Bull. Org. mond. Sante 1963, 29, Suppl., pp. 77-87 Bull. Wld Hlth Org. 19329Sup.p.778

Genetical Aspects of Insecticide Resistance

R. MILANI 1

Studies on the mode of inheritance of insecticide resistance have been making rapid progress over the last few years and now cover some twenty-two species and about seventy different strains. These studies include not only the inheritance of particular forms of resistance but also the genetical aspects of cross-resistance and biochemical properties causing or related to resistance. The author reviews 27 instances of resistance recently subjected to genetic analysis; all butfour were considered to be examples ofmonofactorial inheritance. The use of genetic markers has made it possible in some instances to map the genes responsible for resistance and has proved useful in the study ofthe genetic mecha- nisms involved in cross-resistance andmultiple resistance. Correlations have been established between resistance, genetic constitution, and the activity of certain enzymes. Experiments are described illustrating the technique of crossing genetically marked resistant strains with susceptible strains in the study of the mode of inheritance of resistance to DDT and dieldrin.

When I reviewed this subject in 1960 at the resistance genetically analysed between 1960 and Eleventh International Congress of Entomology 1962 only 6 are to DDT, 13 to dieldrin, one to endrin (Milani, 1962), the data available on the inheritance (in the boll weevil), and 7 to organophosphorus of resistance related to some 14 species and more compounds (diazinon, malathion, parathion). than 50 independent strains. Now, after little more than two years, it is possible to add at least 8 INHERITANCE OF PARTICULAR FORMS OF RESISTANCE more species-more than one third of the material The great majority of the cases analysed have now available-and about 20 new strains (the real proved, or strongly suggested, that it is possible independence of strains is often difficult to establish) to isolate individual factors causing resistance. It (see table). would be an overstatement to claim that these are The species to be added to the previous list are: all instances of monofactorial inheritance, because Anopheles albimanus, A. stephensi, A. quadrima- the possibility of isolating a main factor with a culatus, Culex tarsalis, Cimex lectularius, Pediculus specific action does not necessarily exclude the humanus humanus, Chrysomyia putoria, Tethra- presence of other ancillary ones. Several years ago nychus pacificus, Anthonomus grandis. The new I criticized the reluctance of many workers to additions indicate that the genetical approach is accept the evidence that single genes can cause being extended to organisms not previously in- physiological differences large enough to bring cluded in studies of this type. about resistance (Milani, 1954). During the inter- Genetical studies on resistance now seem to vening years evidence in favour of this interpretation concentrate mainly on three lines of approach: has been accumulating and it has become obvious (1) inheritance of particular fo rms of resistance; that resistance levels sufficient to give full protection (2) genetical aspects of cross-resistance or to insects very often have a simple genetic basis. multiple resistance; However, it is felt now that categorical assertions (3) genetics of biochemical properties causing or have occasionally been based on rather unsatis- related to resistance. factory experiments. Comments on these aspects of inheritance are included in the general considera- The interest is shifting from DDT to other forms tions in the above-mentioned review (Milani, 1962). of insecticide resistance. Out of 27 instances of A detailed analysis of each of the 27 instances of 1 Acting Director, Institute of Zoology, University of resistance referred to above seems unnecessary for Pavia, Italy. the purpose of the present paper. The significant

