Journal of Heredity 2003:94(3)
© 2003 The American Genetic Association 94:227-235
Genetic Traits of the Mosquito Anopheles gambiae: Red Stripe, frizzled, and homochromy1
From the Centers for Disease Control and Prevention, Division of Parasitic Diseases, 4770 Buford Highway, Atlanta, GA 30341 (Benedict, McNitt, and Collins). Current addresses: FAO/IAEA Agriculture and Biotechnology Laboratory, IAEA Laboratories A-2444, Seibersdorf, Austria (Benedict); UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 90403 (McNitt); and the Department of Biology, 317 Galvin Life Sci. Building, University of Notre Dame, Notre Dame, IN 46556 (Collins).
Address correspondence to M. Q. Benedict at the address above, or e-mail: MBenedict{at}cdc.gov.
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Abstract |
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The expression, inheritance, and linkage relationships of three genetic traits were studied in the malaria vector Anopheles gambiae. Red stripe (Rs) is a common phenotypic polymorphism in numerous A. gambiae populations, whereas frizzled (f) and homochromy1 (hom1) were isolated from 60Co-irradiated mosquitoes. Red stripe appears as a diffuse stripe of pigment on the dorsum of larvae and pupae and is variable in expressivity and penetrance. Our data demonstrate that Red stripe results from a heterozygous collarless genotype (i.e., c+ c, chromosome 2) and is essentially sex-limited to females. frizzled is a sex-linked recessive semi-lethal identified by deformed lateral larval setae; its lethality manifests as low rates of adult emergence and brief adult survival. frizzled is located on the X chromosome between pink eye and Mosaic, 3 cM from Mosaic and approximately 12 cM from pink eye. Finally, the mutation homochromy1 (hom1) is on chromosome 2 and causes a recessive phenotype that prevents normal darkening of larvae when reared in a black container. Unlike mutants with this characteristic described thus far, the eye color of hom1 mutants is normal. We determined that hom1 is located between Dieldrin resistance and collarless, approximately 3 cM from the latter. We discuss the possibility of differences in male and female recombination values and the range of values that have been observed in testcrosses for chromosome 2 markers.
The mosquito Anopheles gambiae is the primary vector of malaria in sub-Saharan Africa and is becoming a model organism for genetic and molecular biology studies, many of whose goal is to interfere with its ability to transmit disease (Collins and Besansky 1994; Crampton et al. 1990; Gwadz 1994). In spite of the fact that its genome has been sequenced (Holt et al. 2002), published morphological mutants extant for genetic manipulation and mapping in A. gambiae number only seven: red eye (Beard et al. 1994), pink eye (Benedict et al. 1996a), white (Benedict et al. 1996a; Besansky et al. 1995; Mason 1967), collarless (Mason 1967), Dieldrin resistance (Davidson 1956; Davidson and Hamon 1962), Mosaic (Benedict et al. 2000), and black (Benedict et al. 1999).
Numerous other mutants have been described in anophelines, although even the most recent reviews are now somewhat dated (Kitzmiller 1976; Kitzmiller and Mason 1967; Narang and Seawright 1982), and almost all stocks have been lost or discarded. Most of A. gambiae are currently available at the Malaria Research and Reference Resource Center (MR4, www.malaria.mr4.org).
A red stripe phenotype, which was apparent in larvae and pupae, was described by Mason (1967) in Anopheles arabiensis (a sibling species of A. gambiae), but he was uncertain of the pattern of inheritance. A similar phenotype called red stripe has been observed and analyzed in Anopheles albimanus (Nakashima et al. 1975) and Anopheles quadrimaculatus (Mitchell and Seawright 1984). In spite of their similar appearance, the homology of these traits among the species has not been established.
Anopheline recessive lethals characterized by various deformities of setae, eye, and body shape have been observed (e.g., Seawright and Benedict 1985); however, stocks carrying characterized lethals are usually lost or discarded due to the difficulty of maintaining them. Among this class, it is easiest to detect and maintain those such as the A. albimanus mutants bubblehead (Seawright and Benedict 1985) and curled (Seawright et al. 1982) that are located on the X chromosome, since they are expressed in hemizygous males (XY), and such mutations can be maintained through viable heterozygous sibling females (XX).
