Polygenic cis-regulatory adaptation in the evolution of yeast pathogenicity.
Polygenic cis-regulatory adaptation in the evolution of yeast pathogenicity.
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DOI：
10.1101/gr.134080.111
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发表时间：
2012-10
期刊：
影响因子：
7
通讯作者：
Sinha H
中科院分区：
文献类型：
--
作者：
Fraser HB;Levy S;Chavan A;Shah HB;Perez JC;Zhou Y;Siegal ML;Sinha H
通过水平转移或基因复制/多样化获得新基因是迄今为止微生物致病性进化中涉及的主要机制。相比之下，许多其他进化模式的作用，如基因表达调控的变化，仍然是未知的。最近在芽殖酵母酿酒酵母的一些谱系中发生了向致病性生活方式的转变。在这里，我们确定了一个模块的物理相互作用的蛋白质参与内吞作用，经历了选择性扫描多个顺式调控突变，下调致病性酵母的基因表达水平。为了测试这些适应是否影响毒力，我们创建了一组单等位基因敲除菌株，其半合子状态模拟基因的适应性下调，并测量了它们在哺乳动物宿主中的毒力。尽管在标准实验室条件下没有生长优势，但几乎所有的菌株都比其野生型祖先更具毒性，这表明这些适应可能在致病性的进化中发挥了作用。此外，这些基因座的遗传变异与88种不同酵母菌株的临床来源相关，表明这些适应可能导致了广泛的临床分离株的毒力。我们还检测到多效性的影响，这些适应范围广泛的形态特征，这似乎已减轻补偿突变在其他位点。这些结果表明，顺式调节适应可以发生在物理相互作用的模块的水平，这样的多基因适应导致致病性酵母的进化过程中的毒力增加。
The acquisition of new genes, via horizontal transfer or gene duplication/diversification, has been the dominant mechanism thus far implicated in the evolution of microbial pathogenicity. In contrast, the role of many other modes of evolution—such as changes in gene expression regulation—remains unknown. A transition to a pathogenic lifestyle has recently taken place in some lineages of the budding yeast Saccharomyces cerevisiae. Here we identify a module of physically interacting proteins involved in endocytosis that has experienced selective sweeps for multiple cis-regulatory mutations that down-regulate gene expression levels in a pathogenic yeast. To test if these adaptations affect virulence, we created a panel of single-allele knockout strains whose hemizygous state mimics the genes' adaptive down-regulations, and measured their virulence in a mammalian host. Despite having no growth advantage in standard laboratory conditions, nearly all of the strains were more virulent than their wild-type progenitor, suggesting that these adaptations likely played a role in the evolution of pathogenicity. Furthermore, genetic variants at these loci were associated with clinical origin across 88 diverse yeast strains, suggesting the adaptations may have contributed to the virulence of a wide range of clinical isolates. We also detected pleiotropic effects of these adaptations on a wide range of morphological traits, which appear to have been mitigated by compensatory mutations at other loci. These results suggest that cis-regulatory adaptation can occur at the level of physically interacting modules and that one such polygenic adaptation led to increased virulence during the evolution of a pathogenic yeast.
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影响因子：
9.9
作者：
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通讯作者：
Steinmetz, Lars M.
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