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Identification of novel genes responsible for a pollen killer present in local natural populations of Arabidopsis thaliana. 拟南芥本地自然种群花粉杀手新基因的鉴定。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-13 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011451
Anthony Ricou, Matthieu Simon, Rémi Duflos, Marianne Azzopardi, Fabrice Roux, Françoise Budar, Christine Camilleri

Gamete killers are genetic loci that distort segregation in the progeny of hybrids because the killer allele promotes the elimination of the gametes that carry the sensitive allele. They are widely distributed in eukaryotes and are important for understanding genome evolution and speciation. We had previously identified a pollen killer in hybrids between two distant natural accessions of Arabidopsis thaliana. This pollen killer involves three genetically linked genes, and we previously reported the identification of the gene encoding the antidote that protects pollen grains from the killer activity. In this study, we identified the two other genes of the pollen killer by using CRISPR-Cas9 induced mutants. These two genes are necessary for the killer activity that we demonstrated to be specific to pollen. The cellular localization of the pollen killer encoded proteins suggests that the pollen killer activity involves the mitochondria. Sequence analyses reveal predicted domains from the same families in the killer proteins. In addition, the C-terminal half of one of the killer proteins is identical to the antidote, and one amino acid, crucial for the antidote activity, is also essential for the killer function. Investigating more than 700 worldwide accessions of A. thaliana, we confirmed that the locus is subject to important structural rearrangements and copy number variation. By exploiting available de novo genomic sequences, we propose a scenario for the emergence of this pollen killer in A. thaliana. Furthermore, we report the co-occurrence and behavior of killer and sensitive genotypes in several local populations, a prerequisite for studying gamete killer evolution in the wild. This highlights the potential of the Arabidopsis model not only for functional studies of gamete killers but also for investigating their evolutionary trajectories at complementary geographical scales.

配子杀手是扭曲杂交后代分离的基因位点,因为杀手等位基因促进了携带敏感等位基因的配子的消除。它们广泛分布于真核生物中,对了解基因组进化和物种形成具有重要意义。我们以前已经在两个遥远的自然加入的拟南芥杂种中发现了花粉杀手。这种花粉杀手涉及三个遗传上相关的基因,我们之前报道了编码保护花粉粒免受杀手活动的解毒剂的基因的鉴定。在本研究中,我们利用CRISPR-Cas9诱导突变体鉴定了花粉杀手的另外两个基因。这两个基因对于我们所证明的针对花粉的杀伤活性是必要的。花粉杀手编码蛋白的细胞定位表明,花粉杀手活性涉及线粒体。序列分析揭示了杀手蛋白中来自相同家族的预测结构域。此外,其中一种杀伤蛋白的c端一半与解毒剂完全相同,一种对解毒剂活性至关重要的氨基酸对杀伤功能也是必不可少的。通过对全球700多份拟南芥(a.thaliana)材料的调查,我们证实了该位点存在重要的结构重排和拷贝数变异。通过利用现有的从头基因组序列,我们提出了这种花粉杀手在拟南芥中出现的情景。此外,我们报告了杀伤基因型和敏感基因型在几个地方种群中的共同出现和行为,这是研究野生配子杀伤基因型进化的先决条件。这突出了拟南芥模型的潜力,不仅可以用于配子杀手的功能研究,还可以用于在互补的地理尺度上研究它们的进化轨迹。
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引用次数: 0
The dependence of shugoshin on Bub1-kinase activity is dispensable for the maintenance of spindle assembly checkpoint response in Cryptococcus neoformans. shugoshin对bub1激酶活性的依赖对于维持新型隐球菌的纺锤体组装检查点反应是必不可少的。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-13 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011552
Satya Dev Polisetty, Krishna Bhat, Kuladeep Das, Ivan Clark, Kevin G Hardwick, Kaustuv Sanyal