Among the rarely detected mutations are those that modify normal physiological responses to environmental conditions but otherwise have no visible effect. The Anopheles background-color–stimulated larval color change called homochromy (Fuzeau-Braesch 1972) is one response in which such mutants are easily detected, since the color-change is dramatic and simple to induce. When reared on an illuminated dark background, larvae darken significantly (Achundow 1930; Corradetti 1928), and this effect has been described extensively in various mosquitoes (Benedict and Seawright 1987). Until now, though, all mutants that interfere with this response have been eye-color mutants (Benedict and Chang 1996; Benedict and Seawright 1987). They suggested that the color change is stimulated by perception of the background color by the larval ocelli and effected by a neurophysiological pathway. Therefore, it is reasonable to expect that numerous mutations that interfere with transduction of the appropriate signals or pigment synthesis and transport might interfere with the response.
Because the DNA sequence of A. gambiae has been determined, it is likely that more precise identification of genes will be desirable for both mechanistic studies related to mutant phenotypes and also for chromosome manipulations to produce specific genotypes and karyotypes. Toward this end, we report genetic studies of two morphological characteristics that are most evident during the immature stages: Red stripe (Rs) and frizzled (f). We report the linkage relationship of frizzled to other X chromosome markers, pink eye and Mosaic. We also report the isolation, inheritance, and linkage relationship of a chromosome 2 mutation that eliminates inducible color change called homochromy1 (hom1).
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Materials and Methods |
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Several strains of A. gambiae were used (MR4 "MRA" numbers assigned to stocks are shown where applicable):
- rr cc has been reported previously (Beard et al. 1994) and is homozygous for the recessive phenotype alleles r and c of red eye and collarless respectively.
- p+ c+ DlR r+ (MRA-116) is a multiple marker stock that is homozygous for the dominant phenotype alleles named for pink-eye (p, Benedict et al. 1996a), collarless (Mason 1967), Dieldrin resistance (Dl, Davidson 1956; Davidson and Hamon 1962), and red eye (Beard et al. 1994).
- G3 (MRA-112) is a wild-type stock that is homozygous p+, DlS, r+, and polymorphic for the only two identified alleles of collarless, c and c+.
- Mos p5 and Mos pw are homozygous for the dominant position effect variegation mutant, Mosaic (Benedict et al. 2000), and for one of two pink-eye alleles that produce either red or white pigment respectively. Both p and Mos are located on the X chromosome.
- G3cc is a substrain of G3 (above) selected to homozygosity for c.
- hom1cc (MRA-120) is homozygous for the recessive phenotype alleles hom1, c, and DlS.
- p5 c r (MRA-113) is homozygous for the named alleles.
- b c (MRA-110) is homozygous for the recessive phenotype alleles of black (b, Benedict et al. 1999) and collarless.
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Red Stripe
The Red stripe character was observed in several laboratory stocks maintained at the Centers for Disease Control and Prevention in Atlanta, Georgia, and appears as a poorly delineated stripe of red to pink pigmentation of extremely variable expression on the dorsum of larvae and pupae (Figure 1A,B). It is seldom evident in males, and when it is, the red pigment is not abundant and almost invariably of a less intense color than in females. Red stripe is observed only in phenotypically c+ individuals, which can be identified by white pigment on the dorsum. We designated the Red stripe phenotype as Rs and wild-type as Rs+. We very rarely observe reddish pigmented regions on the thorax and/or abdomen in individuals that are c c, but we do not know if this is genetically related to the trait we call Red stripe, or whether the pigment is the same as that observed in Red stripe.
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One particular strain that was polymorphic for Rs and collarless but was homozygous r had particularly strong expression of Rs. From this stock, we easily purified a stock homozygous for c and r. However, numerous attempts by our group and others (Beard CB, personal communication) to purify a stock that was pure-breeding for Rs—from this or any other stock source—by selection of Rs females and crossing them to sibling males were unsuccessful. Oddly, although neither allele of collarless is lethal, neither did this scheme lead to purification of the c+ allele. In contrast, we noted Rs individuals were absent from the p+ c+ DlR r+ stocks, so this, and the polymorphic G3 stock, were used as sources for Rs+ individuals for subsequent crosses.
