淡色库蚊对拟除虫菊酯击倒抗性（kdr）的分子生态学特征的研究
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摘要
淡色库蚊(Culex pipiens pallens)是我国北方重要的媒介蚊种。随着化学杀
虫剂的广泛使用，蚊虫逐渐产生了抗药性，影响到杀虫剂的使用效果，需要加以
治理。抗药性机制是蚊虫抗药性监测和治理的基础，由于击倒抗性(Knockdown
resistance，kdr)体现了杀虫剂(拟除虫菊酯)与其靶标(钠通道)之间直接的作
用，对kdr的研究有助于更深入地揭示蚊虫抗药性产生和发展的过程。
本研究的主要结果如下：
1 通过抗药性品系选育、RT-PCR、基因序列分析等，初步明确了钠通道ⅡS6
节段L1014F型突变是淡色库蚊kdr产生的分子基础。
2 建立了检测钠通道基因突变的分子生物学方法(AS-PCR，ASO-PCR)。两种
检测方法符合率较高(总符合率为97． 2％)。序列测定结果证实两种方法具有较
高的特异性和敏感性。
3 分别使用溴氰菊酯和Es-生物丙烯菊酯对淡色库蚊进行逐代筛选，在实验室建
立了两种抗药性品系(分别为DEL品系和EBT品系)。
4 实验证实DEL品系对拟除虫菊酯抗药性发展为线性增长方式，EBT品系抗药
性发展为对数增长方式，前者抗药性发展速率显著快于后者。
5 通过增效实验、逐代kdr等位基因频率测定，提示两种品系的抗药性机理有
差别。随着抗药性发展(本实验至F8) ，DEL品系以P450介导的代谢抗性为主，
EBT品系以击倒抗性为主。
6 两种品系的抗性现实遗传力(H2) 比较接近，分别为0． 3804和0． 4192。但
DEL品系抗药性表型标准差(0． 42) 高于EBT品系(0． 19) 。表明EBT品系的抗
药性已处于相对稳定状态，继续施加筛选压抗药性变化不大；而DEL品系的抗
药性则处于不稳定状态，在筛选压力作用下抗药性会继续上升。
7统计分析表明，淡色库蚊实验室种群及自然种群对拟除虫菊酷，特别是对Es-
生物丙烯菊酷(抗药性以击倒抗性为主)的抗药性与七必.等位基因频率之间有显
著的正相关。提示拓介等位基因可作为淡色库蚊对拟除虫菊酷抗药性的分子遗传
标记，用于从分子水平上对蚊虫抗药性进行监测。同时也进一步明确了钠通道
L1014F型突变是淡色库蚊击倒抗性产生的分子基础。
8从686个重组质粒中筛选到8条淡色库蚊微卫星(Mierosatellite)DNA序列，
已在GenBank数据库中注册(Aeeession number:AY573280.AY573287)。用
其中的4个微卫星DNA作为分子遗传标记，研究淡色库蚊自然种群遗传分化对
无动月等位基因扩散的影响。结果表明各自然种群之间有较高的迁移率(平均刀功
值为6.11)，提示种群之间的基因流在一定程度上会影响种群拓介等位基因的扩
散，进而影响种群对拟除虫菊醋抗药性的发展。
Culex pipiens pollens is a principal vector mosquito in northern China. Because of intensive usage of pyrethroid in pest control, the resistance of Cx. pipiens pallens to pyrethroid developed rapidly and widely in many area of China. It's necessary to reveal the mechanism for surveillance and management of mosquito resistance. Knockdown resistance (kdr) is characterized by the direct interaction between pyrethroid and the target site of insects, which will be well done for displaying the occurrence and development of pyrethroid resistance . It was studied the molecular ecological characteristics of the pyrethroid resistance of lab and natural populations of Cx. pipiens pallens in this research, the results were as followed: 1. The substitution of L1014F in IIS6 segment of sodium channel is the molecular basis of kdr resistance of Cx pipiens pallens through resistance selection and on mosquito populations , RT-PCR, and sequence analysis.
