Complex modifier landscape underlying genetic background effects
Complex modifier landscape underlying genetic background effects
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DOI：
10.1073/pnas.1820915116
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发表时间：
2019-03-12
影响因子：
11.1
通讯作者：
Boone, Charles
中科院分区：
文献类型：
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作者：
Hou, Jing;Tan, Guihong;Boone, Charles
给定突变的表型结果可以受到遗传背景的影响。例如，当一个基因的功能丧失在一种遗传背景中导致致死性，而在另一种遗传背景中不导致致死性时，就发生了条件基因必要性。在两个单独的酿酒酵母菌株S288 c和S1278 b之间，类似于1%的酵母基因先前被鉴定为“条件必需的”。“在这里，除了证实一些条件必需基因被非染色体元件修饰外，我们还表明大多数情况下涉及一组复杂的基因组修饰剂。从S288 C/S1278 b杂交菌株的四分体分析和可行的杂交孢子后代的全基因组测序，我们确定了条件必要性的多个基因组区域的复杂集合。对于一个较小的基因子集，包括CYS 3和CYS 4，其中每一个编码的半胱氨酸生物合成途径的组件，我们观察到一个分离模式与一个单一的修饰符与条件必要性相一致。在天然酵母分离物中，我们发现CYS 3/CYS 4条件必要性可能是由两个独立修饰剂MET 1和OPT 1的变化引起的，每个修饰剂都与细胞半胱氨酸生理学相关。有趣的是，OPT 1等位基因变异似乎独立于不同的谱系，罕见的等位基因频率低于0.5%。因此，虽然条件基因的必要性通常是由与复杂的修饰结构相关的遗传相互作用驱动的，但我们的分析也强调了功能相关、遗传独立和罕见变异的作用。
The phenotypic consequence of a given mutation can be influenced by the genetic background. For example, conditional gene essentiality occurs when the loss of function of a gene causes lethality in one genetic background but not another. Between two individual Saccharomyces cerevisiae strains, S288c and S1278b, similar to 1% of yeast genes were previously identified as "conditional essential." Here, in addition to confirming that some conditional essential genes are modified by a nonchromosomal element, we show that most cases involve a complex set of genomic modifiers. From tetrad analysis of S288C/S1278b hybrid strains and whole-genome sequencing of viable hybrid spore progeny, we identified complex sets of multiple genomic regions underlying conditional essentiality. For a smaller subset of genes, including CYS3 and CYS4, each of which encodes components of the cysteine biosynthesis pathway, we observed a segregation pattern consistent with a single modifier associated with conditional essentiality. In natural yeast isolates, we found that the CYS3/CYS4 conditional essentiality can be caused by variation in two independent modifiers, MET1 and OPT1, each with roles associated with cellular cysteine physiology. Interestingly, the OPT1 allelic variation appears to have arisen independently from separate lineages, with rare allele frequencies below 0.5%. Thus, while conditional gene essentiality is usually driven by genetic interactions associated with complex modifier architectures, our analysis also highlights the role of functionally related, genetically independent, and rare variants.