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. 2020 Jul 6;21:463. doi: 10.1186/s12864-020-06873-8

Phylogenetic analysis of the ATP-binding cassette proteins suggests a new ABC protein subfamily J in Aedes aegypti (Diptera: Culicidae)

Janaina Figueira-Mansur 1,#, Carlos G Schrago 2,#, Tiago S Salles 1,3, Evelyn S L Alvarenga 1, Brenda M Vasconcellos 1, Ana Claudia A Melo 1,3, Monica F Moreira 1,3,✉
PMCID: PMC7339416  PMID: 32631258

Abstract

Background

We performed an in-depth analysis of the ABC gene family in Aedes aegypti (Diptera: Culicidae), which is an important vector species of arthropod-borne viral infections such as chikungunya, dengue, and Zika. Despite its importance, previous studies of the Arthropod ABC family have not focused on this species. Reports of insecticide resistance among pests and vectors indicate that some of these ATP-dependent efflux pumps are involved in compound traffic and multidrug resistance phenotypes.

Results

We identified 53 classic complete ABC proteins annotated in the A. aegypti genome. A phylogenetic analysis of Aedes aegypti ABC proteins was carried out to assign the novel proteins to the ABC subfamilies. We also determined 9 full-length sequences of DNA repair (MutS, RAD50) and structural maintenance of chromosome (SMC) proteins that contain the ABC signature.

Conclusions

After inclusion of the putative ABC proteins into the evolutionary tree of the gene family, we classified A. aegypti ABC proteins into the established subfamilies (A to H), but the phylogenetic positioning of MutS, RAD50 and SMC proteins among ABC subfamilies—as well as the highly supported grouping of RAD50 and SMC—prompted us to name a new J subfamily of A. aegypti ABC proteins.

Keywords: Aedes aegypti; MutS, RAD50 and SMC proteins; MDR phenotype; ABC protein classification; ABC protein subfamily J

Background

The ATP-binding cassette (ABC) transporters constitute a diverse gene family consisting of proteins found in all cellular organisms and participating in several different biological pathways [1]. Among these processes, the ABC transporters are mostly involved in extra and intracellular trans membrane ATP energy driven traffic of molecules such as lipids, amino acids, hormones and xenobiotics [2, 3].

Members of this family are characterized by two trans membrane domains (TMD) and two nucleotide-binding domains (NBD) characterized by conserved motifs: Walker A, Walker B, ABC signature (LSGGQ-motif), Q loop, and H loop [1, 4]. The TMD domains of the ABC-transporters are composed of five to ten membrane-spanning regions that are involved in substrate translocation. The four domains (two TMD and two NBD) of a functional ABC transporter might be present in a single protein (full transporter) or in dimers of separate proteins that have at least one TMD and one NBD each (half transporter) [3, 5].

The traditional classification is based on sequence similarity and arranged the ABC protein diversity into eight subfamilies (A- H) [6]. The ABCE and ABCF subfamilies are unique among the ABC proteins because they exhibit a pair of linked nucleotide-binding domains while lacking trans membrane domains [3, 6]. The ABCH subfamily was described for protozoa [7] and insects [8, 9], but it has not yet been found in mammals, bacteria, and yeast genomes. Plants, besides presenting eukaryotic ABC subfamilies A to G, exhibit a heterogeneous and extensive group of ABC proteins that bear similarities to the components of prokaryotic multi-subunit ABC transporters. This group was named subfamily I and includes NBD and TMD domains and homologues of soluble cytosolic proteins that interact with NBDs as well as putative substrate-binding proteins similar to the periplasmic binding proteins [10].

Three other groups of proteins not assigned to the subfamilies mentioned above exhibit ABC transporter domains: (1) the MutS proteins that are responsible for DNA mismatch repair and maintenance of genomic stability [11, 12]; (2) the structural maintenance of chromosome proteins (SMC), which are mostly responsible for chromosome condensation and sister chromatid cohesion [13], and (3) the Rad 50 proteins that also function on DNA repair [8, 9, 14].