During chromosome segregation, the spindle assembly checkpoint (SAC) detects errors in kinetochore-microtubule attachments. Timely activation and maintenance of the SAC until defects are corrected is essential for genome stability. Here, we show that shugoshin (Sgo1), a conserved tension-sensing protein, ensures the maintenance of SAC signals in response to unattached kinetochores during mitosis in a basidiomycete budding yeast Cryptococcus neoformans. Sgo1 maintains optimum levels of Aurora B kinase Ipl1 and protein phosphatase 1 (PP1) at kinetochores. The absence of Sgo1 results in the loss of Aurora BIpl1 with a concomitant increase in PP1 levels at kinetochores. This leads to a premature reduction in the kinetochore-bound Bub1 levels and early termination of the SAC signals. Intriguingly, the kinase function of Bub1 is dispensable for shugoshin's subcellular localization. Sgo1 is predominantly localized to spindle pole bodies (SPBs) and along the mitotic spindle with a minor pool at kinetochores. In the absence of proper kinetochore-microtubule attachments, Sgo1 reinforces the Aurora B kinaseIpl1-PP1 phosphatase balance, which is critical for prolonged maintenance of the SAC response.

在染色体分离过程中,纺锤体组装检查点(SAC)检测着丝点-微管附着的错误。及时激活和维持SAC直到缺陷被纠正是基因组稳定的必要条件。在这里,我们发现shugoshin (Sgo1),一种保守的张力传感蛋白,在担子菌出芽酵母新隐球菌有丝分裂过程中,确保SAC信号的维持,以响应未附着的着丝点。Sgo1维持着丝点上极光B激酶Ipl1和蛋白磷酸酶1 (PP1)的最佳水平。Sgo1的缺失导致极光BIpl1的缺失,并伴随着丝点PP1水平的升高。这导致着丝点结合的Bub1水平过早降低和SAC信号的早期终止。有趣的是,Bub1的激酶功能对于shugoshin的亚细胞定位是必不可少的。Sgo1主要定位于纺锤极体(SPBs)和有丝分裂纺锤体,在着丝点处有少量分布。在没有适当的着丝点-微管附着的情况下,Sgo1加强了Aurora B激酶eipl1 - pp1磷酸酶的平衡,这对于SAC反应的长期维持至关重要。
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引用次数: 0
Ambivalent partnership of the Drosophila posterior class Hox protein Abdominal-B with Extradenticle and Homothorax. 果蝇后类Hox蛋白腹部- b与外胸和同胸的矛盾关系。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-13 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011355
Jesús R Curt, Paloma Martín, David Foronda, Bruno Hudry, Ramakrishnan Kannan, Srividya Shetty, Samir Merabet, Andrew J Saurin, Yacine Graba, Ernesto Sánchez-Herrero

Hox proteins, a sub-group of the homeodomain (HD) transcription factor family, provide positional information for axial patterning in development and evolution. Hox protein functional specificity is reached, at least in part, through interactions with Pbc (Extradenticle (Exd) in Drosophila) and Meis/Prep (Homothorax (Hth) in Drosophila) proteins. Most of our current knowledge of Hox protein specificity stems from the study of anterior and central Hox proteins, identifying the molecular and structural bases for Hox/Pbc/Meis-Prep cooperative action. Posterior Hox class proteins, Abdominal-B (Abd-B) in Drosophila and Hox9-13 in vertebrates, have been comparatively less studied. They strongly diverge from anterior and central class Hox proteins, with a low degree of HD sequence conservation and the absence of a core canonical Pbc interaction motif. Here we explore how Abd-B function interface with that of Exd/Hth using several developmental contexts, studying mutual expression control, functional dependency and intrinsic protein requirements. Results identify cross-regulatory interactions setting relative expression and activity levels required for proper development. They also reveal organ-specific requirement and a binary functional interplay with Exd and Hth, either antagonistic, as previously reported, or synergistic. This highlights context specific use of Exd/Hth, and a similar context specific use of Abd-B intrinsic protein requirements.

