Natural variation in the sequestosome-related gene, sqst-5, underlies zinc homeostasis in Caenorhabditis elegans.
Natural variation in the sequestosome-related gene, sqst-5, underlies zinc homeostasis in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1008986
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发表时间：
2020-11
期刊：
影响因子：
4.5
通讯作者：
Andersen EC
中科院分区：
文献类型：
--
作者：
Evans KS;Zdraljevic S;Stevens L;Collins K;Tanny RE;Andersen EC
锌是一种必需的微量元素，是细胞生长和发育所需的许多酶和转录因子的辅助因子。改变细胞内的锌水平可以产生从细胞增殖到细胞死亡的戏剧性影响。为了避免这种命运，细胞进化出了处理锌过剩和缺乏的机制。锌的稳态在很大程度上是通过锌转运体、通透性通道和其他锌结合蛋白来维持的。这些蛋白质的变异可能会影响它们与锌的相互作用能力，从而提高对环境中自然锌波动的敏感性或抵抗力。我们可以利用线虫线虫秀丽线虫的力量，作为一个易于处理的后生动物模型，用于定量遗传学，以确定可能导致锌反应变化的基因。我们发现实验室适应的菌株(N2)是抗性的，来自夏威夷的一株天然分离物(CB4856)对微摩尔量的外源锌补充敏感。利用一组重组自交系，我们在第三染色体的左臂和第五染色体的中心定位了两个与锌反应相关的大效应数量性状基因座(QTL)。我们利用近等基因系(NIL)验证和提纯了这两个QTL，并确定了与高外源锌抗性相关的隔离体相关基因SQST-5中自然发生的缺失。我们发现，这种缺失在物种内的菌株中相对常见，并且SQST-5的变异与锌抗性有关。我们的结果为生物体如何对环境中自然高水平的锌做出反应，以及锌的动态平衡在个体之间的变化提供了可能的机制。锌虽然是一种重要的金属，但如果生物暴露在浓度过高或过低的环境中，锌可能会有毒。为了防止毒性，生物体已经进化出调节环境中锌摄取的机制。在这里，我们利用两个品系的线虫之间的遗传变异，这些品系对高外源锌的反应不同，以确定可能参与维持适当锌水平的基因。我们确定了四个与锌反应不同有关的基因座。其中一个基因座是与隔离体相关的基因SQST-5。我们发现，SQST-5的靶向缺失导致了对锌的抵抗力增加。尽管SQST-5含有一个保守的锌结合蛋白结构域，但它尚未直接参与线虫的锌反应途径。我们在328个不同的菌株中发现了SQST-5中两种常见的遗传变异形式，这表明SQST-5中的变异肯定出现了多次，可能是对高锌环境的反应。总体而言，我们的研究为锌反应机制的进化提供了一个自然的背景。
Zinc is an essential trace element that acts as a co-factor for many enzymes and transcription factors required for cellular growth and development. Altering intracellular zinc levels can produce dramatic effects ranging from cell proliferation to cell death. To avoid such fates, cells have evolved mechanisms to handle both an excess and a deficiency of zinc. Zinc homeostasis is largely maintained via zinc transporters, permeable channels, and other zinc-binding proteins. Variation in these proteins might affect their ability to interact with zinc, leading to either increased sensitivity or resistance to natural zinc fluctuations in the environment. We can leverage the power of the roundworm nematode Caenorhabditis elegans as a tractable metazoan model for quantitative genetics to identify genes that could underlie variation in responses to zinc. We found that the laboratory-adapted strain (N2) is resistant and a natural isolate from Hawaii (CB4856) is sensitive to micromolar amounts of exogenous zinc supplementation. Using a panel of recombinant inbred lines, we identified two large-effect quantitative trait loci (QTL) on the left arm of chromosome III and the center of chromosome V that are associated with zinc responses. We validated and refined both QTL using near-isogenic lines (NILs) and identified a naturally occurring deletion in sqst-5, a sequestosome-related gene, that is associated with resistance to high exogenous zinc. We found that this deletion is relatively common across strains within the species and that variation in sqst-5 is associated with zinc resistance. Our results offer a possible mechanism for how organisms can respond to naturally high levels of zinc in the environment and how zinc homeostasis varies among individuals. Zinc, although an essential metal, can be toxic if organisms are exposed to concentrations that are too high or too low. To prevent toxicity, organisms have evolved mechanisms to regulate zinc uptake from the environment. Here, we leveraged genetic variation between two strains of the roundworm Caenorhabditis elegans with different responses to high exogenous zinc to identify genes that might be involved in maintaining proper zinc levels. We identified four loci that contributed to differential zinc responses. One of these loci was the sequestosome-related gene sqst-5. We discovered that targeted deletions of sqst-5 caused an increase in resistance to zinc. Although SQST-5 contains a conserved zinc-binding protein domain, it has yet to be directly implicated in the C. elegans zinc response pathway. We identified two common forms of genetic variation in sqst-5 among 328 distinct strains, suggesting that variation in sqst-5 must have emerged multiple times, perhaps in response to an environment of high zinc. Overall, our study suggests a natural context for the evolution of zinc response mechanisms.
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