Although MutS, SMC, and Rad50 proteins show ABC protein characteristics, they have not yet been included in the standard ABC classification for humans, arthropods, and the Caenorhabditis elegans nematode [8, 9, 15, 16]. Nonetheless, in the complete inventory of ABC proteins of the Arabidopsis thaliana plant, SMC proteins were proposed as a new ABC protein subfamily [17].

Some ABC proteins have been associated with multidrug resistance (MDR) phenotype in a variety of organisms. This phenotype is associated with the overexpression of P-glycoproteins (P-gp/MDR/ABCB1), the multidrug resistance protein (MDR/ABCC), and the breast cancer resistance protein (BCRP/ABCG2) [5, 18, 19]. These act as efflux pumps that result in resistance to chemotherapeutics, antibiotics, and antiretroviral drugs [20, 21].

One important control mechanism of vector-borne diseases is vector control, which relies mainly on insecticide treatments of vector populations. In these populations, the insecticide-resistant phenotype arises due to the selection of genetically resistant individuals that exhibit higher fitness under special conditions [22, 23]. Multiple insecticide resistance can be separated into two main categories: cross-resistance—when a single mechanism confers resistance to a range of different insecticides; and multiple resistance—when several coexisting defense mechanisms act in the same organism [24, 25]. The involvement of ABC transporters in insecticide resistance and transport is poorly documented, but an increasing number of studies have shown that ABC transporters have been linked to insecticide and nicotine transport [26–28] and insect resistance to Bacillus thuringiensis toxins and pyrethroids [29, 30]. The high expression of P-gp in insecticide resistant pests such as Heliothis virescens and Helicoverpa armigera has been suggested to be a mechanism of resistance [31, 32].

Recent surveys of the ABC gene family in arthropods included the fruit fly Drosophila melanogaster, the mosquito Anopheles gambiae, the beetle Tribolium castaneum, the honey bee Apis mellifera, the silkmoth Bombyx mori, the water flea Daphia pulex, and the spider mite Tetranychus urticae [16]. Analyses focusing on crustaceans such as the sea lice Caligus rogercresseyi [33] and Lepeophtheirus salmonis [34] were also carried out. These studies left out the A. aegypti mosquito, which is an important vector species of arthropod-borne viral infections such as chikungunya, dengue, and Zika diseases [35]. In 2016, Lu et al. [36] conducted a comparative analysis of the ABC transporter family in three mosquito species (Anopheles gambiae, Aedes aegypti, and Culex pipiens quinquefasciatus) and found 55, 69, and 70 ABC genes, respectively. The search for Aedes aegypti ABC proteins, however, was carried out within a limited evolutionary range because only mosquito sequences were analyzed.

In this study, we surveyed the Aedes aegypti genome in a broader evolutionary spectrum, employing human and Drosophila ABC transporters as queries. By including all the putative proteins that exhibit the ABC domain into a phylogenetic analysis, we showed that SMC, Rad 50, and MutS proteins were part of the main ABC gene family diversification, which justifies the proposition of a new subfamily of the ABC proteins.

Results

The BLASTp search on the A. aegypti genome retrieved 62 complete proteins that were identified as ABC transporters when submitted to the NCBI Conserved Domain Database. The ABC gene family phylogeny recovered subfamilies A-H with significant statistical support (Fig. 1). The sizes of gene subfamilies varied significantly with subfamilies A-C and G consisting of the larger groups. Sister group associations between ABC subfamilies were less resolved. The single exception was the clade with subfamilies ABCA and ABCH that were grouped with maximum statistical support. In all ABC subfamilies, A. aegypti proteins had a tendency to be positioned among human and Drosophila sequences suggesting that the duplication events that gave rise to current ABC diversity took place before the evolution of those lineages. Clusters containing ABC genes exclusively from A. aegypti were found in subfamilies ABCA, ABCC, and ABCG. These clusters indicate mosquito-specific duplication events.

Fig. 1.