The above crossing and stock purification results, combined with the phenotypic and genotypic characteristics of the Rs+ stocks, suggested that the Rs phenotype was associated only with a c+c genotype, but neither a cc nor c+c+. Therefore, we predicted that the Red stripe phenotype might be produced from crosses of various stocks regardless of the stock that contained the c or c+ alleles. Five kinds of crosses were performed to test this hypothesis as follows (a detailed description of the genotypes of individuals used in all crosses can be found in Table 1):
- c homozygotes from either G3 or rr cc were crossed to p+ c+ DlR r+ (Rs+) in both directions (Table 2, crosses A–D). cc females from the G3cc stock were also crossed to p+ c+ DlR r+ (Rs+) males (cross E). Regardless of their sex, or the stock from which the cc individuals came, results of all crosses were similar (Table 2): no significant heterogeneity
2 values were obtained, although a significant deficiency of females was observed in cross D; all progeny were c+ and 98% of the female progeny were Rs and 98% of males were Rs+; among 3,593 progeny scored, 51 males were scored as Rs and 37 females as Rs+. Rs males were distributed fairly evenly across all crosses; however, most of the Rs+ females (36) came from cross B.
- F1 Rs females from crosses C, D, and E were mated with sibling Rs+ males (Table 3, crosses F, G, and H). Again, no significant heterogeneity 2 values were observed. In all crosses, fewer than the expected 25% cc individuals were observed (21, 22, and 18% respectively); however, this deficiency was significant only in crosses G and H. Under the hypothesis that Rs is due to the c+c genotype, we expected 0.5 x 702 or 351 Rs females; 352 were observed. The expected 2:1:1 ratio of Rs : Rs+ : cc females was not observed, though, in cross H, and if the results of crosses F, G, and H are considered together, the total number of the above classes is 352:211:139.
- Rs females from cross F or the G3 stock were crossed to cc from either rr cc or G3, respectively (Table 1, crosses I and J). Out of 25 families scored for collarless, 24 contained phenotypically c+ : c progeny in the ratio of 1:1 (Table 4). The progeny in the remaining family were all c+. Similar crosses were performed using Rs+ females from the same sources and crossing to rr cc males (Table 1, crosses K and L). Out of 13 families scored, 12 contained only c+ progeny (Table 4). The remaining family had a ratio of 1:1 c+ : c.
- The exceptional Rs males observed in crosses A, B, and J. were pooled together and crossed to rr cc females (Tables 1 and 2, cross M). A significant heterogeneity 2 value was not observed. However, c and Rs deviated from 1:1 significantly due to a deficiency of cc types. We observed that all c+ females were Rs.
- One family, number 3 of cross B, contained 14 of the 35 Rs+ females observed in the pooled data. When this family was inbred (Table 3, cross N), results were similar to that of inbreeding crosses in which Rs+ F1 females were rare (F, G, and H).
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frizzled
Among progeny of 60Co-irradiated p+ c+ DlR r+ males crossed to G3cc females, a family was found that contained 13 larvae with deformed setae and 29 wild type (Figure 1, Panel C). The deformed seta phenotype was named frizzled (f). All frizzled individuals were male and died either during pupation, adult emergence, or soon thereafter. Wild-type siblings were crossed to rr cc, and five out of six of the sibling-female crosses resulted in all wild-type female progeny and males that were frizzled or wild, but none of the four sibling-male crosses yielded frizzled progeny. As a tentative hypothesis, frizzled was considered to be a sex-linked semi-lethal. Since we have established this stock, it has been maintained by inbreeding families that contained frizzled larvae. In order to avoid inbreeding depression, females from families that contained frizzled males were outcrossed to G3 approximately every fifth generation, with inbreeding of those families that contain frizzled progeny.