2. Allele specific PCR (AS-PCR) protocol was developed for the estimation of kdr allele and another new approach polymerase chain reaction followed by labeled allele-specific oligonucleotide hybridization (ASO-PCR) was also developed for checking the accuracy of AS-PCR. The accordance percentage between two protocols was up to 97.2%. Sequencing alignment proved the two methods had both identity and sensitivity.
3. A deltamethrin resistance strain and an esbiothrin resistance strain was selected respectively on a natural population by deltamethrin and esbiothrin, called DEL strain and EBT strain.
4. It was found that the increasing style of resistance in DEL strain was linear but was logarithmic in EBT strain during selection. The increasing speed in DEL strain was faster than that in EBT strain.
5. It was metabolic resistance that acted an important role in DEL strain but was kdr resistance in EBT strain, based on PBO synergic experiments and kdr allele frequency detection.
6. The realized population heritability of resistance in DEL strain and EBT strain was 0.3804 and 0.4192 respectively. The conclusion of resistance balance state in DEL strain but conversely in EBT strain was based upon that phenotypic variance of DEL strain (0.42) was higher than EBT strain (0.19).
7. It was showed that the correlation of the prevalence of kdr frequency was significant with the pyrethroid resistance level in natural populations, which suggested that the kdr frequency can be a molecular marker served for resistance monitor on mosquito population.
8. It was revealed that there was higher migration frequency between compared populations (total Nm was 6.11 across all populations) based on the genetic differentiation among natural populations with the microsatellite loci isolated from the genome pool. It was implied that the gene flow among populations will affect the kdr gene expanding, which will bring on the change of the resistance development among population.
虫剂的广泛使用，蚊虫逐渐产生了抗药性，影响到杀虫剂的使用效果，需要加以
治理。抗药性机制是蚊虫抗药性监测和治理的基础，由于击倒抗性(Knockdown
resistance，kdr)体现了杀虫剂(拟除虫菊酯)与其靶标(钠通道)之间直接的作
用，对kdr的研究有助于更深入地揭示蚊虫抗药性产生和发展的过程。
本研究的主要结果如下：
1 通过抗药性品系选育、RT-PCR、基因序列分析等，初步明确了钠通道ⅡS6
节段L1014F型突变是淡色库蚊kdr产生的分子基础。
2 建立了检测钠通道基因突变的分子生物学方法(AS-PCR，ASO-PCR)。两种
检测方法符合率较高(总符合率为97． 2％)。序列测定结果证实两种方法具有较
高的特异性和敏感性。
3 分别使用溴氰菊酯和Es-生物丙烯菊酯对淡色库蚊进行逐代筛选，在实验室建
立了两种抗药性品系(分别为DEL品系和EBT品系)。
4 实验证实DEL品系对拟除虫菊酯抗药性发展为线性增长方式，EBT品系抗药
性发展为对数增长方式，前者抗药性发展速率显著快于后者。
5 通过增效实验、逐代kdr等位基因频率测定，提示两种品系的抗药性机理有
差别。随着抗药性发展(本实验至F8) ，DEL品系以P450介导的代谢抗性为主，
EBT品系以击倒抗性为主。
6 两种品系的抗性现实遗传力(H2) 比较接近，分别为0． 3804和0． 4192。但
DEL品系抗药性表型标准差(0． 42) 高于EBT品系(0． 19) 。表明EBT品系的抗
药性已处于相对稳定状态，继续施加筛选压抗药性变化不大；而DEL品系的抗
药性则处于不稳定状态，在筛选压力作用下抗药性会继续上升。
7统计分析表明，淡色库蚊实验室种群及自然种群对拟除虫菊酷，特别是对Es-
生物丙烯菊酷(抗药性以击倒抗性为主)的抗药性与七必.等位基因频率之间有显
著的正相关。提示拓介等位基因可作为淡色库蚊对拟除虫菊酷抗药性的分子遗传
标记，用于从分子水平上对蚊虫抗药性进行监测。同时也进一步明确了钠通道
L1014F型突变是淡色库蚊击倒抗性产生的分子基础。
8从686个重组质粒中筛选到8条淡色库蚊微卫星(Mierosatellite)DNA序列，
已在GenBank数据库中注册(Aeeession number:AY573280.AY573287)。用
其中的4个微卫星DNA作为分子遗传标记，研究淡色库蚊自然种群遗传分化对
无动月等位基因扩散的影响。结果表明各自然种群之间有较高的迁移率(平均刀功
值为6.11)，提示种群之间的基因流在一定程度上会影响种群拓介等位基因的扩
散，进而影响种群对拟除虫菊醋抗药性的发展。