Fig. 1

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a Maximum likelihood phylogeny of the ABC gene family including SMC, Rad50 and MutS genes. ABC subfamilies are shown with the new mosquito sequences highlighted in blue. b Numbers at branches indicate statistical support (ultra-fast bootstrap) for each subfamily A-J

The variation of the rate of evolution within each ABC subfamily as measured by the heterogeneity of the distance between the common ancestor of all members of the subfamily and the tips was higher in subfamily ABCA. In this subfamily, an interesting pattern of rate increase along lineages was observed (Fig. 1). As expected, deeper nodes exhibited lower statistical support demonstrating that the evolutionary relationships between these subfamilies were not fully resolved. Surprisingly, root placement using the minimal ancestor deviation (MAD) method suggested that subfamily ABCG is a sister to the remaining ABC transporters including the clades consisting of SMC and Rad50 proteins as well as the MutS proteins that were positioned as a sister to subfamily ABCD (Fig. 1).

Discussion

To investigate ABC transporters in the A. aegypti genome within a broader evolutionary context, we identified A. aegypti ABC homologs employing human and D. melanogaster as queries (Table 1). We also identified the conserved domains of all the putative A. aegypti ABC transporters to investigate the assignment of the putative proteins to the described subfamilies of these transporters. We identified ten members of the A. aegypti ABCA subfamily (Fig. 1 and Table 2). This subfamily contains longer proteins that ranged from 1419 to 1673 amino acid residues. Nine of these members have the topology of full transporters with two NBDs and two TMDS (Table 2). The A. aegypti ABCA subfamily was encoded by genes organized in tandem indicating specific gene duplication events (Table 2). Four members of this cluster have genes organized in tandem in the supercontig 1.726, two members belong to the supercontig 1.321, and four belong to other supercontigs (Table 2). The roles of arthropod ABCA members are unclear [16], but this subfamily has been described as involved with lipid transport in mammals [37].

Table 1.

Classification of ABC proteins subfamilies in Homo sapiens and Drosophila melanogaster

Homo sapiens Drosophila melanogaster
Sub-family Seq ID GenBank accession Sub-family Seq ID GenBank accession
A ABCA1 NP_005493 A AAF50836
A ABCA2 NP_001597 A AAF50837
A ABCA3 CAA65825 A AAF50838
A ABCA4_ABCR AAC05632 A AAF50847
A ABCA5 NP_061142 A AAF53329
A ABCA6 NP_525023 A AAF55726
A ABCA7 AAK00959 A AAF57490
A ABCA8 BAA74845 B AAF45509
A ABCA9 NP_525022 B AAF47525
A ABCA10 XP_085647 B AAF48177
A ABCA12 NP_056472 B AAF50669
A ABCA13 NP_689914 B AAF50670
B ABCB1_MDR1_P_gp NP_000918 B AAF53736
B ABCB2_TAP1 CAA40741 B AAF53737
B ABCB_TAP2 AAA59841 B AAF55241
B ABCB4_MDR3 AAA36207 B AAF58271
B ABCB5 AAO73470 B AAF58437
B ABCB6_MTABC3 NP_005680 C AAF46706
B ABCB7 BAA28861 C AAF52639
B ABCB8_MABC1 AAD15748 C AAF52648
B ABCB9 AAF89993 C AAF52866
B ABCB10_MABC2 XP_001871 C AAF53223
B ABCB11_BSEP AAC77455 C AAF53950
C ABCC1_MRP1 AAB46616 C AAF54656
C ABCC2_MRP2 CAA65259 C AAF55707
C ABCC3_MRP3 BAA28146 C AAF56312
C ABCC4_MRP4 NP_005836 C AAF56869
C ABCC5_MRP5 AAB71758 C AAF56870
C ABCC6_MRP6 AAC79696 C AAF58947
C ABCC7_CFTR AAC13657 D AAF49018
C ABCC8_SUR1 AAB02278 D AAF59367
C ABCC9_SUR2 AAC16058 E AAF50342
C ABCC10 NP_258261 F AAF48069
C ABCC11 NP_149163 F AAF48493
C ABCC12 NP_150229 F AAF49142
D ABCD1_ALDP CAA79922 G AAF45826
D ABCD2_ALDR NP_005155 G AAF47020
D ABCD3_PMP70 CAA41416 G AAF49455
D ABCD4_PMP69 AAB83967 G AAF50035
E ABCE1_RNAseL1 CAA53972 G AAF51027
F ABCF1 AAH34488 G AAF51122
F ABCF2 NP_005683 G AAF51130
F ABCF3 NP_060828 G AAF51131
G ABCG1_WHITE1 AAC51098 G AAF51223
G ABCG2_BCRP Q9UNQ0 G AAF51341
G ABCG4_WHITE2 NP_071452 G AAF51548
G ABCG5 AAG40003 G AAF51551
G ABCG8 AAG40004 G AAF52835
J SMC1 AAB34405 G AAF56360
J SMC4 BAA73535 G AAF56361
J SMC3 AAC14893 H AAF52284
J SMC2 AAI44164 H AAF56807
J RAD50 NP_005723 H ABC66191
J SMC5 CAC39247 J SMC1 AAF56231
J SMC6 CAC39248 J SMC4 AAF53560
J MSH4_MutS NP_002431 J SMC2 AAF58197
J MSH3_MutS AAB06045 J RAD50 AAF46847
J MSH5_MutS NP_079535 J SMC5 CAD29584
J MSH2_MutS NP_000242 J SMC6 AAF56254
J MSH6_MutS NP_000170 J MSH2_MutS NP_523565
J MSH6_MutS AAF49656
J SMC3 AAF48625
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Table 2.

