Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs
Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs
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DOI：
10.1093/molbev/msv167
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发表时间：
2015-11-01
影响因子：
10.7
通讯作者：
Bloom, Jesse D.
中科院分区：
文献类型：
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作者：
Doud, Michael B.;Ashenberg, Orr;Bloom, Jesse D.
随着时间的推移，进化会导致蛋白质序列发生变化。这些序列变化在多大程度上导致每个位点对每种氨基酸的潜在偏好发生变化，这是一个重要问题，对比较序列分析方法（例如分子系统发育学）具有影响。为了量化进化过程中位点特异性氨基酸偏好变化的程度，我们对人类流感核蛋白的两个同源物（氨基酸一致性为 94%）进行了深度突变扫描。我们发现，只有一小部分位点表现出氨基酸偏好的变化，超过了我们实验中的噪声。此外，即使在确实表现出可检测到的变化的位点中，相对于非同源蛋白质之间的差异，其幅度也往往很小。鉴于这些密切同源物之间的氨基酸偏好变化有限，我们测试了我们的测量是否可以为描述来自更多样化流感病毒的核蛋白进化的位点特异性替换模型提供信息。我们发现，在拟合人类、猪、马和禽流感核蛋白的系统发育方面，我们的实验所提供的位点特异性进化模型远远优于非位点特异性替代模型。结合两个同源物的实验数据改善了系统发育拟合，部分原因是在多个遗传背景下的测量更好地捕获了具有变化偏好的位点的氨基酸偏好的进化平均值。我们的结果表明，位点特异性氨基酸偏好足够保守，测量一种蛋白质的突变效应提供了可以改进附近同源物的定量进化模型的信息。
Evolution drives changes in a protein's sequence over time. The extent to which these changes in sequence lead to shifts in the underlying preference for each amino acid at each site is an important question with implications for comparative sequence-analysis methods, such as molecular phylogenetics. To quantify the extent that site-specific amino acid preferences shift during evolution, we performed deep mutational scanning on two homologs of human influenza nucleoprotein with 94% amino acid identity. We found that only a modest fraction of sites exhibited shifts in amino acid preferences that exceeded the noise in our experiments. Furthermore, even among sites that did exhibit detectable shifts, the magnitude tended to be small relative to differences between nonhomologous proteins. Given the limited change in amino acid preferences between these close homologs, we tested whether our measurements could inform site-specific substitution models that describe the evolution of nucleoproteins from more diverse influenza viruses. We found that site-specific evolutionary models informed by our experiments greatly outperformed nonsite-specific alternatives in fitting phylogenies of nucleoproteins from human, swine, equine, and avian influenza. Combining the experimental data from both homologs improved phylogenetic fit, partly because measurements in multiple genetic contexts better captured the evolutionary average of the amino acid preferences for sites with shifting preferences. Our results show that site-specific amino acid preferences are sufficiently conserved that measuring mutational effects in one protein provides information that can improve quantitative evolutionary modeling of nearby homologs.