Culex pipiens pollens is a principal vector mosquito in northern China. Because of intensive usage of pyrethroid in pest control, the resistance of Cx. pipiens pallens to pyrethroid developed rapidly and widely in many area of China. It's necessary to reveal the mechanism for surveillance and management of mosquito resistance. Knockdown resistance (kdr) is characterized by the direct interaction between pyrethroid and the target site of insects, which will be well done for displaying the occurrence and development of pyrethroid resistance . It was studied the molecular ecological characteristics of the pyrethroid resistance of lab and natural populations of Cx. pipiens pallens in this research, the results were as followed: 1. The substitution of L1014F in IIS6 segment of sodium channel is the molecular basis of kdr resistance of Cx pipiens pallens through resistance selection and on mosquito populations , RT-PCR, and sequence analysis.
2. Allele specific PCR (AS-PCR) protocol was developed for the estimation of kdr allele and another new approach polymerase chain reaction followed by labeled allele-specific oligonucleotide hybridization (ASO-PCR) was also developed for checking the accuracy of AS-PCR. The accordance percentage between two protocols was up to 97.2%. Sequencing alignment proved the two methods had both identity and sensitivity.
3. A deltamethrin resistance strain and an esbiothrin resistance strain was selected respectively on a natural population by deltamethrin and esbiothrin, called DEL strain and EBT strain.
4. It was found that the increasing style of resistance in DEL strain was linear but was logarithmic in EBT strain during selection. The increasing speed in DEL strain was faster than that in EBT strain.
5. It was metabolic resistance that acted an important role in DEL strain but was kdr resistance in EBT strain, based on PBO synergic experiments and kdr allele frequency detection.
6. The realized population heritability of resistance in DEL strain and EBT strain was 0.3804 and 0.4192 respectively. The conclusion of resistance balance state in DEL strain but conversely in EBT strain was based upon that phenotypic variance of DEL strain (0.42) was higher than EBT strain (0.19).
7. It was showed that the correlation of the prevalence of kdr frequency was significant with the pyrethroid resistance level in natural populations, which suggested that the kdr frequency can be a molecular marker served for resistance monitor on mosquito population.
8. It was revealed that there was higher migration frequency between compared populations (total Nm was 6.11 across all populations) based on the genetic differentiation among natural populations with the microsatellite loci isolated from the genome pool. It was implied that the gene flow among populations will affect the kdr gene expanding, which will bring on the change of the resistance development among population.
引文
陈文美．1986． 我国淡色库蚊种团对拟除虫菊酯杀虫剂抗性现状调查．医学动物防治，2(3) ： 8-11．
黄钢，周立强，刘继敏，等．1995． 河北省淡色库蚊对三种杀虫剂的抗性调查．中国媒介生物 学及控制杂志，6(4) ：313-314．
刘凤梅，甄天民，赵玉强，等．2000． 济宁市淡色库蚊抗药性发展趋势研究．中国媒介生物学 及控制杂志，11(1) ：30-31．
芮昌辉，赵勇，孟香清，译．1997． 害虫抗药性．北京：化学工业出版社，255-247．
余品红，张华勋，明桂珍，1997． 溴氰菊酯浸帐灭蚊六年后对中华按蚊抗药性的现场调查．寄 生虫与医学昆虫学报，4：59-60．
Brengues, C., N. J. Hawkes, F. Chandre et al. 2003 Pryethroid and DDT cross-resistance in Aedes aegypti is correlated with novel mutations in the voltage-gated sodium channel gene. Med. Vet. Entomol., 17: 87-94．
Busvine, J. R. 1951 Mechnism of resistance to insecticide in houseflies. Nature(Lond.), 168: 193-195． (未见原文) .