Hox蛋白是同源结构域(HD)转录因子家族的一个亚群,为发育和进化中的轴向模式提供位置信息。Hox蛋白的功能特异性至少部分是通过与Pbc(果蝇的extraenticle (Exd))和Meis/Prep(果蝇的Homothorax (Hth))蛋白的相互作用而实现的。我们目前对Hox蛋白特异性的大部分知识来自于对Hox蛋白前侧和中央侧的研究,确定Hox/Pbc/Meis-Prep协同作用的分子和结构基础。后Hox类蛋白,果蝇中的Abd-B和脊椎动物中的Hox9-13,研究相对较少。它们与Hox蛋白的前部和中部有很大的差异,具有低程度的HD序列保守性和缺乏核心规范的Pbc相互作用基序。在这里,我们探讨了Abd-B功能如何与Exd/Hth功能结合,研究了相互表达控制、功能依赖和内在蛋白质需求。结果确定了交叉调控相互作用,确定了适当发育所需的相对表达和活性水平。它们还揭示了Exd和Hth的器官特异性需求和二元功能相互作用,如先前报道的那样是拮抗的,或协同的。这突出了Exd/Hth的上下文特定使用,以及类似的Abd-B内在蛋白质需求的上下文特定使用。
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引用次数: 0
metaGE: Investigating genotype x environment interactions through GWAS meta-analysis. meta:通过GWAS荟萃分析调查基因型x环境相互作用。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-10 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011553
Annaïg De Walsche, Alexis Vergne, Renaud Rincent, Fabrice Roux, Stéphane Nicolas, Claude Welcker, Sofiane Mezmouk, Alain Charcosset, Tristan Mary-Huard

Elucidating the genetic components of plant genotype-by-environment interactions is of key importance in the context of increasing climatic instability, diversification of agricultural practices and pest pressure due to phytosanitary treatment limitations. The genotypic response to environmental stresses can be investigated through multi-environment trials (METs). However, genome-wide association studies (GWAS) of MET data are significantly more complex than that of single environments. In this context, we introduce metaGE, a flexible and computationally efficient meta-analysis approach for jointly analyzing single-environment GWAS of any MET experiment. The metaGE procedure accounts for the heterogeneity of quantitative trait loci (QTL) effects across the environmental conditions and allows the detection of QTL whose allelic effect variations are strongly correlated to environmental cofactors. We evaluated the performance of the proposed methodology and compared it to two competing procedures through simulations. We also applied metaGE to two emblematic examples: the detection of flowering QTLs whose effects are modulated by competition in Arabidopsis and the detection of yield QTLs impacted by drought stresses in maize. The procedure identified known and new QTLs, providing valuable insights into the genetic architecture of complex traits and QTL effects dependent on environmental stress conditions. The whole statistical approach is available as an R package.

阐明植物基因型与环境相互作用的遗传成分在气候不稳定、农业实践多样化和由于植物检疫处理限制而造成的病虫害压力日益增加的背景下至关重要。对环境胁迫的基因型反应可以通过多环境试验(METs)进行研究。然而,MET数据的全基因组关联研究(GWAS)比单一环境的研究要复杂得多。在此背景下,我们引入了metaGE,一种灵活且计算效率高的元分析方法,用于联合分析任何MET实验的单环境GWAS。metaGE程序解释了数量性状位点(QTL)效应在不同环境条件下的异质性,并允许检测其等位基因效应变化与环境辅助因子密切相关的QTL。我们评估了所提出的方法的性能,并通过模拟将其与两个竞争程序进行了比较。我们还将metaGE应用于两个具有代表性的例子:检测拟南芥中受竞争调节的开花qtl和玉米中受干旱胁迫影响的产量qtl。该方法确定了已知的和新的QTL,为复杂性状的遗传结构和依赖于环境胁迫条件的QTL效应提供了有价值的见解。整个统计方法可以作为一个R包获得。
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引用次数: 0
ADELLE: A global testing method for trans-eQTL mapping. 阿黛尔:跨eqtl映射的全球测试方法。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-10 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011563
Takintayo Akinbiyi, Mary Sara McPeek, Mark Abney

Understanding the genetic regulatory mechanisms of gene expression is an ongoing challenge. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%-2% of 10,000 traits, among the 8 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. We also apply ADELLE to trans-eQTL mapping in the eQTLGen data, and for 1,451 previously identified trans-eQTLs, we discover trans association with additional expression traits beyond those previously identified. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.