1319 -77- 78 R. MILANI

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data are collected in the accompanying table; where F2 flies showed only intermediate and high information followed by a question mark or written resistance, without segregation of susceptibility. between brackets has been inferred from the pub- lished descriptions. For the sake of uniformity, the GENETIC MAPPING OF GENES FOR RESISTANCE term " monofactorial " has been used as a convenient synonym for "single gene" and " simple inheri- In the housefly a gene for DDT-resistance (kdr) tance ". is linked with several good genetic markers, one of Resistance is indicated as recessive only twice; which is brown body (Milani & Travaglino, 1957). in both instances the insect was a multiresistant To the same linkage group belong the factors for mosquito and the insecticide was DDT, but this DDT resistance of at least three different strains, was not the selecting factor primarily acting in the two of which are certainly different from kdr. This field. linkage group can occasionally follow male-limited The outstanding feature of resistance to dieldrin inheritance, as has been clearly shown by using (or to endrin) is that it regularly reaches inter- morphological genetic markers; male-limited in- mediate levels in the heterozygotes (with two heritance of a low-level DDT-resistance has been exceptions), whereas resistance to organophosphorus described by Kerr (1961). The gene a (aliesterase compounds tends to be dominant or nearly so. activity) is located on the fifth chromosome, like The low level of male-limited DDT-resistance the mutants aristapedia and carmine (ar cm) reported by Kerr (1961) in a strain of housefly has (Franco & Oppenoorth, 1962). Resistance to been entered in the table as " (intermediate?) ", dieldrin recombines freely with the second and the on the assumption that it may depend on obligatory fifth chromosomes, and is not sex-linked. heterozygosis. This assumption is based upon the In Drosophila two genes for resistance control actual LD50 and upon analogy with other genetic well-known properties, described in the section on factors also showing male-limitation, all of which the genetics of biochemical properties related to have an allele in the second chromosome (Sullivan, resistance. 1958, 1961; Franco et al., 1962). The gene for DDT-resistance found in a European strain of the German cockroach is linked with While 23 out of the 27 instances listed in the table balloon wings and is independent of orange body are examples of simple inheritance, in the remaining (Cochran & Ross, 1962). four instances resistance appears to be due to (a) Dieldrin-resistance and DDT-resistance in Aedes two of additive a main factor plus modifier, (b) pairs are factors on the second and non- aegypti controlled by alleles, (c) multifactorial inheritance, (d) chromosome, giving 25 % cross-overs with the segregation in F2. marker yellow larvae (Khan & Brown, 1961). A main factor plus modifiers seems to be respons- ible for dieldrin resistance in a strain of housefly carrying several genetic markers, and therefore GENETIC ASPECTS OF CROSS-RESISTANCE necessarily of mixed and mainly unknown origin. AND MULTIPLE RESISTANCE Two pairs of additive factors have been assumed Resistance to more than one toxicant can depend by Harris et al. (1961) in order to explain the on a single basic property or on the co-existence in inheritance of malathion resistance in a strain of the same strain of distinct defence mechanisms. The houseflies of fairly recent colonization. The pecu- term cross-resistance is used when a single pro- liarity of this strain is that when crossed with sus- perty ensures cross-protection to various toxicants; ceptible flies it gives in F1 and in F2 both susceptible multiple resistance refers to the co-existence of and resistant flies in equal proportion. The hypo- different defence mechanisms in the same strain. thesis that this is due to two pairs of additive alleles Resistance to DDT and to malathion appears to is ingenious. be caused by separate factors in a strain of Culex No segregation of either susceptibility or resistance tarsalis selected with malathion; DDT-resistance has been observed by Abdullah (1961) when examin- was found to be recessive in two strains, whereas ing dieldrin resistance in the R (Savannah laboratory) malathion-resistance was found to be dominant strain of houseflies. This contrasts with the findings (Plapp et al., 1961). These results agree with those of other authors, who have used different strains, of Matsumura & Brown (1961) on the same species but it agrees partially with the results of one of our (see also the section on the genetics of biochemical experiments on the inheritance of dieldrin-resistance properties related to resistance). 80 R. MILANI