The location of frizzled was determined relative to Mosaic, a position effect variegation mutant in division 6 of the X chromosome (Benedict et al. 2000), and to pink-eye located in division 2. Due to the low vigor of frizzled males, mapping schemes were designed that did not require matings of frizzled males. However, this necessitated that relevant linkage data could be obtained only from male progeny of f/f+ females. Mapping crosses were performed as follows: p+ Mos+ females from families containing frizzled larvae were crossed to pw Mos (f+) or p5 Mos (f+) males, and F1 females from families containing frizzled larvae were testcrossed to G3cc, pw c+ DlR r+ or p5 c r (Tables 1 and 5, crosses O, P, and Q). This scheme allowed unequivocal identification of four out of six possible recombinant phenotypes. Since Mos is expressed only in mutant pink-eye backgrounds (i.e., pw or p5), two recombinant phenotypes were indistinguishable from parental types: p+ Mos and p+ Mos+ were phenotypically indistinguishable in both f and f+ males. Therefore, the frequency of these cryptic recombinants can only be inferred from the frequency of unequivocally identifiable complementary types. However, this method was internally inconsistent, because the frequency of cryptic recombinants was found to be inconsistent (Table 5). We therefore report ranges of recombination based on high and low estimates. The order and recombination frequency (%) between the three loci is pink eye : (10.2–13.6) : frizzled : (3.0) : Mosaic. The total distance from pink eye to Mosaic was estimated at 13.2–16.7%, which brackets the estimate of 14.4% reported previously (Benedict et al. 2000), and no double-recombinants were observed. Though no significant heterogeneity 2 values were observed, we note that significant deviation 2 values were obtained for sex (cross O), Mosaic (cross P), and frizzled and pink eye (cross Q).
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homochromy1
While screening a pool of F2 progeny of G3 females crossed to G3 males for eye color mutants using the homochromy method (Benedict and Chang 1996), 25 larvae were found that did not darken normally. These were inbred, and a pure-breeding stock for the mutant, named homochromy1, was established in one generation. The eye color of these larvae, pupae, and adults appeared normal, and all individuals were c+. Since the rapid purification of the trait indicated that the phenotype of this allele was recessive, we performed crosses to place the hom1 allele in coupling with as many recessive phenotype alleles as possible. We crossed hom1 to b c and determined the frequency of double recessives among the F2 progeny (Tables 1 and 6, cross R). No recombinant collarless-hom1 double recessives were obtained (n = 330), and only one individual was a black-hom1 double recessive. Significant
2 deviation from a 3:1 wild to mutant was observed for hom1, but significant heterogeneity 2 values were not obtained. Although F2 recombination frequency estimates are insensitive relative to testcrosses, the frequency of collarless-black double recessives (n = 46) was used to estimate recombination between these markers at approximately 7% (z = 0.073). This value appeared less than the recombination frequency of 22% expected from previous crosses (Benedict et al. 1999). These F2 adults were inbred to create a c hom1 DlS stock.
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Testcrosses were performed to determine the linkage relationship of hom1 to collarless and Dieldrin resistance (crosses S and T). Because the recombination frequency estimate between collarless and Dieldrin resistance in the dihybrid linkage crosses was lower than expected, we considered that hom1 may be associated with recombination suppression in the interval between collarless and Dieldrin resistance. We crossed c hom1 DlS and G3cc females to p+ DlR c+ r+ males, testcrossed F1 males and females to c hom1 DlS, and compared recombination frequencies for collarless and Dieldrin resistance. Average recombination frequencies between collarless and Dieldrin resistance were calculated individually on five female and male testcross families from the G3cc parental cross (crosses U and V). Recombination frequencies were significantly different: 48.2 (±4.2) and 30.3% (±7.1), respectively. However, in the parental crosses to c hom1 DlS, almost identical frequencies of 44.7 (±1.2) and 43.3% (±6.4), respectively, were observed (crosses S and T). Neither heterogeneity nor deviation
2 values were significant in these crosses, and the data were pooled and adjusted for the presence of double recombinants to give an order and recombination frequency (%) of c : (2.9) : hom1 : (43.0) : Dl in the male testcross and c : (3.2) : hom1 : (45.2) : Dl in the female testcross. |
Discussion |