了解基因表达的遗传调控机制是一个持续的挑战。与表达水平相关的遗传变异在接近基因时很容易被识别(即顺式- eqtl),但远离与其表达水平相关的基因的snp(即反式- eqtl)则很难发现,尽管它们占基因表达水平的大部分遗传能力。识别更多trans-eQTL的主要障碍是缺乏足够强大的统计方法来克服trans-eQTL定位的小效应大小和大的多重测试负担的障碍。在这里,我们提出了ADELLE,这是一个功能强大的统计测试框架,只需要汇总统计,并且被设计成对与多个基因表达水平相关的snp最敏感,这是许多反式eqtl的特征。在模拟中,我们表明,对于检测与10,000个性状中0.1%-2%相关的snp,我们认为ADELLE在8种方法中显然是最强大的,在该范围内所有设置的最高功率或功率与最高功率没有显着差异。我们将ADELLE应用于小鼠高级交叉系数据集,并显示其发现在标准分析下不显著的trans- eqtl的能力。我们还将ADELLE应用于eQTLGen数据中的trans- eqtl映射,对于先前鉴定的1451个trans- eqtl,我们发现了与先前鉴定的其他表达性状的反关联。这表明ADELLE是发现基因表达反式调控因子的有力工具。
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引用次数: 0
Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo. OGT活性的遗传逐渐降低揭示了O-GlcNAc在小鼠胚胎中的重要作用。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-09 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011507
Sara Formichetti, Agnieszka Sadowska, Michela Ascolani, Julia Hansen, Kerstin Ganter, Christophe Lancrin, Neil Humphreys, Mathieu Boulard

The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalian Ogt gene is X-linked, and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT's function in vivo by creating a murine allelic series of four single amino acid substitutions, reducing OGT's catalytic activity to a range of degrees. The severity of the embryonic lethality was proportional to the extent of impairment of OGT's catalysis, demonstrating that the O-GlcNAc modification itself is required for early development. We identified hypomorphic Ogt alleles that perturb O-GlcNAc homeostasis while being compatible with embryogenesis. The analysis of the transcriptomes of the mutant embryos at different developmental stages suggested a sexually-dimorphic developmental delay caused by the decrease in O-GlcNAc. Furthermore, a mild reduction of OGT's enzymatic activity was sufficient to loosen the silencing of endogenous retroviruses in vivo.

核蛋白和细胞质蛋白的可逆糖基化(o - glcnac酰化)是由一种酶催化的,即O-GlcNAc转移酶(OGT)。哺乳动物的Ogt基因是x连锁的,它对胚胎发育和增殖细胞的生存能力至关重要。我们通过创建一个由四个单氨基酸取代的小鼠等位基因序列来干扰OGT在体内的功能,在一定程度上降低了OGT的催化活性。胚胎致死的严重程度与OGT催化功能受损的程度成正比,表明O-GlcNAc修饰本身是早期发育所必需的。我们发现了在与胚胎发生相容的同时干扰O-GlcNAc稳态的半胚性Ogt等位基因。对不同发育阶段突变胚胎的转录组分析表明,O-GlcNAc的减少导致了两性二态发育延迟。此外,OGT酶活性的轻度降低足以解除体内内源性逆转录病毒的沉默。
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引用次数: 0
Refining fine-mapping: Effect sizes and regional heritability. 细化精细映射:效应大小和区域遗传性。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-09 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011480
Christian Benner, Anubha Mahajan, Matti Pirinen