The components of a multi-resistant strain of normal ffies, so that the toxicities of PTU and PU Anopheles albimanus from El Salvador can be show respectively negative and positive correlation separated into two main entities; dieldrin-resistance with those of DDT, BHC and parathion in flies is dependent on a single, semi-dominant, genetic carrying either the allele for resistance or the normal factor, while DDT-resistance is dependent on allele at locus 65 on the second chromosome; a single recessive genetic factor. Both forms of however both PTU and PU show positive correlation resistance conform to the rule of showing cross- with the toxicity of nicotine sulfate controlled by resistance to cyclodiene chlorinated hydrocarbons the alleles at locus 50 on the third chromosome, and to gamma-BHC or to DDT analogues respec- resistance being dominant. Selection experiments tively (Davidson & Jackson, 1961a); resistance has support the hypothesis that these correlations are been shown to extend to both larval and adult stages. due to the activities of the genes mentioned, and are The strain of housefly routinely used as a thus true examples of pleiotropy (cross-activity) genetically-marked DDT-resistant strain in our (Ogita, 1961a). laboratory (strain bwb kdr) has been found to be The p-halogenated and o-chloro-derivatives of also resistant to dieldrin. These are two separate both PTU and PU retain the same toxicity correla- forms of resistance, and will be examined in detail tions that characterize the parent compounds, but later. the p-derivatives are more toxic; other para- or Resistance in Drosophila melanogaster has re- N-substituted derivatives do not retain the activity peatedly been shown to extend to unrelated chemi- correlation with DDT, BHC and parathion, but cals, even when caused by well identified genes. most of them retain the positive correlation with Additional evidence has been given by Kikkawa nicotine sulfate (Ogita, 1961b). In Drosophila (1961), who has shown that resistance to parathion melanogaster, one of the factors on the third chromo- is caused mainly by a dominant gene located at locus some seems to control aliesterase activity; flies 64.5 on the second chromosome. All parathion- differing in aliesterase activity have quite similar resistant populations of D. melanogaster have this cholinesterase activity; aliesterase and cholinesterase gene, which plays an important role in cross-resist- also have a different distribution in the body and ance to other organophosphorus compounds, to seem to be under different genetic control. Crosses DDT, and to BHC. The same gene also causes high between flies of high and low aliesterase activity sensitivity to phenylthiourea. give F1 flies of intermediate activity (Ogita, 1961c). Recent work on Aedes aegypti has made it possible Cholinesterase and aliesterase activity do not to localize a gene for dieldrin resistance, closely show any correlation with malathion resistance in linked with that for DDT-resistance (Brown, Culex tarsalis, but high cholinesterase and DDT- A. W. A., personal communication). The close resistance are jointly inherited (Plapp et al., 1961). linkage between these two loci explains how these A similarly persisting association was shown in two forms of resistance can respond either singly or C. tarsalis between malathion resistance and the jointly to pressure from one toxicant. carboxyesterase in the cellular mitochondrial frac- In addition to these examples ofmultiple resistance tion, which was 5-6 times greater in resistant than and cross-resistance, it seems worth mentioning that in normal mosquitos (Matsumura & Brown, 1961); selection pressure with nicotine sulfate has increased the resistant strain (Fresno) originally had more the heat resistance of Drosophila melanogaster phosphatase, a property not related to malathion (Ogaki, 1961); this has been interpreted as a form resistance and lost in the course of the crossing of vigour tolerance due to pleiotropic action of experiments; no difference in aliesterase was observed the same gene primarily recognized as causing between susceptible and resistant mosquitos, in nicotine resistance. agreement with the findings of Plapp and others. Aliesterase activity in the housefly has been found GENETICS OF BIOCHEMICAL PROPERTIES CAUSING to be correlated with the genetic constitution at a RESISTANCE OR RELATED TO RESISTANCE specific locus (a), being high in normal, intermediate The toxicity of phenylthiourea (PTU) is especially in heterozygous and low in homozygous aa flies; the great for Drosophila melanogaster showing resistance low aliesterase activity is generally associated with to DDT, BHC and parathion caused by the dominant resistance to organophosphorus compounds (Oppe- gene at locus 65 on chromosome 2. The same ffies noorth & Van Asperen, 1960). Resistance to diazinon are also more resistant to phenylurea (PU) than by tarsal contact in susceptible straiir carrying the GENETICAL ASPECTS OF INSECTICIDE RESISTANCE

