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Abstract：
Gene knockout studies suggest that ~300 genes in a bacterial genome and ~1,100 genes in a yeast genome cannot be deleted without loss of viability. These single-gene knockout experiments do not account for negative genetic interactions, when two or more genes can each be deleted without effect, but their joint deletion is lethal. Thus, large-scale single-gene deletion studies underestimate the size of a minimal gene set compatible with cell survival. In yeast Saccharomyces cerevisiae, the viability of all possible deletions of gene pairs (2-tuples), and of some deletions of gene triplets (3-tuples), has been experimentally tested. To estimate the size of a yeast minimal genome from that data, we first established that finding the size of a minimal gene set is equivalent to finding the minimum vertex cover in the lethality (hyper)graph, where the vertices are genes and (hyper)edges connect k-tuples of genes whose joint deletion is lethal. Using the Lovász-Johnson-Chvatal greedy approximation algorithm, we computed the minimum vertex cover of the synthetic-lethal 2-tuples graph to be 1,723 genes. We next simulated the genetic interactions in 3-tuples, extrapolating from the existing triplet sample, and again estimated minimum vertex covers. The size of a minimal gene set in yeast rapidly approaches the size of the entire genome even when considering only synthetic lethalities in k-tuples with small k. In contrast, several studies reported successful experimental reductions of yeast and bacterial genomes by simultaneous deletions of hundreds of genes, without eliciting synthetic lethality. We discuss possible reasons for this apparent contradiction.IMPORTANCEHow can we estimate the smallest number of genes sufficient for a unicellular organism to survive on a rich medium? One approach is to remove genes one at a time and count how many of such deletion strains are unable to grow. However, the single-gene knockout data are insufficient, because joint gene deletions may result in negative genetic interactions, also known as synthetic lethality. We used a technique from graph theory to estimate the size of minimal yeast genome from partial data on synthetic lethality. The number of potential synthetic lethal interactions grows very fast when multiple genes are deleted, revealing a paradoxical contrast with the experimental reductions of yeast genome by ~100 genes, and of bacterial genomes by several hundreds of genes.
摘要：
基因敲除研究表明，细菌基因组中的〜300个基因和酵母基因组中的〜1,100个基因不能在不丧失生存力的情况下被删除。这些单基因敲除实验没有解释负面的遗传相互作用，当两个或更多的基因可以各自删除而没有效果时，但它们的关节缺失是致命的.因此，大规模单基因缺失研究低估了与细胞存活相容的最小基因集的大小.在酿酒酵母中，基因对（2元组）的所有可能缺失的生存力，以及基因三联体（3元组）的一些缺失，已经过实验测试。从这些数据中估计酵母最小基因组的大小，我们首先确定，找到最小基因集的大小相当于找到杀伤力（超）图中的最小顶点覆盖，其中顶点是基因，（超）边连接其关节缺失致命的基因的k元组。使用Lovász-Johnson-Chvatal贪婪近似算法，我们计算了合成致死2元组图的最小顶点覆盖率为1,723个基因。接下来我们模拟了3元组中的遗传相互作用，从现有的三元组样本推断，并再次估计最小顶点覆盖。酵母中最小基因集的大小迅速接近整个基因组的大小，即使只考虑k小的k元组中的合成杀伤力。几项研究报告说，通过同时删除数百个基因，成功地减少了酵母和细菌基因组的实验，不会引起合成致死性.我们讨论这种明显矛盾的可能原因。重要信息我们如何估计足以使单细胞生物在丰富的培养基上存活的最小数量的基因？一种方法是一次删除一个基因，并计算有多少这样的缺失菌株无法生长。然而,单基因敲除数据不足，因为联合基因缺失可能导致负面的遗传相互作用，也被称为合成杀伤力。我们使用图论的技术从合成致死性的部分数据中估计最小酵母基因组的大小。当多个基因缺失时，潜在的合成致死相互作用的数量增长非常快，揭示了与酵母基因组约100个基因的实验性减少的矛盾对比，和数百种基因的细菌基因组。
