Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection.
Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection.
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DOI：
10.1534/genetics.117.201970
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发表时间：
2017-08
期刊：
影响因子：
3.3
通讯作者：
Jiggins FM
中科院分区：
文献类型：
--
作者：
Cao C;Cogni R;Barbier V;Jiggins FM
常发现主效基因是感染易感性变异的重要原因。在这里，我们描述了一个名为pastrel的基因的自然变异，该基因解释了黑腹果蝇种群中对果蝇C病毒（DCV）易感性的一半以上遗传变异。我们发现了广泛的等位基因异质性，来自世界各地的pastrel的7个等位基因的样本赋予4个表型不同的抗性水平。通过在转基因果蝇中修改候选SNP，我们发现最大的影响是由氨基酸多态性引起的，当祖先苏氨酸突变为丙氨酸时，大大增加了对DCV的抗性。祖先的易感等位基因的过表达提供了对DCV的强保护;表明该突变起到了改善现有限制因子的作用。Pastrel基因座还包含复杂的结构变异和改变基因表达的顺式调节多态性。我们发现Pastrel的高表达与DCV感染后存活率的增加相关。为了理解为什么这种变异在种群中保持不变，我们研究了导致果蝇抗性的氨基酸变异周围的遗传变异。我们没有发现自然选择导致等位基因频率或地理频率变化的证据，这表明这是一个古老的多态性，一直保持在一个稳定的频率。总的来说，我们的数据表明，复杂的遗传变异在一个单一的基因座可以控制易感性的有毒天然病原体。
It is common to find that major-effect genes are an important cause of variation in susceptibility to infection. Here we have characterized natural variation in a gene called pastrel that explains over half of the genetic variance in susceptibility to the Drosophila C virus (DCV) in populations of Drosophila melanogaster. We found extensive allelic heterogeneity, with a sample of seven alleles of pastrel from around the world conferring four phenotypically distinct levels of resistance. By modifying candidate SNPs in transgenic flies, we show that the largest effect is caused by an amino acid polymorphism that arose when an ancestral threonine was mutated to alanine, greatly increasing resistance to DCV. Overexpression of the ancestral, susceptible allele provides strong protection against DCV; indicating that this mutation acted to improve an existing restriction factor. The pastrel locus also contains complex structural variation and cis-regulatory polymorphisms altering gene expression. We find that higher expression of pastrel is associated with increased survival after DCV infection. To understand why this variation is maintained in populations, we investigated genetic variation surrounding the amino acid variant that is causing flies to be resistant. We found no evidence of natural selection causing either recent changes in allele frequency or geographical variation in frequency, suggesting that this is an old polymorphism that has been maintained at a stable frequency. Overall, our data demonstrate how complex genetic variation at a single locus can control susceptibility to a virulent natural pathogen.