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Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility. 外显子组测序确定了罕见的复发拷贝数变异和遗传性乳腺癌症易感性。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-14 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010889
Timo A Kumpula, Sandra Vorimo, Taneli T Mattila, Luke O'Gorman, Galuh Astuti, Anna Tervasmäki, Susanna Koivuluoma, Tiina M Mattila, Mervi Grip, Robert Winqvist, Outi Kuismin, Jukka Moilanen, Alexander Hoischen, Christian Gilissen, Tuomo Mantere, Katri Pylkäs

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

拷贝数变异(CNVs)是遗传变异的主要来源,可以破坏基因或影响基因剂量。众所周知,它们是各种疾病的诱因或诱因。然而,CNVs在遗传性乳腺癌症易感性中的作用尚未得到彻底研究。为了解决这一问题,我们对98例芬兰北部癌症高危病例中罕见的CNV进行了基于全基因组测序的分析。过滤后,用正交方法对选定的候选等位基因进行验证和表征,包括基于PCR的方法、光学基因组图谱和长读测序。这揭示了三种复发性改变:在RAD52中与逆转录转座子插入(德林)同时发生的31kb缺失,在HSD17B14中的13.4kb缺失,以及RAD51C的64kb部分重复。值得注意的是,所有这些基因都编码参与先前被确定为对癌症发展至关重要的途径的蛋白质。在地理匹配的病例和对照中对变异进行了基因分型(总共278例遗传性和1983例未选择的癌症病例,以及1229例对照)。RAD52-delins和HSD17B14缺失在有遗传性疾病易感性指征的病例中均显示出显著富集。在7/278例病例中发现了RAD52脱链(2.5%,P=0.034,OR=2.86,95%CI=1.10-7.45),在8/278例患者中发现了HSD17B14缺失(2.9%,P=0.014,OR=3.28,95%CI=1.31-8.23),对照组中这两种变体的频率为11/1229(0.9%)。这表明RAD52和HSD17B13在遗传性乳腺癌癌症易感性中的作用。RAD51C重复非常罕见,仅在2/278遗传性病例和2/1229对照组中发现(P=0.157,OR=4.45,95%CI=0.62~31.70)。在这些基因中发现复发性CNVs,尤其是在芬兰人群中RAD52和HSD17B14改变的频率相对较高,强调了在寻找遗传性疾病易感性的遗传因素时,与单核苷酸变体一起研究CNVs的重要性。
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引用次数: 0
Matriptase-dependent epidermal pre-neoplasm in zebrafish embryos caused by a combination of hypotonic stress and epithelial polarity defects. 由低张应激和上皮极性缺陷联合引起的斑马鱼胚胎中基质蛋白酶依赖性表皮前肿瘤。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-11 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010873
Julia Hatzold, Verena Nett, Stephanie Brantsch, Jin-Li Zhang, Joy Armistead, Heike Wessendorf, Rebecca Stephens, Patrick O Humbert, Sandra Iden, Matthias Hammerschmidt

Aberrantly up-regulated activity of the type II transmembrane protease Matriptase-1 has been associated with the development and progression of a range of epithelial-derived carcinomas, and a variety of signaling pathways can mediate Matriptase-dependent tumorigenic events. During mammalian carcinogenesis, gain of Matriptase activity often results from imbalanced ratios between Matriptase and its cognate transmembrane inhibitor Hai1. Similarly, in zebrafish, unrestrained Matriptase activity due to loss of hai1a results in epidermal pre-neoplasms already during embryogenesis. Here, based on our former findings of a similar tumor-suppressive role for the Na+/K+-pump beta subunit ATP1b1a, we identify epithelial polarity defects and systemic hypotonic stress as another mode of aberrant Matriptase activation in the embryonic zebrafish epidermis in vivo. In this case, however, a different oncogenic pathway is activated which contains PI3K, AKT and NFkB, rather than EGFR and PLD (as in hai1a mutants). Strikingly, epidermal pre-neoplasm is only induced when epithelial polarity defects in keratinocytes (leading to disturbed Matriptase subcellular localization) occur in combination with systemic hypotonic stress (leading to increased proteolytic activity of Matriptase). A similar combinatorial effect of hypotonicity and loss of epithelial polarity was also obtained for the activity levels of Matriptase-1 in human MCF-10A epithelial breast cells. Together, this is in line with the multi-factor concept of carcinogenesis, with the notion that such factors can even branch off from one and the same initiator (here ATP1a1b) and can converge again at the level of one and the same mediator (here Matriptase). In sum, our data point to tonicity and epithelial cell polarity as evolutionarily conserved regulators of Matriptase activity that upon de-regulation can constitute an alternative mode of Matriptase-dependent carcinogenesis in vivo.

