Putting genetic interactions in context through a global modular decomposition
Putting genetic interactions in context through a global modular decomposition
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DOI：
10.1101/gr.117176.110
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发表时间：
2011-08-01
期刊：
影响因子：
7
通讯作者：
Myers, Chad L.
中科院分区：
文献类型：
--
作者：
Bellay, Jeremy;Atluri, Gowtham;Myers, Chad L.
基因相互作用为研究基因功能提供了一个强有力的视角，但我们对产生这些相互作用的具体机制的了解仍然相对有限。酿酒酵母的全球遗传相互作用图谱的可用性，覆盖了所有可能的双突变组合的30%，为遗传相互作用网络中的天然结构及其与基因功能和模块化组织的关系提供了前所未有的公正评估机会。为此，我们开发了一种数据挖掘方法，以详尽地发现该网络中的所有块结构，从而允许其完全模块化分解。由此产生的模块化结构揭示了个体遗传相互作用背景在其解释中的重要性，揭示了遗传相互作用中心之间的明显趋势，以及对重复基因进化的见解。块成员关系还揭示了酵母基因组中令人惊讶的多功能性，并使VIP1和IPK1与DNA复制和修复之间存在新的关联，这得到了实验证据的支持。我们的模块化分解也为检验负遗传相互作用的途径间模型和正遗传相互作用的途径内模型提供了基础。虽然我们发现大多数涉及负遗传相互作用的模块化结构符合通路间模型，但我们发现目前的积极遗传相互作用模型无法解释检测到的80%的模块化结构。我们还发现必要基因和非必要基因的模块结构之间存在差异。
Genetic interactions provide a powerful perspective into gene function, but our knowledge of the specific mechanisms that give rise to these interactions is still relatively limited. The availability of a global genetic interaction map in Saccharomyces cerevisiae, covering similar to 30% of all possible double mutant combinations, provides an unprecedented opportunity for an unbiased assessment of the native structure within genetic interaction networks and how it relates to gene function and modular organization. Toward this end, we developed a data mining approach to exhaustively discover all block structures within this network, which allowed for its complete modular decomposition. The resulting modular structures revealed the importance of the context of individual genetic interactions in their interpretation and revealed distinct trends among genetic interaction hubs as well as insights into the evolution of duplicate genes. Block membership also revealed a surprising degree of multifunctionality across the yeast genome and enabled a novel association of VIP1 and IPK1 with DNA replication and repair, which is supported by experimental evidence. Our modular decomposition also provided a basis for testing the between-pathway model of negative genetic interactions and within-pathway model of positive genetic interactions. While we find that most modular structures involving negative genetic interactions fit the between-pathway model, we found that current models for positive genetic interactions fail to explain 80% of the modular structures detected. We also find differences between the modular structures of essential and nonessential genes.