Characterization of the 62 A. aegypti ABC proteins

Sub-family Name VectorBase (accession number) Size (amino acids) Predicted topology Location
(gene)		 Orientation
(gene)
A
AaegABCA3L1 AAEL012702-PA 1669 TMD1-NBD1-TMD2-NBD2 1.726: 372101–377,726 +
AaegABCA3L2 AAEL012700-PA 1648 TMD1-NBD1-TMD2-NBD2 1.726: 388899–394,375 +
AaegABCA3L3 AAEL012701-PA 1622 TMD1-NBD1-TMD2-NBD2 1.726: 409854–439,050 +
AaegABCA3L4 AAEL012698-PA 1652 TMD1-NBD1-TMD2-NBD2 1.726: 450626–459,977 +
AaegABCA3L5 AAEL008388-PA 1666 TMD1-NBD1-TMD2-NBD2 1.321: 644618–664,804 –
AaegABCA3L6 AAEL008384-PA 1660 TMD1-NBD1-TMD2-NBD2 1.321: 675803–697,600 –
AaegABCA3L7 AAEL001938-PA 1673 TMD1-NBD1-TMD2-NBD2 1.46: 792516–818,527 –
AaegABCA5L AAEL004331-PA 1419 TMD1-NBD1-TMD2-NBD2 1.115: 240545–271,476 +
AaegABCA5L AAEL018040-PA 1987 TMD1-NBD1-TMD2-NBD2 3.322: 613800–714,818 –
AaegABCA18 AAEL017572-PA 347 NBD 1.176: 1628836–1,629,879 –
B
AaegABCB1L/AaegP-gp AAEL010379-PA 1307 TMD1-NBD1-TMD2-NBD2 1.474: 313030–327,570 +
AaegABCB6L AAEL000434-PA 693 TMD-NBD 1.8: 3711414–3,730,662 +
AaegABCB7L AAEL006717-PA 734 TMD-NBD 1.219: 178589–203,717 –
AaegABCB8L AAEL002468-PA 703 TMD-NBD 1.58: 1203051–1,224,141 –
AaegABCB10L AAEL008134-PA 848 TMD-NBD 1.302: 73729–107,503 +
C
AaegABCC1L1 AAEL005026-PA 1384 TMD0-TMD1-NBD1-TMD2-NBD2 1.139: 1168407–1,184,363 +
AaegABCC1L2 AAEL005045-PA 1514 TMD0-TMD1-NBD1-TMD2-NBD2 1.139: 1184563–1,195,380 –
AaegABCC1L3 AAEL005030-PA 1396 TMD0-TMD1-NBD1-TMD2-NBD2 1.139: 1233513–1,252,972 –
AaegABCC1L4 AAEL004743-PA 1089 TMD0-TMD1-NBD1 1.129: 994901–1,030,978 +
AaegABCC1L5 AAEL017209-PA 903 TMD0 -TMD1-NBD1 1.107: 820177–825,969 –
AaegABCC4L1 AAEL013567-PA 1311 TMD1-NBD1-TMD2-NBD2 1.871: 281423–317,150 +
AaegABCC4L2 AAEL005918-PA 1312 TMD1-NBD1-TMD2-NBD2 1.180: 664096–681,744 –
AaegABCC4L3 AAEL005937-PA 1300 TMD1-NBD1-TMD2-NBD2 1.180: 724473–765,746 +
AaegABCC4L4 AAEL005929-PA 1413 TMD1-NBD1-TMD2-NBD2 1.180: 786121–801,780 +
AaegABCC4L5 AAEL013834-PA 1235 TMD1-NBD1-TMD2-NBD2 1.936: 291553–353,031 –
AaegABCC4L6 AAEL012395-PA 1357 TMD1-NBD1-TMD2-NBD2 1.688: 67831–72,390 –
AaegABCC4L7 AAEL012386-PA 1351 TMD1-NBD1-TMD2-NBD2 1.688: 87463–91,714 +
AaegABCC4L8 AAEL012192-PA 1345 TMD1-NBD1-TMD2-NBD2 1.664: 660781–670,973 –
AaegABCC10L AAEL006622-PA 1540 TMD0-TMD1-NBD1-TMD2-NBD2 1.213: 838086–915,438 +
AaegABCC14 AAEL005499-PA 1382 TMD1-NBD1-TMD2-NBD2 1.160: 1362499–1,398,139 –
D
AaegABCD2L AAEL002913-PA 659 TMD-NBD 1.71: 1617561–1,676,168 +
AaegABCD3L AAEL010047-PA 753 TMD-NBD 1.449: 843528–895,566 +
E
AaegABCE1L AAEL010059-PA 609 NBD1-NBD2 1.450: 713084–727,146 +
F
AaegABCF1L AAEL001101-PA 894 NBD1-NBD2 1.23: 2941514–2,961,984 –
AaegABCF2L AAEL010977-PA 602 NBD1-NBD2 1.529: 122943–143,748 –
AaegABCF3L AAEL010359-PA 609 NBD1-NBD2 1.450: 713084–727,146 +
