The fitness consequences of aneuploidy are driven by condition-dependent gene effects.
The fitness consequences of aneuploidy are driven by condition-dependent gene effects.
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DOI：
10.1371/journal.pbio.1002155
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发表时间：
2015-05
期刊：
影响因子：
9.8
通讯作者：
Dunham MJ
中科院分区：
文献类型：
--
作者：
Sunshine AB;Payen C;Ong GT;Liachko I;Tan KM;Dunham MJ
非整倍性是肿瘤细胞的标志，然而非整倍性与细胞增殖能力或细胞适应性之间的精确关系仍然难以捉摸。在这项研究中，我们结合了一个系统的，全基因组筛选端粒扩增的健身效果，以解决非整倍性和细胞健身之间的关系，从实验室进化的群体分离的非整倍体克隆的详细分析酿酒酵母。我们发现，非整倍体克隆上升到高人口频率在营养有限的进化实验，并显示出增加健身相对于野生型。直接竞争实验证实，从进化群体中分离出的四个非整倍体事件中有三个本身就足以提高适应性。为了将范围扩大到这一小部分样本之外，我们创建了一个全基因组范围的> 1，800个二倍体酵母菌株的集合，每个菌株含有不同的端粒扩增子（Tamp），大小从0.4到1，000 kb不等。在营养有限的恒化器中使用合并的竞争实验，然后对菌株识别条形码进行高通量测序，我们确定了这些> 1，800个Tamp在三种不同条件下的适应性效应。我们的数据显示，端粒扩增探索的适应度景观比单基因扩增探索的适应度景观要广泛得多。正如在进化的克隆中所观察到的那样，我们发现大多数坦帕的健身效果是特定条件的，少数人在所有三种条件下都表现出共同的效果。通过整合我们的数据与以前的工作，检查单基因扩增基因组范围内的健身效果，我们发现，一个小数目的基因在每个夯实的健身效果集中负责。我们的全基因组Tamp筛选证实，在实验室进化的种群中发现的端粒扩增通常会增加适应性。我们的研究结果表明，Tamps是产生大的，通常是条件依赖性的变化，在健身，是重要的驱动因素，增加健身无性进化的人口突变。一种在酿酒酵母中产生数千种非整倍体菌株的新方法使作者能够剖析非整倍体在适应和进化中的复杂作用。在大多数肿瘤中观察到非整倍性（基因组区域的拷贝数改变），但仍不清楚非整倍性是否是癌症的原因或后果。来自酿酒酵母和哺乳动物细胞的证据表明，非整倍体细胞往往比正常细胞生长得更慢;然而，非整倍体也被证明会促进肿瘤形成和微生物适应。为了解决这个矛盾，我们采取了两种方法来研究适应性（以细胞生长为衡量标准）和非整倍体之间的关系。首先，我们研究了从实验室进化的S。酿酒酵母，并发现大多数这样的事件提高细胞的健身，具有大的效应大小，并显示在不同的条件下不同的健身效果。其次，我们开发了一种方法来创建数千个跨越酵母基因组的非整倍体菌株，并使用合并的竞争实验，然后进行条形码测序来确定它们的相对适合度。这些全基因组数据揭示了非整倍性具有既大又广的影响（多效性）。我们发现，无论是积极的和消极的健身效果通常是由一个小数目的基因在每个非整倍体事件。我们的结论是，非整倍体在实验室进化实验中的酵母菌的适应过程中的功能是重要的，并提出它有可能在癌症的演变过程中发挥适应性作用。
Aneuploidy is a hallmark of tumor cells, and yet the precise relationship between aneuploidy and a cell’s proliferative ability, or cellular fitness, has remained elusive. In this study, we have combined a detailed analysis of aneuploid clones isolated from laboratory-evolved populations of Saccharomyces cerevisiae with a systematic, genome-wide screen for the fitness effects of telomeric amplifications to address the relationship between aneuploidy and cellular fitness. We found that aneuploid clones rise to high population frequencies in nutrient-limited evolution experiments and show increased fitness relative to wild type. Direct competition experiments confirmed that three out of four aneuploid events isolated from evolved populations were themselves sufficient to improve fitness. To expand the scope beyond this small number of exemplars, we created a genome-wide collection of >1,800 diploid yeast strains, each containing a different telomeric amplicon (Tamp), ranging in size from 0.4 to 1,000 kb. Using pooled competition experiments in nutrient-limited chemostats followed by high-throughput sequencing of strain-identifying barcodes, we determined the fitness effects of these >1,800 Tamps under three different conditions. Our data revealed that the fitness landscape explored by telomeric amplifications is much broader than that explored by single-gene amplifications. As also observed in the evolved clones, we found the fitness effects of most Tamps to be condition specific, with a minority showing common effects in all three conditions. By integrating our data with previous work that examined the fitness effects of single-gene amplifications genome-wide, we found that a small number of genes within each Tamp are centrally responsible for each Tamp’s fitness effects. Our genome-wide Tamp screen confirmed that telomeric amplifications identified in laboratory-evolved populations generally increased fitness. Our results show that Tamps are mutations that produce large, typically condition-dependent changes in fitness that are important drivers of increased fitness in asexually evolving populations. A novel method to create thousands of aneuploid strains in Saccharomyces cerevisiae allows the authors to dissect the complex role of aneuploidy in adaptation and evolution. Aneuploidy (altered copy number of genomic regions) is observed in the majority of tumors, but it remains unclear whether aneuploidy is a cause or consequence of cancer. Evidence from the yeast Saccharomyces cerevisiae and mammalian cells has shown that aneuploid cells tend to grow more slowly than normal cells; however, aneuploidy has also been shown to promote tumor formation and microbial adaptation. To address this paradox, we took two approaches to study the relationship between fitness—measured as cellular growth—and aneuploidy. First, we examined aneuploid events isolated from laboratory-evolved populations of S. cerevisiae and found that the majority of such events improve cellular fitness, have a large effect-size, and show diverse fitness effects under different conditions. Second, we developed a method to create thousands of aneuploid strains spanning the yeast genome and used pooled competition experiments followed by barcode sequencing to determine their relative fitnesses. These genome-wide data revealed aneuploidy to have effects that were both large and wide-ranging (pleiotropic). We found that both the positive and negative fitness effects are typically driven by a small number of genes within each aneuploidy event. We conclude that aneuploidy is functionally important in the process of adaptation of yeast during laboratory evolution experiments and propose that it has the potential to play an adaptive role during the evolution of cancers.
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