Recent statistical approaches have shown that the set of all available genetic variants explains considerably more phenotypic variance of complex traits and diseases than the individual variants that are robustly associated with these phenotypes. However, rapidly increasing sample sizes constantly improve detection and prioritization of individual variants driving the associations between genomic regions and phenotypes. Therefore, it is useful to routinely estimate how much phenotypic variance the detected variants explain for each region by taking into account the correlation structure of variants and the uncertainty in their causal status. Here we extend the FINEMAP software to estimate the effect sizes and regional heritability under the probabilistic model that assumes a handful of causal variants per region. Using the UK Biobank (UKB) data to simulate genomic regions, we demonstrate that FINEMAP provides higher precision and enables more detailed decomposition of regional heritability into individual variants than the variance component model implemented in BOLT or the fixed-effect model implemented in HESS, particularly when there are only a few causal variants in the fine-mapped region. Using data from 2,940 plasma proteins from the UKB study, we observed that on average FINEMAP identified 2.5 causal variants at an association signal and captured 36% more regional heritability than the variant with the lowest P-value. We estimate that in genomic regions with notable contribution to the total heritability, FINEMAP captures on average 13% and 40% more heritability than BOLT and HESS respectively. Our analysis shows how FINEMAP, BOLT and HESS relate to each other in cases where inference of a variant-level picture of the regional genetic architecture is possible.

最近的统计方法表明,与与这些表型密切相关的单个变异相比,所有可用遗传变异的集合解释了复杂性状和疾病的更多表型变异。然而,快速增加的样本量不断提高了个体变异的检测和优先级,推动了基因组区域和表型之间的关联。因此,考虑到变异的相关结构及其因果状态的不确定性,常规估计检测到的变异在每个区域解释了多少表型变异是有用的。在这里,我们扩展了FINEMAP软件,在假设每个地区有少量因果变量的概率模型下估计效应大小和区域遗传度。使用UK Biobank (UKB)数据模拟基因组区域,我们证明FINEMAP提供了更高的精度,并且能够比BOLT中实施的方差成分模型或HESS中实施的固定效应模型更详细地将区域遗传力分解为单个变异,特别是当精细映射区域中只有少数因果变异时。使用来自UKB研究的2940个血浆蛋白的数据,我们观察到FINEMAP平均在关联信号中识别出2.5个因果变异,并且比具有最低p值的变异捕获了36%的区域遗传率。我们估计,在对总遗传率有显著贡献的基因组区域,FINEMAP的遗传率比BOLT和HESS分别高出13%和40%。我们的分析显示了FINEMAP、BOLT和HESS在推断区域遗传结构的变异水平图是可能的情况下是如何相互关联的。
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引用次数: 0
Estimating evolutionary and demographic parameters via ARG-derived IBD. 通过arg衍生的IBD估计进化和人口参数。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011537
Zhendong Huang, Jerome Kelleher, Yao-Ban Chan, David Balding

Inference of evolutionary and demographic parameters from a sample of genome sequences often proceeds by first inferring identical-by-descent (IBD) genome segments. By exploiting efficient data encoding based on the ancestral recombination graph (ARG), we obtain three major advantages over current approaches: (i) no need to impose a length threshold on IBD segments, (ii) IBD can be defined without the hard-to-verify requirement of no recombination, and (iii) computation time can be reduced with little loss of statistical efficiency using only the IBD segments from a set of sequence pairs that scales linearly with sample size. We first demonstrate powerful inferences when true IBD information is available from simulated data. For IBD inferred from real data, we propose an approximate Bayesian computation inference algorithm and use it to show that even poorly-inferred short IBD segments can improve estimation. Our mutation-rate estimator achieves precision similar to a previously-published method despite a 4 000-fold reduction in data used for inference, and we identify significant differences between human populations. Computational cost limits model complexity in our approach, but we are able to incorporate unknown nuisance parameters and model misspecification, still finding improved parameter inference.