G
AaegWhite* AAEL016999-PA 692 NBD-TMD 1.71: 816675–879,820 –
AaegABCG/whiteL1 AAEL008138-PA 773 NBD-TMD 1.303: 412767–432,830 +
AaegABCG/whiteL2 AAEL008672-PA 689 NBD-TMD 1.340: 378892–469,513 +
AaegABCG/whiteL3 AAEL008624-PA 593 NBD-TMD 1.337: 23491–61,022 –
AaegABCG/whiteL4 AAEL008632-PA 607 NBD-TMD 1.337: 68512–71,099 –
AaegABCG/whiteL5 AAEL008628-PA 571 NBD-TMD 1.337: 85665–99,799 –
AaegABCG/whiteL6 AAEL008625-PA 606 NBD-TMD 1.337: 119628–131,014 +
AaegABCG/whiteL7 AAEL008629-PA 723 NBD-TMD 1.337: 131034–224,797 –
AaegABCG/whiteL8 AAEL008631-PA 759 NBD-TMD 1.337: 276979–394,542 –
AaegABCG/whiteL9 AAEL008635-PA 676 NBD-TMD 1.337: 470559–525,334 –
AaegABCG/whiteL10 AAEL013372-PA 599 NBD-TMD 1.830: 256110–301,680 +
AaegABCG/scarletL1 AAEL003703-PA 616 NBD-TMD 1.94: 984346–994,398 –
AaegABCG/scarletL2 AAEL017106-PA 689 NBD-TMD 1.1174: 142758–145,023 –
AaegABCG8L1 AAEL012170-PA 275 NBD 1.662: 13565–20,660 +
AaegABCG8L2 AAEL011265-PA 787 NBD-TMD 1.561: 434947–481,728 +
H
AaegABCH1 AAEL005249-PA 872 NBD-TMD 1.147: 1132338–1,176,150 +
AaegABCH2 AAEL005491-PA 783 NBD-TMD 1.159: 901905–920,193 +
AaegABCH3 AAEL014428-PA 727 NBD-TMD 1.1111: 126773–184,623 +
AaegABCH4L5 AAEL018334-PA 814 NBD-TMD 1.181:178199–420,930 –
J
AaegSMC1L1 AAEL005802-PA 1227 NBD 1.175: 1418947–1,437,720 –
AaegSMC1L2 AAEL015592-PA 594 NBD 1.3565: 4371–6283 –
AaegSMC2L AAEL003449-PA 1182 NBD 1.86: 847376–874,751 –
AaegSMC3L AAEL006937-PA 1201 NBD 1.229: 536438–586,285 –
AaegSMC4L AAEL001655-PA 1347 NBD 1.38: 1385452–1,432,324 +
AaegSMC6L AAEL002581-PA 1107 NBD 1.61: 165187–198,927 +
AaegRAD50L1 AAEL005245-PA 1034 NBD 1.147: 747831–755,196 –
AaegRAD50L2 AAEL014748-PA 1051 NBD 1.1248: 101280–115,288 –
AaegMutS6L AAEL011780-PA 1130 NBD 1.612: 217022–240,932 +
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Five sequences retrieved from the A. aegypti genome were assigned to the ABCB subfamily (Fig. 1, Table 2). This subfamily is composed of putative homologs of the human P-glycoprotein, which plays key physiological roles such as the excretion of toxic compounds and the multidrug resistance phenotype [3, 26, 27, 37, 38]. The identified A. aegypti ABCB proteins are intimately related to the human mitochondrial transporters HsABCB6, HsABCB7, HsABCB8, and HsABCB10 leading us to suppose that these proteins have a similar role associated with the iron metabolism and the transport of Fe/S protein precursors from the mitochondria to the cytoplasm [37, 39]. We also note that one D. melanogaster protein classified as belonging to the ABCB (CG31792_B) subfamily was recovered in the ABCC clade. This may be due to misclassification or to recent duplication and functional change. In either case, this protein should be further investigated.

