The fate of genes after duplication Gene duplication within an organism is a relatively common event during evolution. However, we cannot predict the fate of the duplicated genes: Will they be lost, evolve, or overlap in function within an organismal lineage or species? Kuzmin et al. explored the fate of duplicated gene function within the yeast Saccharomyces cerevisiae (see the Perspective by Ehrenreich). They examined how experimental deletions of one or two duplicated genes (paralogs) affected yeast fitness and were able to determine which genes have likely evolved new essential functions and which retained functional overlap, a condition the authors refer to as entanglement. On the basis of these results, they propose how entanglement affects the evolutionary trajectory of gene duplications. Science, this issue p. eaaz5667; see also p. 1424 Gene feature analysis and modeling are used to study evolutionary trajectories of duplicated genes in yeast. INTRODUCTION Whole-genome duplication (WGD) events are pervasive in eukaryotes, shaping the genomes of simple single-celled organisms, such as yeast, as well as those of more complex metazoans, including humans. Most duplicated genes are eliminated after WGD because one copy accumulates deleterious mutations, leading to its loss. However, a significant proportion of duplicates persists, and factors that result in duplicate gene retention are poorly understood but critical for understanding the evolutionary forces that shape genomes. RATIONALE Quantifying the functional divergence of paralog pairs is of particular interest because of the strong selection against functional redundancy. Negative genetic interactions identify functional relationships between genes and provide a means to directly capture the functional relationship between duplicated genes. Genetic interactions occur when the phenotype associated with a combination of mutations in two or more different genes deviates from the expected combined effect of the individual mutations. A negative genetic interaction refers to a combination of mutations that generates a stronger fitness defect than expected, such as synthetic lethality. Here, we used systematic analysis of digenic and trigenic interaction profiles to assess the functional relationship of retained duplicated genes. RESULTS To map both digenic and trigenic interactions of duplicated genes, we profiled query strains carrying single-deletion mutations and the corresponding double-deletion mutations for 240 different dispensable paralog pairs originating from the yeast WGD event. In total, we tested ~550,000 double and ~260,000 triple mutants for genetic interactions, and identified ~4700 negative digenic interactions and ~2500 negative trigenic interactions. We quantified the trigenic interaction fraction, defined as the ratio of negative trigenic interactions to the total number of interactions associated with the paralog pair. The distribution of the resulting trigenic interaction fractions was distinctly bimodal, with two-thirds of paralogs exhibiting a low trigenic interaction fraction (diverged paralogs) and one-third showing a high trigenic interaction fraction (functionally redundant paralogs). Paralogs with a high trigenic interaction fraction showed a relatively low asymmetry in their number of digenic interactions, low rates of protein sequence divergence, and a negative digenic interaction within the gene pair. We correlated position-specific evolutionary rate patterns between paralogs to assess constraints acting on their evolutionary trajectories. Paralogs with a high trigenic interaction fraction showed more correlated evolutionary rate patterns and thus were more evolutionarily constrained than paralogs with a low trigenic interaction fraction. Computational simulations that modeled duplicate gene evolution revealed that as the extent of the initial entanglement (overlap of functions) of paralogs increased, so did the range of functional redundancy at steady state. Thus, the bimodal distribution of the trigenic interaction fraction may reflect that some paralogs diverged, primarily evolving distinct functions without redundancy, while others converged to an evolutionary steady state with substantial redundancy due to their structural and functional entanglement. CONCLUSION We propose that the evolutionary fate of a duplicated gene is dictated by an interplay of structural and functional entanglement. Paralog pairs with high levels of entanglement are more likely to revert to a singleton state. In contrast, unconstrained paralogs will tend to partition their functions and adopt divergent roles. Intermediately entangled paralog pairs may partition or expand nonoverlapping functions while also retaining some common, overlapping functions, such that they can both adopt paralog-specific roles and maintain functional redundancy at an evolutionary steady state. Complex genetic interaction analysis of duplicated genes. The trigenic interaction fraction, which incorporates digenic and trigenic interactions, captures the functional relationship of duplicated genes and follows a bimodal distribution. Paralogs with a high trigenic interaction fraction are under evolutionary constraints reflecting their structural and functional entanglement. Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.