markers carmine or aristapedia has been traced Omdurman (reverted from a dieldrin-resistant to a locus on the fifth chromosome; during these strain) LD50= 0.045 ,ug per female fly. experiments a susceptible strain of housefly with low aliesterase activity was also discovered (Franco The toxicological tests were done by topical appli- & Oppenoorth, 1962). Resistance and susceptibility cation of acetone solutions either of dieldrin or of to organophosphorus compounds have now been DDT (1 ,IlIfly) and by tarsal contact with filter paper found associated with either low or high aliesterase surfaces impregnated with Risella oil solutions of activity; the most common associations, however, DDT, to measure knock-down rates. are resistance with low activity, susceptibility with Flies were tested when 4-6 (usually 5) days old. high activity. It is not yet clear to what extent The ffies were bred from eggs collected from linkage or pleiotropy may correspond with the small mass cultures of 10 pairs each. Each batch observed facts. of flies to be tested was divided into three main It has recently been shown (Brown, A. W. A., samples, in order that all types of toxicological personal communication) that larvae of resistant test could be run at the same time on flies from the Aedes aegypti surviving dieldrin treatment show same batch. increased resistance when fully grown. This is the Crosses included reciprocal parental crosses, first evidence of post-adaptation in resistance; it back-crosses of F1 hybrids to the parent strains, certainly operates with resistant mosquitos, but not and inbreeding of F1 flies to obtain the F2 genera- with susceptible ones. Further research will show tions. if it also operates with heterozygotes. This question The linkage between bwb and kdr allows nearly has been mentioned here because of its bearing on 48 % interchange in the heterozygous females, but the genetic control of potentialities for enzymatic only a small percentage in males, varying according adaptation. to the strain. It follows that in order to detect linkage relations the most informative cross is the THE USE OF GENETIC MARKERS FOR THE STUDY OF back-cross of heterozygous males to double recessive MULTIPLE RESISTANCE females, as briefly reported below.

A screening for dieldrin resistance of the housefly Inheritance knock-down resistance to DDT strains kept in the Institute of Zoology of the of University of Pavia has revealed a dieldrin resistance The inheritance of knock-down resistance was in not traceable to any intentional or accidental full agreement with that expected from previous selective pressure with this toxicant. results (Milani & Travaglino, 1957). The hybrids Special attention was given to the strain bwb kdr, homozygous for the gene kdr causing DDT- ( and S + + in Fig. 1) are more tolerant than resistance, and homogeneously resistant to dieldrin. This strain was submitted to genetic analysis, aimed susceptible flies (9 and 3 + +) but knock-down at detecting: (a) the mode of inheritance of its dieldrin re- proceeds rapidly; a wide gap divides the most sistance; tolerant F1 hybrids from the less resistant homo- (b) the genetic relation between bwb kdr DDT-resistance, in dieldrin resistance and the marker bwb (brown body); zygotes (males only) ( bwbb kdr Fig. 1). (c) the impact of the testing method on the genetic inferences; The progeny of the heterozygous males back- crossed to bwb kdr females (F1 R1 (&S heter.)) are (d) the influence of the susceptible strains used on flies of normal colour or brown body, in equal pro- the results of crosses. portion in both sexes. With a few exceptions among The strains used were: the females, the ffies of normal colour had the same bwb kdr (laboratory, resistant to DDT and knock-down rate as the F1 flies and the brown body dieldrin): LD50 (dieldrin) = 5 ,ug per female flies were resistant (Fig. 2). It is, in fact, to be fly; expected that normal flies would be heterozygous S (Oppenoorth): LDr0 (dieldrin) = 0.04 ,g per and brown flies homozygous resistant, apart from female fly; a few cross-overs. 82 R. MILANI

