Loss-of-function mutation survey revealed that genes with background-dependent fitness are rare and functionally related in yeast.
Loss-of-function mutation survey revealed that genes with background-dependent fitness are rare and functionally related in yeast.
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DOI：
10.1073/pnas.2204206119
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发表时间：
2022-09-13
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在不同的个体中，由于遗传背景的影响，相同的突变可能导致不同的表型。这在各种系统中都很常见，包括许多人类疾病。虽然已经观察到这种背景效应的孤立例子，但仍然缺乏对大量个体的系统看法。在这里，我们调查了遗传背景效应与基因功能丧失突变在酵母天然分离的群体。我们发现，约15%的基因可以显示背景依赖的适应度变化。与线粒体功能相关的基因明显被过度代表，并且与参与转录和染色质重塑以及核-细胞质运输的基因显示出相反的适应性增益或损失模式，表明潜在的功能性重新布线。在自然种群中，由于个体之间存在遗传变异，相同的突变可能导致不同的表型结果。这种遗传背景效应是常见的，包括在许多人类疾病的情况下。然而，迄今为止，在物种水平上对这些影响的系统表征仍然缺乏。在这里，我们试图利用转座子饱和策略全面调查39个天然分离的酿酒酵母中与基因功能丧失（LoF）突变相关的背景依赖性状。通过分析总共4,469个基因的模型适应度变异性，我们发现，与参考菌株S288C相比，15%的基因在受到LoF突变的影响时，在某些天然分离株中表现出显著的适应度增加或损失表型。在这632个具有预测背景相关适应度效应的基因中，大约2/3影响多个背景，预测适应度变化梯度，而1/3特定于单一遗传背景。与线粒体功能相关的基因在一组基因中表现出持续的变异，并与其他参与转录和染色质重塑以及核细胞质运输的基因表现出潜在的功能性重新布线。这种重新布线的效果很可能受到遗传背景和环境的双重调节。虽然背景特异性病例很少，并且跨越不同的细胞过程，但它们在个体水平上可能具有功能相关性。具有背景依赖适应度效应的基因在整体遗传相互作用网络中具有中间连通性，在种群水平上表现出宽松的选择压力，突出了其潜在的进化特征。
In different individuals, the same mutation can lead to different phenotypes due to genetic background effects. This is commonly observed in various systems, including many human diseases. While isolated examples of such background effects have been observed, a systematic view across a large number of individuals is still lacking. Here, we surveyed genetic background effects associated with gene loss-of-function mutations across a population of natural isolates of the yeast Saccharomyces cerevisiae. We found that ∼15% of genes can display a background-dependent fitness change. Genes related to mitochondrial functions are significantly overrepresented, and showed reversed patterns of fitness gain or loss with genes involved in transcription and chromatin remodeling as well as in nuclear–cytoplasmic transport, suggesting a potential functional rewiring. In natural populations, the same mutation can lead to different phenotypic outcomes due to the genetic variation that exists among individuals. Such genetic background effects are commonly observed, including in the context of many human diseases. However, systematic characterization of these effects at the species level is still lacking to date. Here, we sought to comprehensively survey background-dependent traits associated with gene loss-of-function (LoF) mutations in 39 natural isolates of Saccharomyces cerevisiae using a transposon saturation strategy. By analyzing the modeled fitness variability of a total of 4,469 genes, we found that 15% of them, when impacted by a LoF mutation, exhibited a significant gain- or loss-of-fitness phenotype in certain natural isolates compared with the reference strain S288C. Out of these 632 genes with predicted background-dependent fitness effects, around 2/3 impact multiple backgrounds with a gradient of predicted fitness change while 1/3 are specific to a single genetic background. Genes related to mitochondrial function are significantly overrepresented in the set of genes showing a continuous variation and display a potential functional rewiring with other genes involved in transcription and chromatin remodeling as well as in nuclear–cytoplasmic transport. Such rewiring effects are likely modulated by both the genetic background and the environment. While background-specific cases are rare and span diverse cellular processes, they can be functionally related at the individual level. All genes with background-dependent fitness effects tend to have an intermediate connectivity in the global genetic interaction network and have shown relaxed selection pressure at the population level, highlighting their potential evolutionary characteristics.
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影响因子：
7.7
作者：
Johnson MS;Gopalakrishnan S;Goyal J;Dillingham ME;Bakerlee CW;Humphrey PT;Jagdish T;Jerison ER;Kosheleva K;Lawrence KR;Min J;Moulana A;Phillips AM;Piper JC;Purkanti R;Rego-Costa A;McDonald MJ;Nguyen Ba AN;Desai MM
通讯作者：
Desai MM
DOI：
10.1073/pnas.1820915116
发表时间：
2019-03-12
影响因子：
11.1
作者：
Hou, Jing;Tan, Guihong;Boone, Charles
通讯作者：
Boone, Charles
影响因子：
56.9
作者：
Blomen, Vincent A.;Majek, Peter;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.
影响因子：
3.3
作者：
Chandler, Christopher H.;Chari, Sudarshan;Dworkin, Ian
通讯作者：
Dworkin, Ian
影响因子：
9.9
作者：
Galardini, Marco;Busby, Bede P.;Beltrao, Pedro
通讯作者：
Beltrao, Pedro