II型跨膜蛋白酶基质蛋白酶-1活性异常上调与一系列上皮衍生癌的发展和进展有关,多种信号通路可介导基质蛋白酶依赖性致瘤事件。在哺乳动物致癌过程中,基质酶活性的增加通常是由于基质酶与其同源跨膜抑制剂Hai1之间的比例不平衡造成的。同样,在斑马鱼中,由于hai1a的缺失而导致的无限制的基质酶活性导致胚胎发生过程中的表皮前肿瘤。在此,基于我们先前发现的Na+/K+-泵β亚基ATP1b1a具有类似的肿瘤抑制作用,我们确定上皮极性缺陷和全身低张应激是体内胚胎斑马鱼表皮中基质蛋白酶异常激活的另一种模式。然而,在这种情况下,一种不同的致癌途径被激活,它包含PI3K、AKT和NFkB,而不是EGFR和PLD(如在hai1a突变体中)。引人注目的是,只有当角质形成细胞中的上皮极性缺陷(导致基质蛋白酶亚细胞定位紊乱)与系统性低张应激(导致基质酶的蛋白水解活性增加)相结合时,才会诱导表皮前肿瘤。对于人MCF-10A乳腺上皮细胞中基质蛋白酶-1的活性水平,也获得了类似的低张力和上皮极性丧失的组合效应。总之,这符合致癌作用的多因素概念,即这些因素甚至可以从同一个引发剂(此处为ATP1a1b)分支出来,并可以在同一个介体(此处为基质酶)的水平上再次聚集。总之,我们的数据表明,张力和上皮细胞极性是基质酶活性的进化保守调节因子,在去调节后,可以构成体内基质酶依赖性致癌的另一种模式。
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引用次数: 0
Systematic analysis of tup1 and cyc8 mutants reveals distinct roles for TUP1 and CYC8 and offers new insight into the regulation of gene transcription by the yeast Tup1-Cyc8 complex. 对tup1和cyc8突变体的系统分析揭示了tup1和cyc8的不同作用,并为酵母tup1-cyc8复合物对基因转录的调节提供了新的见解。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-11 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010876
Brenda Lee, Michael Church, Karsten Hokamp, Mohamed M Alhussain, Atif A Bamagoos, Alastair B Fleming

The Tup1-Cyc8 complex in Saccharomyces cerevisiae was one of the first global co-repressors of gene transcription discovered. However, despite years of study, a full understanding of the contribution of Tup1p and Cyc8p to complex function is lacking. We examined TUP1 and CYC8 single and double deletion mutants and show that CYC8 represses more genes than TUP1, and that there are genes subject to (i) unique repression by TUP1 or CYC8, (ii) redundant repression by TUP1 and CYC8, and (iii) there are genes at which de-repression in a cyc8 mutant is dependent upon TUP1, and vice-versa. We also reveal that Tup1p and Cyc8p can make distinct contributions to commonly repressed genes most likely via specific interactions with different histone deacetylases. Furthermore, we show that Tup1p and Cyc8p can be found independently of each other to negatively regulate gene transcription and can persist at active genes to negatively regulate on-going transcription. Together, these data suggest that Tup1p and Cyc8p can associate with active and inactive genes to mediate distinct negative and positive regulatory roles when functioning within, and possibly out with the complex.