One of the most diverse subfamilies identified in the mosquito genome was the ABCC with 15 members—all full transporters (Table 2). This subfamily presents a high diversity of sequences as well as functional roles when compared with the human ABCC proteins. These functions are related to ion transport, cell surface receptors, toxin secretion, and multidrug resistance [38]. A sub-clade containing all the MRP from humans and D. melanogaster was recovered including four A. aegypti proteins (AaegABCC1L1, AaegABCC1L2, AaegABCC1L4, and AaegABCC1L5) suggesting that these proteins might also be responsible for protection against xenobiotics [40] and for the MDR phenotype [38, 41].

The ABCD and ABCE subfamilies were the least diverse of the groups identified in humans—the former is known to appear as half transporters forming homo or heterodimers in peroxisomes acting in lipid transport [3, 39, 42]. The ABCD subfamily has two members and the ABCE subfamily has only one protein described for most eukaryotes (Table 2) with the exception of A. thaliana [17]. This was consistent with the findings of a single ABCE gene in the A. aegypti genome. These proteins lack the TMD and were first described as the RNAseL protein participating in ribosome biogenesis and protein translation [37–39, 43–46]. Like ABCE proteins, the ABCF subfamily also lacks the TMD and is involved in the ribosome complex formation and activation [46–48]; only three of these proteins were found in the mosquito genome in our analysis.

Although only five members of the ABCG proteins were described in humans [3, 37], 15 proteins belonging to this group were identified for A. aegypti (Table 2). This number is greater than the 11 genes previously identified in An. gambiae [9]. This excessive number of ABCG proteins in A. aegypti mosquito is likely due to a series of duplication events that is supported by the tandem organization observed in the supercontig 1.337 of the A. aegypti genome (Table 2). In D. melanogaster, the white gene is the most studied gene from the ABCG subfamily, and the product of this gene can form dimers with the scarlet and brown proteins (scarlet and brown genes, respectively). These dimers are transporters of eye pigment precursors in D. melanogaster [49, 50]. Only one ortholog of the white and scarlet proteins was found in the A. aegypti genome but no ortholog of the brown protein was found. In humans, ABCG5 and ABCG8 are glycoproteins that also form obligate heterodimers. These are useful to limit the absorption of plant sterols and cholesterol from the diet and promote secretion of plant sterols and cholesterol from liver cells into the bile. Based on their head-to-head orientation and clear orthologous relationships with human ABCG5 and ABCG8, these arthropod ABCGs probably have a similar role as their human orthologues [37].