从基因组序列样本推断进化和人口统计学参数通常首先推断同源(IBD)基因组片段。通过利用基于祖先重组图(ARG)的高效数据编码,我们获得了与现有方法相比的三个主要优势:(i)不需要对IBD片段施加长度阈值,(ii) IBD可以在没有重组的难以验证的要求下定义,以及(iii)仅使用与样本量线性扩展的序列对集合中的IBD片段可以减少计算时间,而统计效率几乎没有损失。当从模拟数据中获得真实的IBD信息时,我们首先展示了强有力的推断。对于从真实数据中推断出的IBD,我们提出了一种近似贝叶斯计算推理算法,并使用它来证明即使推断较差的IBD短段也可以提高估计。尽管用于推断的数据减少了4000倍,但我们的突变率估计器实现了与先前发表的方法相似的精度,并且我们确定了人群之间的显着差异。在我们的方法中,计算成本限制了模型的复杂性,但我们能够纳入未知的干扰参数和模型错误规范,仍然可以找到改进的参数推理。
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引用次数: 0
Light-regulated microRNAs shape dynamic gene expression in the zebrafish circadian clock. 光调节的microrna在斑马鱼生物钟中塑造动态基因表达。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011545
Zuo Wang, Shuang Wang, Yi Bi, Alessandra Boiti, Shengxiang Zhang, Daniela Vallone, Xianyong Lan, Nicholas S Foulkes, Haiyu Zhao

A key property of the circadian clock is that it is reset by light to remain synchronized with the day-night cycle. An attractive model to explore light input to the circadian clock in vertebrates is the zebrafish. Circadian clocks in zebrafish peripheral tissues and even zebrafish-derived cell lines are entrainable by direct light exposure thus providing unique insight into the function and evolution of light regulatory pathways. Our previous work has revealed that light-induced gene transcription is a key step in the entrainment of the circadian clock as well as enabling the more general adaptation of zebrafish cells to sunlight exposure. However, considerable evidence points to post-transcriptional regulatory mechanisms, notably microRNAs (miRNAs), playing an essential role in shaping dynamic changes in mRNA levels. Therefore, does light directly impact the function of miRNAs? Are there light-regulated miRNAs and if so, which classes of mRNA do they target? To address these questions, we performed a complete sequencing analysis of light-induced changes in the zebrafish transcriptome, encompassing small non-coding RNAs as well as mRNAs. Importantly, we identified sets of light-regulated miRNAs, with many regulatory targets representing light-inducible mRNAs including circadian clock genes and genes involved in redox homeostasis. We subsequently focused on the light-responsive miR-204-3-3p and miR-430a-3p which are predicted to regulate the expression of cryptochrome genes (cry1a and cry1b). Luciferase reporter assays validated the target binding of miR-204-3-3p and miR-430a-3p to the 3'UTRs of cry1a and cry1b, respectively. Furthermore, treatment with mimics and inhibitors of these two miRNAs significantly affected the dynamic expression of their target genes but also other core clock components (clock1a, bmal1b, per1b, per2, per3), as well as the rhythmic locomotor activity of zebrafish larvae. Thus, our identification of light-responsive miRNAs reveals new intricacy in the multi-level regulation of the circadian clockwork by light.