酿酒酵母中的Tup1-Cyc8复合物是最早发现的全球基因转录共阻遏物之一。然而,尽管进行了多年的研究,但对Tup1p和Cyc8p对复杂功能的贡献还缺乏充分的了解。我们检测了TUP1和CYC8单缺失和双缺失突变体,结果表明CYC8比TUP1抑制更多的基因,并且有一些基因受到(i)TUP1或CYC8的独特抑制,(ii)TUP1和CYC8的冗余抑制,以及(iii)CYC8突变体中的去抑制依赖于TUP1的基因,反之亦然。我们还发现,Tup1p和Cyc8p可以对通常被抑制的基因做出不同的贡献,很可能是通过与不同的组蛋白脱乙酰酶的特异性相互作用。此外,我们发现Tup1p和Cyc8p可以相互独立地负调控基因转录,并且可以在活性基因上持续负调控正在进行的转录。总之,这些数据表明,Tup1p和Cyc8p可以与活性和非活性基因结合,在复合物内或可能在复合物外发挥作用时,介导不同的负调控和正调控作用。
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引用次数: 0
The Ypk1 protein kinase signaling pathway is rewired and not essential for viability in Candida albicans. Ypk1蛋白激酶信号通路被重新连接,对白色念珠菌的生存能力不是必需的。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-10 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010890
Bernardo Ramírez-Zavala, Ines Krüger, Andreas Wollner, Sonja Schwanfelder, Joachim Morschhäuser

Protein kinases are central components of almost all signaling pathways that control cellular activities. In the model organism Saccharomyces cerevisiae, the paralogous protein kinases Ypk1 and Ypk2, which control membrane lipid homeostasis, are essential for viability, and previous studies strongly indicated that this is also the case for their single ortholog Ypk1 in the pathogenic yeast Candida albicans. Here, using FLP-mediated inducible gene deletion, we reveal that C. albicans ypk1Δ mutants are viable but slow-growing, explaining prior failures to obtain null mutants. Phenotypic analyses of the mutants showed that the functions of Ypk1 in regulating sphingolipid biosynthesis and cell membrane lipid asymmetry are conserved, but the consequences of YPK1 deletion are milder than in S. cerevisiae. Mutational studies demonstrated that the highly conserved PDK1 phosphorylation site T548 in its activation loop is essential for Ypk1 function, whereas the TORC2 phosphorylation sites S687 and T705 at the C-terminus are important for Ypk1-dependent resistance to membrane stress. Unexpectedly, Pkh1, the single C. albicans orthologue of Pkh1/Pkh2, which mediate Ypk1 phosphorylation at the PDK1 site in S. cerevisiae, was not required for normal growth of C. albicans under nonstressed conditions, and Ypk1 phosphorylation at T548 was only slightly reduced in pkh1Δ mutants. We found that another protein kinase, Pkh3, whose ortholog in S. cerevisiae cannot substitute Pkh1/2, acts redundantly with Pkh1 to activate Ypk1 in C. albicans. No phenotypic effects were observed in cells lacking Pkh3 alone, but pkh1Δ pkh3Δ double mutants had a severe growth defect and Ypk1 phosphorylation at T548 was completely abolished. These results establish that Ypk1 is not essential for viability in C. albicans and that, despite its generally conserved function, the Ypk1 signaling pathway is rewired in this pathogenic yeast and includes a novel upstream kinase to activate Ypk1 by phosphorylation at the PDK1 site.

蛋白激酶是几乎所有控制细胞活动的信号通路的中心成分。在模式生物酿酒酵母中,控制膜脂质稳态的同源蛋白激酶Ypk1和Ypk2对生存能力至关重要,先前的研究强烈表明,在致病性白色念珠菌中,它们的单一同源蛋白激酶也存在这种情况。在这里,使用FLP介导的诱导型基因缺失,我们发现白色念珠菌ypk1Δ突变体是可行的,但生长缓慢,这解释了以前未能获得无效突变体的原因。突变体的表型分析表明,Ypk1在调节鞘脂生物合成和细胞膜脂质不对称方面的功能是保守的,但Ypk1缺失的后果比酿酒酵母中的要轻。突变研究表明,其激活环中高度保守的PDK1磷酸化位点T548对Ypk1的功能至关重要,而C末端的TORC2磷酸化位点S687和T705对Ypk1-依赖性膜胁迫抗性至关重要。出乎意料的是,在非表达条件下,白色念珠菌的正常生长不需要Pkh1/Pkh2的单一白色念珠菌同源物Pkh1,它介导酿酒酵母PDK1位点的Ypk1磷酸化,并且在Pkh1Δ突变体中,T548处的Ypkl磷酸化仅略有减少。我们发现另一种蛋白激酶,Pkh3,其在酿酒酵母中的直系同源物不能取代Pkh1/2,与Pkh1冗余作用以激活白色念珠菌中的Ypk1。在缺乏单独的Pkh3的细胞中没有观察到表型效应,但pkh1ΔPkh3Δ双突变体具有严重的生长缺陷,并且T548处的Ypk1磷酸化被完全消除。这些结果表明,Ypk1对白色念珠菌的生存能力不是必需的,尽管其功能通常是保守的,但Ypk1信号通路在这种致病酵母中被重新连接,并包括一种新的上游激酶,通过PDK1位点的磷酸化激活Ypk1。
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引用次数: 0
Rege-1 promotes C. elegans survival by modulating IIS and TOR pathways. Rege-1通过调节IIS和TOR途径促进秀丽隐杆线虫的存活。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-09 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010869
Yi-Ting Tsai, Chen-Hsi Chang, Hsin-Yue Tsai