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Inheritance ofkill resistance to DDT Influence of the susceptible strain used on the results of crosses The inheritance of kill resistance, as assessed by topical application of scalar doses, has given similar The reciprocal crosses between Omdurman (a results (Fig. 3). It should be noted, however, that reverted susceptible strain) and bwb kdr flies gave the regression lines of the hybrids are close to those male progeny only when the parental males were of the resistant flies and a wide gap divides them Omdurman flies, but when they were bwb kdr flies the from the susceptible ones. The difference in toler- progeny had a normal sex ratio. The toxicological ance between males and females is most marked in tests with dieldrin indicated that the F1 hybrids were the hybrids, with reciprocal crosses showing similar intermediate between the parental strains, with characteristics. marked sexual differences (LD60 = 0.9 ,tg for The progeny of the F1 males backcrossed to females; 0.4 ,ug for males). bwb kdr females again shows that the flies of normal In the next generation, various irregularities in colour, expected to be heterozygous, gave a response the sex-ratio and in the class frequencies of mendelian similar to that of the F1 generation, while the bwb segregation of bwb were noted. The responses to flies were resistant (Fig. 4). treatment were equally complex, and an indication of sex linkage or of linkage with bwb was found only Inheritance ofdieldrin resistance in occasional offspring; there were no susceptible F2 males. The responses to dieldrin treatment are shown In contrast to the results previously described, in Fig. 5 and 6. The F1 flies ( bw kd A) are the results of the crosses between the strains Omdur- man and bwb kdr showed greater complexity, with intermediate between susceptible and resistant. The irregularities in the sex ratio and/or the segregation sexual difference is maximal among susceptible, of bwb. The available evidence does not permit minimal among heterozygous flies. discrimination between complexity in the overall The tolerance of the flies obtained from the test genetic background of these hydrids and complexity cross (F1 R1 ( 3' heter.)) spread over the ranges of in the genetic control of dieldrin resistance. heterozygous and resistant flies, without relevant differences between flies of different colour; the Miscellaneous experiments on the inheritance of sexual differences are greater than among the F1 or dieldrin resistance in the housefly the resistant ffies. The highest dose used for resistant flies was not tried on the F1 R1 flies; the trend of A second strain of housefly carrying the genetic the regression lines suggests that these flies might markers ar cm on the fifth chromosome was found reach resistance levels higher than those found in resistant to dieldrin. This strain has recently been the original resistant strain. The flies obtained developed from several unrelated strains; its dieldrin from crosses are more vigorous than those of the resistance is not due to deliberate selection or strain bwb kdr, and this might account for some of planned crosses, and is of similar degree to, but the differences. slightly higher than, that of strain bwb kdr. The results of these experiments clearly indicate The results of crosses between this resistant strain that the linkage between the gene for DDT-resistance (ar cm) and the susceptible strain S (Oppenoorth) (kdr) and the marker bwb shows up whatever are generally in agreement with the hypotheses toxicological test is adopted. of simple inheritance and of free recombination The response to dieldrin treatment is similar for between resistance and the fifth chromosome normal and for bwb flies obtained from the test markers. cross, indicating no linkage between dieldrin Crosses between the two resistant strains, bwb kdr resistance and the marker gene. and ar cm, gave a majority of F1 flies slightly more Tests on flies from other crosses also gave results resistant than the parent strains, while a minority of in full agreement with the hypothesis that there is some 10% were more susceptible. The resistance a linkage between DDT-resistance and the gene levels were comparable to those of the " inter- bwb, whereas dieldrin-resistance is independent of mediate " heterozygotes obtained from crosses bwb. Moreover, the general evidence suggests simple between resistant and susceptible strains. The F2 inheritance for both forms of resistance. flies showed a marked segregation of " inter- GENETICAL ASPECTS OF INSECTICIDE RESISTANCE 85

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mediates" in both sexes; a few susceptible males These results suggest that the factors for dieldrin were also present. Some crosses gave indications of resistance present in the two strains are different, interactions between the sex chromosome and the and that they are additive and subject to recombina- fifth chromosome. tion.