Clark J.M., Lee S.H., Kim H.J., et al. 2001 DNA-based genotyping techniques for the detection of point mutations associated with insecticide resistance in Colorado potato beetle Leptinotarsa decemlineata. Pest Manag. Sci. 57:968-974．
Curtis, C. F. et al. 1978 Ecol. Entomol., 3: 273-287． (未见原文)
Dong, K. 1997 A single amino acid change in the/para sodium channel protein is associated with knockdown-resistance (kdr)to pyrethroid insecticides in German cockroach. Insect Biochem. Mol. Biol, 27: 93-100．
Dong, Y. X. and Tang Z. H. 2000 Molecular mechanism of target resistance in the organophosphate and pyrethroid resistant Helicoverpa armigera, Entomol. Sinica, 7: 58-64．
Gibson, A. J., M. P. Osborn, H. F. Ross et al. 1998 An electrophysiological investigation of the
susceptible (Cooper) and resistant (kdr,super-kdr) strains of the adult housefly, Musca domestica L. Pestic.Sci., 23: 283-292．
Guerrero, F. D., R. C. Jamroz, D. Kammlah et al. 1997 Toxicological and molecular characterization of pyrethroid resistant horn flies, Haematobia irritans: identification of kdr and super-kdr point mutations. Insect Biochem. Mol. Biol, 27: 745-755．
Ingles, P. J., P. M. Adams, D. C. Knipple et al. 1997 Characterization of voltage-sensitive sodium channel gene coding sequences from insecticide-susceptible and knockdown-resistant house fly strains. Insect Biochem. Mol. Bioi, 27: R5．
Jamroz R.C., Guerrero F.D., Kammlah D.M. et al. 1998． Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans). Insect Biochem. Mol. Biol. 28:1031-1037．
Kaminker, J. S., C. M. Bergman, B. Kronmiller et al. 2002 The transposable elements of the Drosophila melanogaster euchromatin: a genomics perspective. Genome Bioi, 3: RESEARCH0084．
Knipple, D. C., K. E. Doyle, P. A. Marsella-Herrick et al. 1994 Tight genetic linkage between the kdr insecticide resistance trait and a voltage-sensitive sodium channel gene in the house fly. Proc. Natl Acad. Sci. U.S.A., 91: 2483-2487．
Kwok S., Kellogg D.E., Mckinney N., et al. 1989． Effects of primer-template mismatches on the polymerase chain reaction: Human immunodeficiency virus type 1 model studies. Nucleic Acids Res. 18:999-1005
Lee, S. H., J. B. Dunn, J. M. Clark et al. 1999 Molecular analysis of kdr-like resistance in a permethrin-resistant strain of Colorado potato beetle. Pestic. Biochem. Physiol, 63: 53-75．
Lee, S. H., K. S. Yoon, M. S. Williamson et al. 2000 Molecular analysis of kdr-like resistance in permethrin-resistant strains of head lice. Pediculus capitis. Pestic. Biochem. Physiol, 66: 130-143．
Liu Q., Thorland E.C., Heit J.A., et al. 1997． Overlapping PCR for Bidirectional PCR Amplification of Specific Alleles: A Rapid One-Tube Method for Simultaneously Differentiating Homozygotes and Heterozygotes. Genome Res. 7: 389-398．
Martinez-Torres, D., F. Chandre, M. S. Williamson et al. 1998 Molecular characterization of
pyrethroid knockdown resistance(kdr) in the major malaria vector Anopheles gambiae s. s. Insect Mol. Biol., 7: 179-184．
Martinez-Torres, D., S. P. Foster, L. M. Field et al. 1999a A sodium channel point mutation is associated with resistance to DDT and pyrethroid insecticides in the peach-potato aphid,
Myzus persicae(Sulzer) (Hemiptera:Aphididae). Insect Mol. Biol., 8: 339-346．