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Our hypothesis that the Red stripe character is due to an interaction of c and c+ alleles led to several predictions: (1) Crosses of cc Rs+ to c+c+ (Rs+) should result in F1 females that are virtually all Rs and males that are Rs+. This expectation was confirmed, with the exception of approximately 2% of the individuals that were either Rs+ females or Rs males. We believe that these exceptions are due to highly variable expressivity that results in rare presence in males and occasional absence in females. This conclusion was confirmed by crosses of exceptional types performed to determine their genotype. These resulted in progeny phenotypes that would be expected if their parents were of the predicted genotype, but the phenotype did not penetrate. (2) We predicted that inbreeding Rs+ F1 females from the above crosses with sibling males would result in a 2:1:1 ratio of c+ Rs : c+ Rs+ : c c phenotypes reflecting the expected ratio expected for the c+ c+ : c c+ : c c genotypes. This expectation was met in two of four crosses. However, there appears to be a consistent deficiency of cc types that also affects the deviation from the above segregation. While collarless generally assorts in a very predictable Mendelian fashion in testcrosses (Benedict et al. 1999; Mason 1967), the relative deficiency of cc individuals in these crosses may be due to a linked recessive lethal that is common in our stocks. (3) Crosses of Rs females to cc should result in a 1:1 ratio of c+ : c phenotypes among the progeny. With only one exception out of 25 families, this expectation was also met. Conversely, the prediction that Rs+ females crossed to cc males would result in only c+ progeny held true with but one exception. Both exceptions to our prediction were relatively uncommon, and we believe these exceptions again reflect the difficulty in distinguishing the phenotype in some individuals. Finally, (4) selection and inbreeding Rs individuals with siblings or any other Rs individuals would never result in a pure-breeding strain. All of our unpublished results are consistent with this expectation.
Crosses demonstrate that the Red stripe character is strongly sex-influenced, and essentially sex-limited, and results from the interaction of c and c+ alleles. It is possible that the c+ and c alleles that we are using in our crosses are unique in this interaction or that modifiers may be present elsewhere in the genome. Indeed, though we believe our general explanation is sufficient to explain the expression of the Red stripe, it does not rule out the possibility of other relevant genes that are tightly linked to collarless. Practically, we find that this hypothesis is reliable to identify females of a known collarless genotype.
In contrast to the presence or absence of discrete white pigment granules, consisting of uric acid, that distinguish the collarless alleles (Benedict et al. 1996b), the Red stripe pigment is diffusely distributed on the dorsum. We have no data indicating the identity of the pigment, but we have observed that in red eye homozygotes, the Red stripe is always yellowish or golden color (unpublished. data). The eye pigment that the red-eye gene affects is an ommochrome (Beard et al. 1994), and these authors suggested that the red-eye gene might affect the oxidation state of ommochrome pigments, since normal amounts of intermediates in the biosynthesis pathway appear to be present. Since ommochromes are yellow, red, or brown, and their color changes depending on their oxidation state, it is possible that the Red stripe consists of ommochromes whose oxidation state is affected similarly to that of the eye pigments in red eye individuals.
Mason (1967) described a red stripe phenotype in another member of the A. gambiae complex, A. arabiensis. However, he suggested that the red stripe might be polygenic and assigned no gene(s) symbol. Based on photographs and his description, we believe that the trait we observe in A. gambiae s.s. is the same as Mason observed. He observed that expression was sex-influenced, but our experience suggests that the expression is so strongly sex-influenced that identifying Red stripe males is very difficult, if not impossible. Therefore, we prefer to describe Rs as sex-limited. Unlike our results, he was able to develop pure-breeding lines. It is possible that his strains were natural balanced lethals maintained by lack of recombination between collarless and some unknown recessive lethal. In any case, he makes no mention of whether the trait could be observed in cc individuals or only in c+c or c+c+. Mason also reported that, when crosses were performed between strains, all F1 females had red stripes. Unfortunately, no record of the collarless phenotype of the parents was presented.
Comparison of the Red stripe phenotype in A. gambiae with the Red stripe characters in A. albimanus (Nakashima et al. 1975) and A. quadrimaculatus (Mitchell and Seawright 1984) is difficult. While the collarless and stripe genes associated with their expression may appear similar, this comparison is superficial, since the c allele of A. gambiae results in complete absence of white pigmentation, and not simply a change in pattern as in the A quadrimaculatus and A. albimanus stripe alleles. Certainly, the Red stripe phenomena we observed in these strains do not necessitate a polygenic hypothesis as suggested by Nakashima et al. (1975). Moreover, no additional alleles have been identified, as in the allelic series in A. quadrimaculatus, in which the red stripe is due to a codominant phenotype allele in a three-allele series (Mitchell and Seawright 1984). It is quite possible that there are various modifiers or tightly linked lethals in the different species and that all of the genetic explanations that have been posited for the various species are correct.