Xrku~SUM t L'etude de l'heredite de la resistance aux insec- insecticides, deja connue, a et verifi&e sur une souche ticides s'etend actuellement a quelque 20 especes et a 70 de drosophile resistante au parathion, isolee apres trai- souches. tement par les rayons X. Les genes de resistance au DDT et a la dieldrine chez Chez la drosophile, la correlation negative entre la Aedes aegypti ont ete localises de faron precise dans sensibilite 'a la phenylthiouree et la resistance croisee leurs groupes de linkage. Chez la mouche domestique, siegeant au locus 65 du chromosome II s'etend aux deri- on a decouvert les groupes de linkage du gene entrainant ves p-halog6n6s et o-chlores; elle se perd chez d'autres la resistance aux organophosphores. On a prouve, d'autre derives p- ou N- substitues. L'activite aliesterasique est part, la libre recombinaison de facteurs de resistance a contr6l6e par un facteur du troisieme chromosome, inde- la dieldrine avec les chromosomes sexuels, et celle de pendamment de celle de la cholinesterase. deux autosomes. Chez Culex tarsalis, I'activite cholinesterasique est L'independance, sur le plan genetique, de la resistance heritee parallelement a la resistance au DDT, mais, au DDT et a la dieldrine a e demontree chez des souches comme F'activite aliesterasique, independamment de la multi-resistantes d'A. aegypti et de Musca domestica. resistance au malathion. L'activite carboxylesterasique L'hypothese d'une resistance croisee a des substances et la resistance au malathion sont heritees ensemble. chimiquement apparentees - DDT et ses derives, derives A la fin de l'article, l'auteur d6montre le r6le des du cyclodiene et HCH - a et confirmee par les etudes marqueurs genetiques dans 1'etude de la resistance aux genetiques. L'absence de relation entre la sensibilite a la insecticides, en decomposant la multi-resistance d'une phenylthiouree et la resistance au DDT et a d'autres souche de mouche domestique en ses divers facteurs.

REFERENCES Abdullah, M. (1961) J. Hered., 52, 179 Khan, N. H. & Brown, A. W. A. (1961) Bull. Wld Hlth Andres, L. A. & Prout, T. (1960) J. econ. Ent., 53, Org., 24, 519 626 Kikkawa, H. (1961) A.R. Fac. Sci. Osaka, 9, 1 Bragassa, C. B. & Brazzel, J. R. (1961) J. econ. Ent., 54, Matsumura, F. & Brown, A. W. A. (1961) J. econ. Ent., 311 54, 1176 Busvine, J. R. & Bell, J. D. (1962) In: Information Circular Milani, R. (1954) Riv. Parassit., 15, 513 on Insecticide Resistance, No. 35, p. 12 (unpublished Milani, R. (1962) The genetics of resistance. In: Ver- WHO report) handlungen des XI. internationalen Kongresses fur Cochran, D. G. & Ross, M. H. (1962) Bull. Wld Hlth Entomologie, Wien, 1960, vol. 3, p. 232 Org., 27, 257 Milani, R. & Travaglino, A. (1957) Riv. Parassit., 18, 199 Davidson, G. & Hamon, J. (1962) In: Information Ogaki, M. (1961) In: Information Circular on Insecticide Circular on Insecticide Resistance, No. 35, p. 6 (un- Resistance, No. 32, p. 6 (unpublished WHO report) published WHO report) Ogita, Z. (1961a) Botyu-Kagaku, 26, 7 Davidson, G. & Jackson, C. E. (1961a) Nature (Lond.), Ogita, Z. (1961b) Botyu-Kagaku, 26, 18 190, 364 Ogita, Z. (1961c) Botyu-Kagaku, 26, 93 Davidson, G. & Jackson, C. E. (1961b) Bull. Wld Hlth Oppenoorth, F. J. & Van Asperen, K. (1960) Science, Org., 25, 209 132, 298 Franco, M. G., Lanna, T. M. & Milani, R. (1962) Atti Plapp, F. W., Borgard, D. E., Darrow, D. J. & Eddy, Ass. Genet. Ital., 7, 198 G. W. (1961) Mosquito News, 21, 315 Franco, M. G. & Oppenoorth, F. J. (1962) Ent. exp. Rozeboom, L. E. & Hobbs, J. (1960) Bull. Wid Hlth appl. (Amst.), 5, 119 Org., 22, 587 Guneidy, A. M. & Busvine, J. R. (1962) In: Information Rozeboom, L. E. & Johnson, R. (1961) Amer. J. trop. Circular on Insecticide Resistance, No. 35, p. 9 (un- Med. Hyg., 10, 775 published WHO report) Sullivan, R. L. (1958) Sex limitation ofseveral loci in the Harris, R. L., Wearden, S. & Roan, C. C. (1961) J. econ. housefly. In: Proceedings of the Tenth International Ent., 54, 40 Congress of Genetics, vol. 2, p. 282 Kerr, R. W. (1961) Aust. J. Biol. Sci., 14, 605 Sullivan, R. L. (1961) J. Hered., 52, 283