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通过复杂的遗传相互作用分析探索全基因组重复基因保留

基因复制后的命运 生物体内的基因复制是进化过程中相对常见的事件。然而，我们无法预测重复基因的命运：它们是否会丢失、进化或在有机体谱系或物种内功能重叠？库兹明等人。探索了酿酒酵母中重复基因功能的命运（参见 Ehrenreich 的观点）。他们研究了实验删除一个或两个重复基因（旁系同源物）如何影响酵母的适应性，并能够确定哪些基因可能进化出新的基本功能，哪些保留功能重叠，作者将这种情况称为纠缠。根据这些结果，他们提出了纠缠如何影响基因重复的进化轨迹。科学，本期第 14 页。eaaz5667；另见 p. 1424 基因特征分析和建模用于研究酵母中重复基因的进化轨迹。引言全基因组复制（WGD）事件在真核生物中普遍存在，塑造了简单单细胞生物（例如酵母）以及更复杂的后生动物（包括人类）的基因组。大多数重复基因在全基因组检测后被消除，因为其中一个拷贝积累了有害突变，导致其丢失。然而，很大一部分重复基因仍然存在，导致重复基因保留的因素人们知之甚少，但对于理解塑造基因组的进化力量至关重要。基本原理 由于对功能冗余的强烈选择，量化旁系同源对的功能分歧特别令人感兴趣。负向遗传相互作用可识别基因之间的功能关系，并提供直接捕获重复基因之间功能关系的方法。当与两个或多个不同基因的突变组合相关的表型偏离单个突变的预期组合效应时，就会发生遗传相互作用。负面的遗传相互作用是指产生比预期更强的适应性缺陷的突变组合，例如综合致死率。在这里，我们使用双基因和三基因相互作用谱的系统分析来评估保留的重复基因的功能关系。结果 为了绘制重复基因的双基因和三基因相互作用图谱，我们对源自酵母 WGD 事件的 240 个不同的可有可无的旁系同源对的携带单缺失突变和相应双缺失突变的查询菌株进行了分析。总的来说，我们测试了约 550,000 个双突变体和约 260,000 个三基因突变体的遗传相互作用，并鉴定了约 4700 个负二基因相互作用和约 2500 个负三基因相互作用。我们量化了三基因相互作用分数，定义为负三基因相互作用与旁系同源对相关的相互作用总数的比率。所得三基因相互作用分数的分布明显是双峰的，三分之二的旁系同源物表现出低三基因相互作用分数（分歧的旁系同源物），三分之一显示高三基因相互作用分数（功能冗余的旁系同源物）。具有高三基因相互作用分数的旁系同源物在其双基因相互作用数量上表现出相对较低的不对称性、较低的蛋白质序列分歧率以及基因对内的负双基因相互作用。我们将旁系同源物之间特定位置的进化速率模式相关联，以评估对其进化轨迹的约束。具有高三基因相互作用分数的旁系同源物显示出更相关的进化速率模式，因此比具有低三基因相互作用分数的旁系同源物在进化上受到更多限制。模拟重复基因进化的计算模拟表明，随着旁系同源物初始缠结（功能重叠）程度的增加，稳态下功能冗余的范围也随之增加。因此，三基因相互作用分数的双峰分布可能反映了一些旁系同源物的分化，主要进化出没有冗余的不同功能，而另一些则由于其结构和功能纠缠而收敛到具有大量冗余的进化稳态。结论我们认为重复基因的进化命运是由结构和功能纠缠的相互作用决定的。具有高纠缠水平的旁系同源对更有可能恢复到单态。相反，不受约束的旁系同源物往往会划分其功能并采取不同的角色。中间纠缠的旁系同源对可以分割或扩展非重叠功能，同时还保留一些常见的重叠功能，使得它们既可以采用旁系同源特定的角色，又可以在进化稳定状态下保持功能冗余。重复基因的复杂遗传相互作用分析。三基因相互作用部分包含双基因和三基因相互作用，捕获重复基因的功能关系并遵循双峰分布。具有高三基因相互作用分数的旁系同源物受到进化限制，反映了它们的结构和功能纠缠。全基因组复制在包括人类基因组在内的许多生物体的基因组进化中发挥着核心作用。大多数重复基因被消除，而影响持久重复基因保留的因素仍然知之甚少。我们描述了与源自全基因组复制事件的酵母旁系同源物的系统复杂遗传相互作用分析。对每个旁系同源物的缺失突变体的双基因相互作用和双突变体的三基因相互作用进行作图，可以深入了解它们的作用并定量测量它们的功能冗余。三基因相互作用分析区分了两类旁系同源物：功能更加多样化的子集和保留更多功能重叠的子集。基因特征分析和建模表明，重复基因的进化轨迹是由功能和结构缠结因素共同决定的。