Metabolic pathways are known to sense the environmental stimuli and result in physiological adjustments. The responding processes need to be tightly controlled. Here, we show that upon encountering P. aeruginosa, C. elegans upregulate the transcription factor ets-4, but this upregulation is attenuated by the ribonuclease, rege-1. As such, mutants with defective REGE-1 ribonuclease activity undergo ets-4-dependent early death upon challenge with P. aeruginosa. Furthermore, mRNA-seq analysis revealed associated global changes in two key metabolic pathways, the IIS (insulin/IGF signaling) and TOR (target of rapamycin) kinase signaling pathways. In particular, failure to degrade ets-4 mRNA in activity-defective rege-1 mutants resulted in upregulation of class II longevity genes, which are suppressed during longevity, and activation of TORC1 kinase signaling pathway. Genetic inhibition of either pathway way was sufficient to abolish the poor survival phenotype in rege-1 worms. Further analysis of ETS-4 ChIP data from ENCODE and characterization of one upregulated class II gene, ins-7, support that the Class II genes are activated by ETS-4. Interestingly, deleting an upregulated Class II gene, acox-1.5, a peroxisome β-oxidation enzyme, largely rescues the fat lost phenotype and survival difference between rege-1 mutants and wild-types. Thus, rege-1 appears to be crucial for animal survival due to its tight regulation of physiological responses to environmental stimuli. This function is reminiscent of its mammalian ortholog, Regnase-1, which modulates the intestinal mTORC1 signaling pathway.

已知代谢途径可以感知环境刺激并导致生理调整。应对过程需要严格控制。在这里,我们发现,当遇到铜绿假单胞菌时,秀丽隐杆线虫上调转录因子ets-4,但这种上调被核糖核酸酶rege-1减弱。因此,具有缺陷的REGE-1核糖核酸酶活性的突变体在用铜绿假单胞菌攻击时经历ets-4依赖性的早期死亡。此外,信使核糖核酸序列分析揭示了两种关键代谢途径的相关全局变化,即IIS(胰岛素/IGF信号传导)和TOR(雷帕霉素靶点)激酶信号传导途径。特别是,在活性缺陷的rege-1突变体中未能降解ets-4mRNA导致II类寿命基因的上调(在寿命期间受到抑制),以及TORC1激酶信号通路的激活。任何一种途径的遗传抑制都足以消除rege-1蠕虫的低存活表型。来自ENCODE的ETS-4-ChIP数据的进一步分析和一个上调的II类基因ins-7的表征支持II类基因被ETS-4激活。有趣的是,删除上调的II类基因acox-1.5,一种过氧化物酶体β-氧化酶,在很大程度上挽救了rege-1突变体和野生型之间的脂肪损失表型和存活差异。因此,由于rege-1对环境刺激的生理反应的严格调节,它似乎对动物的生存至关重要。这种功能让人想起其哺乳动物直系同源物Regnase-1,它调节肠道mTORC1信号通路。
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引用次数: 0
The RNA-binding protein Adad1 is necessary for germ cell maintenance and meiosis in zebrafish. RNA结合蛋白Adad1是斑马鱼生殖细胞维持和减数分裂所必需的。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-08 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010589
Kazi Nazrul Islam, Anuoluwapo Ajao, Kavita Venkataramani, Joshua Rivera, Shailja Pathania, Katrin Henke, Kellee Renee Siegfried

