Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico.
Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico.
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DOI：
10.1371/journal.pntd.0004263
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发表时间：
2015-12
影响因子：
3.8
通讯作者：
Black Iv WC
中科院分区：
文献类型：
--
作者：
Vera-Maloof FZ;Saavedra-Rodriguez K;Elizondo-Quiroga AE;Lozano-Fuentes S;Black Iv WC
埃及伊蚊（Aedes aegypti（L.）是登革热病毒的主要城市传播媒介。目前有25亿人面临感染和减少Ae的风险。埃及人是减少传播风险的最有效手段。拟除虫菊酯广泛用于控制成蚊，特别是在登革热爆发期间。拟除虫菊酯通过与结构域II和III的跨膜螺旋亚基6（S6）的界面形成的两个不同拟除虫菊酯受体位点相互作用，促进电压门控钠通道蛋白（VGSC）的活化并延长其活化。结构域II和III中的S6突变协同作用，使得双突变体比单独结构域中的突变体具有更高的拟除虫菊酯抗性。计算机模型预测了这两个结构域中突变之间的变构相互作用。在Ae。埃及伊蚊，2006年发现了结构域II的S6中的Ile 1，016突变，并发现其与墨西哥田间种群的拟除虫菊酯抗性相关。2010年，第二个突变，结构域III的S6中的Cys 1，534被发现，并且还发现与拟除虫菊酯抗性相关，并且与Ile 1，016的频率相关。对Ae中的Ile 1，016和Cys 1，534进行了连锁不平衡分析。从2000年至2012年在墨西哥收集的埃及伊蚊，以测试自然种群中域II和III中S6之间的统计关联。我们估计了1，016和1，534中四种双位点单倍型的频率：Val 1，016/Phe 1，534（敏感），Val 1，016/Cys 1，534，Ile 1，016/Phe 1，534和Ile 1，016/Cys 1，534（抗性）。敏感的Val 1，016/Phe 1，534单倍型从接近固定到灭绝，抗性的Ile 1，016/Cys 1，534单倍型在所有收集物中从接近零的频率增加到频率范围从0.5-0.9。Val 1，016/Cys 1，534单倍型在所有收集中增加，直到2008年，之后它开始随着Ile 1，016/Cys 1，534增加而下降。然而，Ile 1，016/Phe 1，534单倍型很少被检测到;在一个收集物中，其频率仅为0.09，随后下降。vgsc基因中的拟除虫菊酯抗性需要两个突变的连续进化。Ile 1，016/Phe 1，534单倍型似乎具有低适应性，表明Ile 1，016不太可能独立进化。相反，Cys 1,534突变首先进化，但只赋予低水平的抗性。结构域II的S6中的Ile 1，016然后从Val 1，016/Cys 1，534单倍型产生，并且由于双突变体赋予更高的拟除虫菊酯抗性而被快速选择。这种模式表明，在结构域II和III中的S6突变的频率的知识是重要的，以预测人口的潜力，发展kdr。具有高Val 1，016/Cys 1，534频率的易感人群具有高KDR进化风险，而没有任何突变的易感人群不太可能进化高水平的KDR，至少在10年内。不断使用拟除虫菊酯杀虫剂促使蚊子种群产生抗药性。在埃及伊蚊中，登革热、黄热病和基孔肯雅病毒的主要蚊子载体，拟除虫菊酯抗性主要与电压门控钠通道蛋白的突变有关。一个突变发生在密码子1，016，涉及缬氨酸被异亮氨酸取代（Ile 1，016），第二个突变位于密码子1，534的结构域III亚基6，用半胱氨酸取代苯丙氨酸（Cys 1，534）。在墨西哥，我们发现Cys 1,534存在于先前分析Ile 1016的相同蚊子集合中。在这项研究中，我们对2000-2012年墨西哥收藏的Ile 1，016和Cys 1，534进行了连锁不平衡分析。我们的分析表明，拟除虫菊酯抗性需要两个突变的顺序进化，并且Cys 1,534必须首先发生，并且似乎使Ile 1,016突变能够存活。
Worldwide the mosquito Aedes aegypti (L.) is the principal urban vector of dengue viruses. Currently 2.5 billion people are at risk for infection and reduction of Ae. aegypti populations is the most effective means to reduce the risk of transmission. Pyrethroids are used extensively for adult mosquito control, especially during dengue outbreaks. Pyrethroids promote activation and prolong the activation of the voltage gated sodium channel protein (VGSC) by interacting with two distinct pyrethroid receptor sites, formed by the interfaces of the transmembrane helix subunit 6 (S6) of domains II and III. Mutations of S6 in domains II and III synergize so that double mutants have higher pyrethroid resistance than mutants in either domain alone. Computer models predict an allosteric interaction between mutations in the two domains. In Ae. aegypti, a Ile1,016 mutation in the S6 of domain II was discovered in 2006 and found to be associated with pyrethroid resistance in field populations in Mexico. In 2010 a second mutation, Cys1,534 in the S6 of domain III was discovered and also found to be associated with pyrethroid resistance and correlated with the frequency of Ile1,016. A linkage disequilibrium analysis was performed on Ile1,016 and Cys1,534 in Ae. aegypti collected in Mexico from 2000–2012 to test for statistical associations between S6 in domains II and III in natural populations. We estimated the frequency of the four dilocus haplotypes in 1,016 and 1,534: Val1,016/Phe1,534 (susceptible), Val1,016/Cys1,534, Ile1,016/Phe1,534, and Ile1,016/Cys1,534 (resistant). The susceptible Val1,016/Phe1,534 haplotype went from near fixation to extinction and the resistant Ile1,016/Cys1,534 haplotype increased in all collections from a frequency close to zero to frequencies ranging from 0.5–0.9. The Val1,016/Cys1,534 haplotype increased in all collections until 2008 after which it began to decline as Ile1,016/Cys1,534 increased. However, the Ile1,016/Phe1,534 haplotype was rarely detected; it reached a frequency of only 0.09 in one collection and subsequently declined. Pyrethroid resistance in the vgsc gene requires the sequential evolution of two mutations. The Ile1,016/Phe1,534 haplotype appears to have low fitness suggesting that Ile1,016 was unlikely to have evolved independently. Instead the Cys1,534 mutation evolved first but conferred only a low level of resistance. Ile1,016 in S6 of domain II then arose from the Val1,016/Cys1,534 haplotype and was rapidly selected because double mutants confer higher pyrethroid resistance. This pattern suggests that knowledge of the frequencies of mutations in both S6 in domains II and III are important to predict the potential of a population to evolve kdr. Susceptible populations with high Val1,016/Cys1,534 frequencies are at high risk for kdr evolution, whereas susceptible populations without either mutation are less likely to evolve high levels of kdr, at least over a 10 year period. Constant use of pyrethroid insecticides has driven mosquito populations to develop resistance. In Aedes aegypti, the primary mosquito vector of dengue, yellow Fever, and chikungunya viruses, pyrethroid resistance is primarily associated with mutations in the voltage-gated sodium channel protein. One mutation occurs in codon 1,016 and involves a replacement of valine with isoleucine (Ile1, 016), and a second located in subunit 6 of domain III in codon 1,534, replaces phenylalanine with cysteine (Cys1,534). In Mexico, we found that Cys1,534 was present in the same mosquito collections that were previously analyzed for Ile1,016. In this study, we performed a linkage disequilibrium analysis on both Ile1,016 and Cys1,534 in Mexican collections from 2000–2012. Our analysis suggests that pyrethroid resistance requires the sequential evolution of the two mutations and that Cys1,534 must occur first and appears to enable the Ile1,016 mutation to survive.