Quantifying Selection against Synonymous Mutations in HIV-1 env Evolution
Quantifying Selection against Synonymous Mutations in HIV-1 env Evolution
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DOI：
10.1128/jvi.01529-13
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发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Neher, Richard A.
中科院分区：
文献类型：
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作者：
Zanini, Fabio;Neher, Richard A.
人类免疫缺陷病毒1型(HIV-1)在患者体内的进化是由适应性免疫系统驱动的，导致HIV-1蛋白的快速变化。当细胞毒性CD8(+)T细胞或中和抗体瞄准新的表位时，病毒通常会通过损害识别的非同义突变逃脱。同义突变不会影响这种相互作用，通常被认为是中性的。我们通过跟踪来自env基因C2-V5部分的纵向患者内数据中的同义突变来检验这一假设。我们发现，大多数同义变种都丢失了，尽管它们在病毒群体中经常出现频率很高，这表明病毒的成本。利用已发表的SHAPE(选择性2‘-羟基酰化分析)数据，我们发现破坏gp120可变环两侧RNA茎碱基对的同义突变比其他同义突变更有可能丢失：这些RNA发夹可能对HIV-1重要。计算模型表明，为了与数据一致，这个基因组区域的大部分同义突变需要是有害的，每天的成本约为0.002。这种针对同义替换的弱选择不会导致横截面数据的强大保守模式，但会显著减缓进化速度。我们的发现与RNA结构的大规模模式在功能上相关，而精确的碱基配对模式不相关的概念是一致的。
Intrapatient evolution of human immunodeficiency virus type 1 (HIV-1) is driven by the adaptive immune system resulting in rapid change of HIV-1 proteins. When cytotoxic CD8(+) T cells or neutralizing antibodies target a new epitope, the virus often escapes via nonsynonymous mutations that impair recognition. Synonymous mutations do not affect this interplay and are often assumed to be neutral. We test this assumption by tracking synonymous mutations in longitudinal intrapatient data from the C2-V5 part of the env gene. We find that most synonymous variants are lost even though they often reach high frequencies in the viral population, suggesting a cost to the virus. Using published data from SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) assays, we find that synonymous mutations that disrupt base pairs in RNA stems flanking the variable loops of gp120 are more likely to be lost than other synonymous changes: these RNA hairpins might be important for HIV-1. Computational modeling indicates that, to be consistent with the data, a large fraction of synonymous mutations in this genomic region need to be deleterious with a cost on the order of 0.002 per day. This weak selection against synonymous substitutions does not result in a strong pattern of conservation in cross-sectional data but slows down the rate of evolution considerably. Our findings are consistent with the notion that large-scale patterns of RNA structure are functionally relevant, whereas the precise base pairing pattern is not.