In contrast to Red stripe, which we consider to be simply a peculiar phenotype associated with a specific genotype of a previously described A. gambiae gene, frizzled is a novel sex-linked recessive semi-lethal identified by kinked lateral larval setae. The lethality is manifested as low rates of adult male emergence, and, when it does occur, brief survival. Although it may be possible to establish a stock by mating frizzled males, we have not attempted to do so, since the vigor of such a stock would be very low. Moreover, we are not certain that the female phenotype is similar to that of males, since we have not produced that genotype. frizzled shows tight linkage with Mosaic and is probably quite close to the junction of the euchromatic and heterochromatic portions of the X chromosome.
In normal anophelines, rearing larvae in black containers induces radical darkening of the larval body, though a small percentage of individuals in some A. quadrimaculatus stocks do not change color, yet have apparently normal eye color (Seawright JA, personal communication). Larvae homozygous for the recessive phenotype allele hom1 do not demonstrate the normal color-change. Because numerous genes certainly affect color-change signal initiation, transduction, and pigment formation, we gave the homochromy1 gene a generic name that reflects its role in color change without specifying a specific function in the process. We have previously reported that eye-color mutants do not show this response (Benedict and Chang 1996; Benedict and Seawright 1987), but in contrast, hom1 eye pigmentation appears normal. Combining the linkage information about hom1 with previously published information, the order of the available biochemical and morphological markers on chromosome 2 can be deduced from previous information (Benedict et al. 1999; Zheng et al. 1996) to be D l–b–hom1–c. We can also approximate the distances between black and hom1 as approximately 20 cM. Due to the possibility of confusing the black phenotype and the darkening due to inducible color change, we do not recommend using black and hom1 in crosses that require scoring both traits.
The location and phenotype of the Dieldrin resistance marker used in this study are consistent with it being an allele of the Drosophila melanogaster resistance to dieldrin [rdl (French-Constant et al. 1991), Aedes aegypti (Thompson et al. 1993), A. gambiae, and A. stephensi (Andreasen MH, personal communication)] genes identified as gamma aminobutyric acid (GABA) receptors. The most highly similar A. gambiae sequence to these is within 0.3 megabases of BAC clone 26K20, which would place it on chromosome 2L in divisions 23c or d, and certainly within the 2La inversion region (Sharakhova MV, personal communication). This is consistent with the linkage data we present here. If true, recombination suppression due to this inversion may account for much of the variation in distances measured between loci relative to Dl.
From our crosses, we see no consistent difference in recombination rates between males and females; however, there was a surprising range of recombination frequencies among siblings in cross S, the same testcross in which the estimate of distance between hom1 and Dieldrin resistance varied from the other crosses. Recombination among families in this testcross ranged from 14.0 to 44.7% when based solely on morphological/biochemical data (data not shown). Similarly, in a previously published report of recombination for chromosome 2 (Zheng et al. 1996, 1997), morphological/biochemical data showed a similar wide range of recombination between lunate and Dieldrin resistance (5.4 to 25.8%, average 16%). This was observed in spite of the fact that the testcrosses were performed with genetically similar sibling F1 males. The particular two families these authors analyzed for microsatellite linkage to lunate and Dieldrin resistance had recombination values above and below the average value of 16%, but the final composite recombination frequency was only 10%. We concur with their assessment and again emphasize that one should be cautious to interpret recombination frequencies in strains in which floating inversions such as 2La and 2Rbc are abundant and well known (Coluzzi and Sabatini 1967). Moreover, those intending to clone genes based on positional cloning should closely examine and confirm published recombination estimates, and possibly locus orders, before undertaking large-scale efforts.
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Footnotes |
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Corresponding Editor: Stephen W. Schaeffer
Received July 15, 2002
Accepted January 30, 2003
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