The double stranded RNA binding protein Adad1 (adenosine deaminase domain containing 1) is a member of the adenosine deaminase acting on RNAs (Adar) protein family with germ cell-specific expression. In mice, Adad1 is necessary for sperm differentiation, however its function outside of mammals has not been investigated. Here, through an N-ethyl-N-nitrosourea (ENU) based forward genetic screen, we identified an adad1 mutant zebrafish line that develops as sterile males. Further histological examination revealed complete lack of germ cells in adult mutant fish, however germ cells populated the gonad, proliferated, and entered meiosis in larval and juvenile fish. Although meiosis was initiated in adad1 mutant testes, the spermatocytes failed to progress beyond the zygotene stage. Thus, Adad1 is essential for meiosis and germline maintenance in zebrafish. We tested if spermatogonial stem cells were affected using nanos2 RNA FISH and a label retaining cell (LRC) assay, and found that the mutant testes had fewer LRCs and nanos2-expressing cells compared to wild-type siblings, suggesting that failure to maintain the spermatogonial stem cells resulted in germ cell loss by adulthood. To identify potential molecular processes regulated by Adad1, we sequenced bulk mRNA from mutants and wild-type testes and found mis-regulation of genes involved in RNA stability and modification, pointing to a potential broader role in post-transcriptional regulation. Our findings suggest that the RNA regulatory protein Adad1 is required for fertility through regulation of spermatogonial stem cell maintenance in zebrafish.

双链RNA结合蛋白Adad1(含有1的腺苷脱氨酶结构域)是腺苷脱氨蛋白酶作用于具有生殖细胞特异性表达的RNA(Adar)蛋白家族的成员。在小鼠中,Adad1是精子分化所必需的,但其在哺乳动物之外的功能尚未得到研究。在这里,通过基于N-乙基-N-亚硝基脲(ENU)的正向遗传筛选,我们鉴定了一个发育为不育雄性的adad1突变斑马鱼系。进一步的组织学检查显示,成年突变鱼完全缺乏生殖细胞,但生殖细胞在幼鱼和幼鱼的性腺中繁殖并进入减数分裂。尽管减数分裂是在adad1突变睾丸中开始的,但精母细胞未能进展到合子期之后。因此,Adad1对斑马鱼的减数分裂和种系维持至关重要。我们使用nanos2 RNA FISH和标记保留细胞(LRC)分析测试了精原干细胞是否受到影响,发现与野生型同胞相比,突变睾丸的LRC和nanos2表达细胞更少,这表明未能维持精原干干细胞会导致成年后生殖细胞损失。为了确定Adad1调节的潜在分子过程,我们对突变体和野生型睾丸的大量信使核糖核酸进行了测序,发现了参与RNA稳定性和修饰的基因的错误调节,指出了在转录后调节中潜在的更广泛作用。我们的研究结果表明,通过调节斑马鱼精原干细胞的维持,RNA调节蛋白Adad1是生育所必需的。
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引用次数: 0
Nascent evolution of recombination rate differences as a consequence of chromosomal rearrangements. 染色体重排导致重组率差异的恶性进化。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-07 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010717
Karin Näsvall, Jesper Boman, Lars Höök, Roger Vila, Christer Wiklund, Niclas Backström

Reshuffling of genetic variation occurs both by independent assortment of chromosomes and by homologous recombination. Such reshuffling can generate novel allele combinations and break linkage between advantageous and deleterious variants which increases both the potential and the efficacy of natural selection. Here we used high-density linkage maps to characterize global and regional recombination rate variation in two populations of the wood white butterfly (Leptidea sinapis) that differ considerably in their karyotype as a consequence of at least 27 chromosome fissions and fusions. The recombination data were compared to estimates of genetic diversity and measures of selection to assess the relationship between chromosomal rearrangements, crossing over, maintenance of genetic diversity and adaptation. Our data show that the recombination rate is influenced by both chromosome size and number, but that the difference in the number of crossovers between karyotypes is reduced as a consequence of a higher frequency of double crossovers in larger chromosomes. As expected from effects of selection on linked sites, we observed an overall positive association between recombination rate and genetic diversity in both populations. Our results also revealed a significant effect of chromosomal rearrangements on the rate of intergenic diversity change between populations, but limited effects on polymorphisms in coding sequence. We conclude that chromosomal rearrangements can have considerable effects on the recombination landscape and consequently influence both maintenance of genetic diversity and efficiency of selection in natural populations.