The ABCH subfamily was exclusively found in insects with no reports in mammals, plants, or yeast [9, 37]. Here, four members of the ABCH subfamily were identified in the A. aegypti genome (Fig. 1 and Table 2). This included the sequence AAEL018334, which has been previously assigned to ABCG subfamily. Although these are proteins with unknown function, topological similarities with the ABCG proteins have suggested that the ABCH might be involved in sterol transport and multidrug resistance [51, 52].

Insect P-glycoproteins and multidrug-resistance associated proteins are frequently associated with pesticide resistance as reported in Heliothis virescens and Helicoverpa armigera [30, 31] and insecticide transport. The expression of A. aegypti P-gp (AAEL010379) increases eightfold in the temephos-treated larvae, and silencing of this gene expression significantly increases temephos toxicity [27]. These findings suggested that ABC transport, which consists of ATP-dependent efflux pumps, might be involved with compound traffic and multidrug resistance phenotypes. New insights into insecticide efflux, ATP-dependent efflux pump inhibitors, and/or RNAi associated with pesticides will potentially assist in the development of control strategies for important vectors of infectious diseases like A. aegypti.

Rad50 shares topological and sequence features with SMC proteins [52]. Notably, Rad50 has a relatively well-conserved LSGG motif compared to the classic ABC proteins. Moreover, it has an extensive coiled region that facilities dimerization of large molecules restoring the close proximity of the Walker A and B motifs for nucleotide binding [53]. SMCs have more degenerated versions of this signature motif and contain minimal Walker A and B motifs (Supplemental material 1) [54]. Finally, perhaps a distant lineage but still within the ABC diversification [55], are the DNA repair enzymes such as MutS [56].

SMC proteins formed a highly supported clade with the Rad50 proteins. These proteins form dimers and have a conserved mechanism of conformational change observed in the classic ABC proteins. The ATP binding and NBD dimerization promote changes in the substrate-binding domains that are important for the function of the ABC-type ATPases. The substrate-binding domains of the SMC and Rad50 proteins are located in similar positions as the classic ABC proteins [52]. The ABC proteins subfamilies are grouped together based on sequence similarity and proteins belonging to the same subfamily usually have similar functions. Our results showed that ABC subfamilies were always strongly recovered in the gene family phylogeny and that the sequences of SMC and Rad50 proteins formed a well-supported clade (100 bootstrap support), sister to MutS proteins, and ABC transporters excluding ABCG. Functional similarities are also observed within the groups.

We know the following: (i) SMC and Rad50 proteins exhibit similar functions on DNA repair and chromosomal maintenance [8, 9, 11, 12, 14], (ii) they form a strongly supported clade with ABC transporters phylogeny, and (iii) they exhibit the structural and sequence characteristics of ABC proteins. Thus, we propose these proteins be included in the ABC gene family with the creation of a new subfamily called J (Fig. 1; Table 2) that includes ABC proteins involved in DNA repair and structural maintenance of the chromosomes.

Conclusions

In summary, we found 53 classic complete ABC proteins annotated in the A. aegypti genome that were classified in traditional ABC subfamilies (A-H) as reported in other species. We also found 9 sequences of the Rad, MutS, and SMC in the Aedes genome database that clustered with human and D. melanogaster orthologs in the same clade. Considering other similarities observed between these enzymes and the classic ABC proteins, we propose these proteins be included in the ABC gene family followed by creation of a new subfamily called J that includes ABC enzymes involved in DNA repair and the structural maintenance of the chromosome.

Methods

Sequence sampling and alignment

We selected protein sequences of ABC protein subfamilies from humans (46 sequences) and Drosophila melanogaster (50 sequences) including sequences from SMC, Rad50, and MutS genes ensuring a broad evolutionary diversity. These sequences were used as query for BLAST searches of A. aegypti ABC proteins. To identify A. aegypti ABC proteins, human and Drosophila sequences were used as queries to search sequences on the mosquito genome (VectorBase) and on the NCBI protein database using BLASTp [57]. Sequences resulting from these searches that had more than 30% identity were considered as homologous (Supplemental material 2).