昼夜节律钟的一个关键特性是,它被光重置,以保持与昼夜周期同步。斑马鱼是探索脊椎动物生物钟的光输入的一个有吸引力的模型。斑马鱼外周组织甚至斑马鱼衍生细胞系的昼夜节律时钟可被直接光照射,从而为光调节途径的功能和进化提供了独特的见解。我们之前的工作表明,光诱导基因转录是昼夜节律时钟的一个关键步骤,也是斑马鱼细胞对阳光照射更普遍的适应。然而,大量证据表明转录后调控机制,特别是microRNAs (miRNAs),在形成mRNA水平的动态变化中起着至关重要的作用。那么,光是否会直接影响mirna的功能呢?是否存在光调控的mirna,如果存在,它们针对的是哪类mRNA ?为了解决这些问题,我们对斑马鱼转录组的光诱导变化进行了完整的测序分析,包括小的非编码rna和mrna。重要的是,我们确定了一系列光调控的mirna,其中许多调控靶点代表了光诱导的mrna,包括昼夜节律钟基因和参与氧化还原稳态的基因。我们随后将重点放在光响应性miR-204-3-3p和miR-430a-3p上,它们被预测可以调节隐色素基因(cry1a和cry1b)的表达。荧光素酶报告基因检测证实了miR-204-3-3p和miR-430a-3p分别与cry1a和cry1b的3' utr结合。此外,用这两种mirna的模拟物和抑制剂处理显著影响了它们的靶基因的动态表达,以及其他核心时钟成分(clock1a, bmal1b, per1b, per2, per3),以及斑马鱼幼虫的节律运动活动。因此,我们对光响应性mirna的鉴定揭示了光对生物钟的多层次调节的新复杂性。
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引用次数: 0
Improving polygenic prediction from summary data by learning patterns of effect sharing across multiple phenotypes. 通过学习跨多种表型的效应共享模式,从汇总数据改进多基因预测。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-01-07 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pgen.1011519
Deborah Kunkel, Peter Sørensen, Vijay Shankar, Fabio Morgante

Polygenic prediction of complex trait phenotypes has become important in human genetics, especially in the context of precision medicine. Recently, mr.mash, a flexible and computationally efficient method that models multiple phenotypes jointly and leverages sharing of effects across such phenotypes to improve prediction accuracy, was introduced. However, a drawback of mr.mash is that it requires individual-level data, which are often not publicly available. In this work, we introduce mr.mash-rss, an extension of the mr.mash model that requires only summary statistics from Genome-Wide Association Studies (GWAS) and linkage disequilibrium (LD) estimates from a reference panel. By using summary data, we achieve the twin goal of increasing the applicability of the mr.mash model to data sets that are not publicly available and making it scalable to biobank-size data. Through simulations, we show that mr.mash-rss is competitive with, and often outperforms, current state-of-the-art methods for single- and multi-phenotype polygenic prediction in a variety of scenarios that differ in the pattern of effect sharing across phenotypes, the number of phenotypes, the number of causal variants, and the genomic heritability. We also present a real data analysis of 16 blood cell phenotypes in the UK Biobank, showing that mr.mash-rss achieves higher prediction accuracy than competing methods for the majority of traits, especially when the data set has smaller sample size.

复杂性状表型的多基因预测在人类遗传学中变得非常重要,特别是在精准医学的背景下。最近,mr.mash提出了一种灵活且计算效率高的方法,该方法可以联合对多个表型进行建模,并利用这些表型之间的效应共享来提高预测精度。然而,mr.mash的一个缺点是它需要个人层面的数据,而这些数据通常是不公开的。在这项工作中,我们引入mr.mash-rss,这是mr.mash模型的扩展,它只需要来自全基因组关联研究(GWAS)的汇总统计数据和来自参考小组的连锁不平衡(LD)估计。通过使用汇总数据,我们实现了双重目标,即提高mr.mash模型对非公开数据集的适用性,并使其可扩展到生物库大小的数据。通过模拟,我们发现mr.mash-rss在不同的情况下与当前最先进的单表型和多表型多基因预测方法竞争,并且通常优于当前最先进的方法,这些方法在不同的表型之间的效应共享模式、表型数量、因果变异数量和基因组遗传性方面存在差异。我们还展示了UK Biobank中16种血细胞表型的真实数据分析,表明mr.mash-rss在大多数性状方面的预测精度高于竞争方法,特别是在数据集样本量较小的情况下。
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PLoS Genetics
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