遗传变异的重组既通过染色体的独立分类发生,也通过同源重组发生。这种重组可以产生新的等位基因组合,并打破有利和有害变体之间的联系,从而增加自然选择的潜力和效力。在这里,我们使用高密度连锁图来表征木白蝶(Leptide sinapis)两个种群的全局和区域重组率变化,这两个种群由于至少27条染色体的分裂和融合而在核型上存在显著差异。将重组数据与遗传多样性的估计值和选择措施进行比较,以评估染色体重排、杂交、遗传多样性维持和适应之间的关系。我们的数据表明,重组率受到染色体大小和数量的影响,但由于较大染色体中双交叉频率较高,核型之间交叉数量的差异减少了。正如从连锁位点的选择效应中所预期的那样,我们观察到两个群体的重组率和遗传多样性之间存在总体正相关。我们的研究结果还揭示了染色体重排对群体间基因多样性变化率的显著影响,但对编码序列多态性的影响有限。我们的结论是,染色体重排可以对重组景观产生相当大的影响,从而影响自然种群遗传多样性的维持和选择的效率。
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引用次数: 0
Segregational drift hinders the evolution of antibiotic resistance on polyploid replicons. 分离漂移阻碍了多倍体复制子抗生素耐药性的进化。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-03 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010829
Ana Garoña, Mario Santer, Nils F Hülter, Hildegard Uecker, Tal Dagan

The emergence of antibiotic resistance under treatment depends on the availability of resistance alleles and their establishment in the population. Novel resistance alleles are encoded either in chromosomal or extrachromosomal genetic elements; both types may be present in multiple copies within the cell. However, the effect of polyploidy on the emergence of antibiotic resistance remains understudied. Here we show that the establishment of resistance alleles in microbial populations depends on the ploidy level. Evolving bacterial populations under selection for antibiotic resistance, we demonstrate that resistance alleles in polyploid elements are lost frequently in comparison to alleles in monoploid elements due to segregational drift. Integrating the experiments with a mathematical model, we find a remarkable agreement between the theoretical and empirical results, confirming our understanding of the allele segregation process. Using the mathematical model, we further show that the effect of polyploidy on the establishment probability of beneficial alleles is strongest for low replicon copy numbers and plateaus for high replicon copy numbers. Our results suggest that the distribution of fitness effects for mutations that are eventually fixed in a population depends on the replicon ploidy level. Our study indicates that the emergence of antibiotic resistance in bacterial pathogens depends on the pathogen ploidy level.

治疗中抗生素耐药性的出现取决于耐药性等位基因的可用性及其在人群中的建立。新的抗性等位基因编码在染色体或染色体外遗传元件中;这两种类型都可以存在于细胞内的多个拷贝中。然而,多倍体对抗生素耐药性出现的影响仍然研究不足。在这里,我们表明微生物种群中抗性等位基因的建立取决于倍性水平。在抗生素抗性选择下进化的细菌种群,我们证明,与单倍体元件中的等位基因相比,多倍体元件中的抗性等位基因由于分离漂移而频繁丢失。将实验与数学模型相结合,我们发现理论结果与经验结果之间存在显著的一致性,证实了我们对等位基因分离过程的理解。利用该数学模型,我们进一步表明,多倍体对有利等位基因建立概率的影响在低复制子拷贝数时最强,在高复制子拷贝数时为平稳期。我们的结果表明,最终在群体中固定的突变的适应度效应的分布取决于复制子倍性水平。我们的研究表明,细菌病原体中抗生素耐药性的出现取决于病原体的倍性水平。
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引用次数: 2
The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans. 大肠杆菌导致人类血液感染的细菌基因决定因素。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-02 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pgen.1010842
Judit Burgaya, Julie Marin, Guilhem Royer, Bénédicte Condamine, Benoit Gachet, Olivier Clermont, Françoise Jaureguy, Charles Burdet, Agnès Lefort, Victoire de Lastours, Erick Denamur, Marco Galardini, François Blanquart

Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostic, prevention and treatment is still lacking. We used a collection of 912 BSI and 370 commensal E. coli isolates collected in France over a 17-year period (2000-2017). We compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity continuously increased through 1980, 2000, to 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.