Martinez-Torres, D., C. Chevillon, A. BrunBarale et al. 1999b Voltage-dependent Na+ channels in pyrethroid-resistant Culex pipiens L mosquitoes. Pestic. Sci. , 55: 1012-1020．
McCaffery, A. R., J. W. Holloway and R. T. Gladwell 1995 Nerve insensitivity resistance to cypermethrin in larvae of the tobacco budworm Heliothis virescens from USA cotton field populations. Pestic. Sci., 44: 237-247．
Miyazaki, M., K. Ohyama, D. Y. Dunlap et al. 1996 Cloning and sequencing of the para-type sodium channel gene from susceptible and kdr-resistant German cockroaches(Blattella germanica) and housefly(Musca domestica). Mol. Gen. Genet., 252: 61-68．
Narahashi, T. 1996 Neuronal ion channels as the target sites of insecticides. Pharmacology & Toxicology, 78: 1-14．
Ranson, H., B. Jensen, J. M. Vulule et al. 2000 Identification of a point mutation in the voltage-gated sodium channel gene of Kenyan Anopheles gambiae associated with resistance to DDT and pyrethroids. Insect Mol. Biol., 9: 491-497．
Salgado, V. L., S. N. Irving and T. A. Miller 1983 Depolarization of motor nerve terminals by pyrethroids in susceptible and kdr-resiatant houseflies. Pestic. Biochem. Physiol., 20: 100-114．
Salgado, V. L., S. N. Irving and T. A. Miller 1983 The importance of nerve terminal depolarization in pyrethroid poisoning of insects. Pestic. Biochem. Physiol., 20: 169-182．
Schuler, T. H., D. Martinez-Torres, A. J. Thompson et al. 1998 Toxicological, electrophysiological, and molecular characterisation of knockdown resistance to pyrethroid insecticides in the diamondback moth. Plutellaxylostella(L.) Pestic. Biochem. Physiol., 59: 169-182．
Smith, T. J., S. H. Lee, P. J. Ingles et al. 1997 The L1014F point mutation in the house fly Vssc1 sodium channel confers knockdown resistance to pyrethroids. Insect Biochem. Mol. Biol, 27: 807-812．
Taylor, C. E. et al,1979 J. Econ. Entomol. ,105-109． (未见原文)
Vais, H., M. S. Williamson, S. J. Goodson et al. 2000a Activation of Drosophila sodium channels promotes modification by deltamethrin reductions in affinity caused by kdr mutation. J. Gen. Physiol. 115:305-318．
Williamson, M. S., D. Martinez-Torres, C. A. Hick et al. 1996 Identification of mutations in the housefly para-type sodium channel gene associated with knockdown resistance (kdr) to pyrethroid insecticides. Mol. Gen. Genet., 252: 51-60．
Warmke, J. W., R. A. G. Reenan, P. Wang et al. 1997 Functional expression of Drosophila para sodium channels: modulation by the membrane protein tipE and toxin pharmacology. J. Gen. Physiol. 110:119-133．
Weber, J.L. 1990 Informativeness of human (dC-dA)n.(dC-dA)n polymorphisms. Genomics, 7:524-530．
黄钢，周立强，刘继敏，等．1995． 河北省淡色库蚊对三种杀虫剂的抗性调查．中国媒介生物 学及控制杂志，6(4) ：313-314．
刘凤梅，甄天民，赵玉强，等．2000． 济宁市淡色库蚊抗药性发展趋势研究．中国媒介生物学 及控制杂志，11(1) ：30-31．
芮昌辉，赵勇，孟香清，译．1997． 害虫抗药性．北京：化学工业出版社，255-247．
余品红，张华勋，明桂珍，1997． 溴氰菊酯浸帐灭蚊六年后对中华按蚊抗药性的现场调查．寄 生虫与医学昆虫学报，4：59-60．
Brengues, C., N. J. Hawkes, F. Chandre et al. 2003 Pryethroid and DDT cross-resistance in Aedes aegypti is correlated with novel mutations in the voltage-gated sodium channel gene. Med. Vet. Entomol., 17: 87-94．
Busvine, J. R. 1951 Mechnism of resistance to insecticide in houseflies. Nature(Lond.), 168: 193-195． (未见原文) .
