早期胚胎中氧化DNA损伤的修复作用而导致生殖突变。
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