大肠埃希菌既是一种高发的共生菌,也是引起血流感染(BSI)的主要机会性病原体。目前仍缺乏对人类肠道外致病性与共感性分离菌基因组决定因素的系统分析,而这些分析可为发病机制、诊断、预防和治疗提供信息。我们使用了 17 年间(2000-2017 年)在法国收集的 912 株 BSI 和 370 株普通大肠杆菌分离物。我们比较了它们的泛基因组、遗传背景(系统群、ST、O 群)、毒力相关基因(VAG)和抗菌药耐药性基因的存在情况,发现在所有比较中,共生菌和 BSI 分离物之间都存在显著差异。以来自泛基因组的所有遗传变异为基础并控制种群结构的机器学习线性模型揭示了 VAG 的类似差异,发现了与致病性(引起 BSI 的能力)相关的新变异,并准确地将 BSI 菌株与普通菌株进行了分类。致病性是一种高遗传性状,细菌基因变异可解释高达 69% 的变异。最后,通过对 1980 年的共生菌株进行补充,我们预测致病性在 1980 年、2000 年到 2010 年期间持续上升。我们的研究结果表明,大肠杆菌在共生和致病之间的转变过程中表现出了巨大的遗传变异,而且该物种正朝着更高的致病性演化。
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引用次数: 0
Restoration of energy homeostasis under oxidative stress: Duo synergistic AMPK pathways regulating arginine kinases. 氧化应激下能量稳态的恢复:调节精氨酸激酶的双协同AMPK途径。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-08-01 DOI: 10.1371/journal.pgen.1010843
Nan Zhang, Xiangkun Meng, Heng Jiang, Huichen Ge, Kun Qian, Yang Zheng, Yoonseong Park, Jianjun Wang

Rapid depletion of cellular ATP can occur by oxidative stress induced by reactive oxygen species (ROS). Maintaining energy homeostasis requires the key molecular components AMP-activated protein kinase (AMPK) and arginine kinase (AK), an invertebrate orthologue of the mammalian creatine kinase (CK). Here, we deciphered two independent and synergistic pathways of AMPK acting on AK by using the beetle Tribolium castaneum as a model system. First, AMPK acts on transcriptional factor forkhead box O (FOXO) leading to phosphorylation and nuclear translocation of the FOXO. The phospho-FOXO directly promotes the expression of AK upon oxidative stress. Concomitantly, AMPK directly phosphorylates the AK to switch the direction of enzymatic catalysis for rapid production of ATP from the phosphoarginine-arginine pool. Further in vitro assays revealed that Sf9 cells expressing phospho-deficient AK mutants displayed the lower ATP/ADP ratio and cell viability under paraquat-induced oxidative stress conditions when compared with Sf9 cells expressing wild-type AKs. Additionally, the AMPK-FOXO-CK pathway is also involved in the restoration of ATP homeostasis under oxidative stress in mammalian HEK293 cells. Overall, we provide evidence that two distinct AMPK-AK pathways, transcriptional and post-translational regulations, are coherent responders to acute oxidative stresses and distinguished from classical AMPK-mediated long-term metabolic adaptations to energy challenge.

活性氧(ROS)诱导的氧化应激可导致细胞ATP的快速消耗。维持能量稳态需要amp活化蛋白激酶(AMPK)和精氨酸激酶(AK)的关键分子成分,精氨酸激酶是哺乳动物肌酸激酶(CK)的无脊椎同源物。在这里,我们以甲虫Tribolium castaneum为模型系统,破译了AMPK作用于AK的两条独立和协同的途径。首先,AMPK作用于转录因子叉头盒O (FOXO),导致FOXO磷酸化和核易位。磷酸化- foxo直接促进AK在氧化应激下的表达。同时,AMPK直接使AK磷酸化,从而改变酶催化的方向,使磷酸精氨酸-精氨酸池快速产生ATP。进一步的体外实验表明,与表达野生型AK的Sf9细胞相比,表达磷酸化缺陷AK突变体的Sf9细胞在百草枯诱导的氧化应激条件下表现出更低的ATP/ADP比率和细胞活力。此外,AMPK-FOXO-CK通路也参与哺乳动物HEK293细胞氧化应激下ATP稳态的恢复。总的来说,我们提供的证据表明,两种不同的AMPK-AK途径,转录和翻译后调控,是急性氧化应激的一致反应者,与经典的ampk介导的长期代谢适应能量挑战不同。
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引用次数: 2
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