Clark J.M., Lee S.H., Kim H.J., et al. 2001 DNA-based genotyping techniques for the detection of point mutations associated with insecticide resistance in Colorado potato beetle Leptinotarsa decemlineata. Pest Manag. Sci. 57:968-974．
Curtis, C. F. et al. 1978 Ecol. Entomol., 3: 273-287． (未见原文)
Dong, K. 1997 A single amino acid change in the/para sodium channel protein is associated with knockdown-resistance (kdr)to pyrethroid insecticides in German cockroach. Insect Biochem. Mol. Biol, 27: 93-100．
Dong, Y. X. and Tang Z. H. 2000 Molecular mechanism of target resistance in the organophosphate and pyrethroid resistant Helicoverpa armigera, Entomol. Sinica, 7: 58-64．
Gibson, A. J., M. P. Osborn, H. F. Ross et al. 1998 An electrophysiological investigation of the
susceptible (Cooper) and resistant (kdr,super-kdr) strains of the adult housefly, Musca domestica L. Pestic.Sci., 23: 283-292．
Guerrero, F. D., R. C. Jamroz, D. Kammlah et al. 1997 Toxicological and molecular characterization of pyrethroid resistant horn flies, Haematobia irritans: identification of kdr and super-kdr point mutations. Insect Biochem. Mol. Biol, 27: 745-755．
Ingles, P. J., P. M. Adams, D. C. Knipple et al. 1997 Characterization of voltage-sensitive sodium channel gene coding sequences from insecticide-susceptible and knockdown-resistant house fly strains. Insect Biochem. Mol. Bioi, 27: R5．
Jamroz R.C., Guerrero F.D., Kammlah D.M. et al. 1998． Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans). Insect Biochem. Mol. Biol. 28:1031-1037．
Kaminker, J. S., C. M. Bergman, B. Kronmiller et al. 2002 The transposable elements of the Drosophila melanogaster euchromatin: a genomics perspective. Genome Bioi, 3: RESEARCH0084．
Knipple, D. C., K. E. Doyle, P. A. Marsella-Herrick et al. 1994 Tight genetic linkage between the kdr insecticide resistance trait and a voltage-sensitive sodium channel gene in the house fly. Proc. Natl Acad. Sci. U.S.A., 91: 2483-2487．
Kwok S., Kellogg D.E., Mckinney N., et al. 1989． Effects of primer-template mismatches on the polymerase chain reaction: Human immunodeficiency virus type 1 model studies. Nucleic Acids Res. 18:999-1005
Lee, S. H., J. B. Dunn, J. M. Clark et al. 1999 Molecular analysis of kdr-like resistance in a permethrin-resistant strain of Colorado potato beetle. Pestic. Biochem. Physiol, 63: 53-75．
Lee, S. H., K. S. Yoon, M. S. Williamson et al. 2000 Molecular analysis of kdr-like resistance in permethrin-resistant strains of head lice. Pediculus capitis. Pestic. Biochem. Physiol, 66: 130-143．
Liu Q., Thorland E.C., Heit J.A., et al. 1997． Overlapping PCR for Bidirectional PCR Amplification of Specific Alleles: A Rapid One-Tube Method for Simultaneously Differentiating Homozygotes and Heterozygotes. Genome Res. 7: 389-398．
Martinez-Torres, D., F. Chandre, M. S. Williamson et al. 1998 Molecular characterization of
pyrethroid knockdown resistance(kdr) in the major malaria vector Anopheles gambiae s. s. Insect Mol. Biol., 7: 179-184．
Martinez-Torres, D., S. P. Foster, L. M. Field et al. 1999a A sodium channel point mutation is associated with resistance to DDT and pyrethroid insecticides in the peach-potato aphid,
Myzus persicae(Sulzer) (Hemiptera:Aphididae). Insect Mol. Biol., 8: 339-346．
Martinez-Torres, D., C. Chevillon, A. BrunBarale et al. 1999b Voltage-dependent Na+ channels in pyrethroid-resistant Culex pipiens L mosquitoes. Pestic. Sci. , 55: 1012-1020．
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