Department of Microbiology and Immunology, University of California, San Francisco, CA 94158.
Assay Development, Lucira Health, Emeryville, CA 94608.
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2016818118.
is the most common cause of systemic fungal infections in humans and is considerably more virulent than its closest known relative, To investigate this difference, we constructed interspecies hybrids and quantified mRNA levels produced from each genome in the hybrid. This approach systematically identified expression differences in orthologous genes arising from -regulatory sequence changes that accumulated since the two species last shared a common ancestor, some 10 million y ago. We documented many orthologous gene-expression differences between the two species, and we pursued one striking observation: All 15 genes coding for the enzymes of glycolysis showed higher expression from the genome than the genome in the interspecies hybrid. This pattern requires evolutionary changes to have occurred at each gene; the fact that they all act in the same direction strongly indicates lineage-specific natural selection as the underlying cause. To test whether these expression differences contribute to virulence, we created a strain in which all 15 glycolysis genes were produced at modestly elevated levels and found that this strain had significantly increased virulence in the standard mouse model of systemic infection. These results indicate that small expression differences across a deeply conserved set of metabolism enzymes can play a significant role in the evolution of virulence in fungal pathogens.
是人类系统性真菌感染的最常见原因，其毒力比其最接近的亲缘种明显更强。为了研究这种差异，我们构建了种间杂种，并定量分析了杂种中每个基因组产生的 mRNA 水平。这种方法系统地鉴定了由于自两个物种最后一次共享共同祖先（约 1000 万年前）以来积累的 - 调控序列变化而导致的同源基因表达差异。我们记录了两个物种之间的许多同源基因表达差异，并对一个显著的观察结果进行了探讨：种间杂种中，所有编码糖酵解酶的 15 个基因的表达均来自 基因组，而不是 基因组。这种模式要求每个基因都发生进化变化；事实上，它们都朝着同一个方向作用，强烈表明种系特异性自然选择是其潜在原因。为了测试这些表达差异是否有助于毒力，我们构建了一个菌株，其中所有 15 个糖酵解基因的表达水平适度升高，发现该菌株在系统性感染的标准小鼠模型中具有显著增加的毒力。这些结果表明，在一组深度保守的代谢酶中，微小的表达差异可能在真菌病原体毒力的进化中发挥重要作用。