All putative homologous sequences were submitted to the NCBI Conserved Domain Database [58, 59] to confirm the presence of the ATP-binding cassette domain. Datasets were aligned using the MUSCLE software [60] and then pruned for removal of regions with high frequency of indels using TrimAL using the “gappyout” command (Supplemental material 3) [61].

Inference of ABC gene genealogy

The maximum likelihood (ML) tree topology was inferred with the IqTree 1.6 [62] program employing the LG + R10 model of amino acid substitution that was chosen by the Bayesian information criterion. This model uses the LG amino acid replacement matrix [63] coupled with ten relative rate classes to accommodate among-site rate heterogeneity [64]. Branch support was assessed by the ultrafast bootstrap implementation of IqTree using 1000 replicates [65]. IqTree was executed via the command “iqtree -s infile -bb 1000”. Because no outgroup was included in our analysis, rooting of the ABC gene genealogy was performed using the minimal ancestor deviation method of Tria at al. [66]. Rooting is necessary for establishing the chronological direction of the ABC gene family evolution (Supplemental material 4).

Supplementary information

12864_2020_6873_MOESM1_ESM.pdf (56.9KB, pdf)

Additional file 1. Sequences.txt: Rad50, SMC and MutS sequences highlighted Walker A and Walker B motifs and ABC signature.

12864_2020_6873_MOESM2_ESM.txt (124.2KB, txt)

Additional file 2. ABC.txt: Unaligned ABC sequences used in this study.

12864_2020_6873_MOESM3_ESM.txt (216KB, txt)

Additional file 3. ABCalin.txt: Aligned and trimmed ABC sequences employed in evolutionary analyses.

12864_2020_6873_MOESM4_ESM.txt (8.9KB, txt)

Additional file 4. ABC.unrooted.txt: Unrooted maximum likelihood phylogenetic tree of the ABC gene family.

Acknowledgments

The authors are grateful to Dr. Silvia Andrade Justi (Walter Reed Biosystematics Unit, Smithsonian Institute and Walter Reed Army, Institute of Research Entomology branch Maryland, USA) for providing assistance in accomplishing this work. We dedicate this paper to the memory of our friend Dr. Mario Alberto Cardoso da Silva Neto for his interest in mosquitoes.

Abbreviations

MDR

Multidrug resistance protein

P-gp

P-glycoproteins

BCRP

Breast cancer resistance protein

SMC

Structural maintenance of chromosome proteins

TMD

Trans membrane domains

NBD

Nucleotide-binding domains

NCBI

National Center for Biotechnology Information

MAD

Minimal ancestor deviation

Authors’ contributions

The authors JFM, CGS and MFM conceptualization, writing-original draft preparation, JFM, TSS, BMV search genomics data. JFM, MFM, TSS, BMV and CGS did bioinformatics analyses. ESLA and ACAM critically revised the manuscript. All authors reviewed the manuscript and approved the final manuscript.

Funding

This work was supported by the Fundação Carlos Chagas Filho de Amparo.

à Pesquisa do Estado do Rio de Janeiro (FAPERJ-E-26/201.331/2016-REDE ZIKA), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular (INCT-EM/CNPq),

and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Availability of data and materials

The datasets analysed during the current study are available in the GenBank and VectorBase repositories. All accession numbers were listed in Tables 1 and 2.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

One of the authors (CGS) is a member of the editorial board for the BMC Genomics journal.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Janaina Figueira-Mansur and Carlos G. Schrago contributed equally to this work.

Supplementary information

Supplementary information accompanies this paper at 10.1186/s12864-020-06873-8.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

12864_2020_6873_MOESM1_ESM.pdf (56.9KB, pdf)

Additional file 1. Sequences.txt: Rad50, SMC and MutS sequences highlighted Walker A and Walker B motifs and ABC signature.

12864_2020_6873_MOESM2_ESM.txt (124.2KB, txt)

Additional file 2. ABC.txt: Unaligned ABC sequences used in this study.

12864_2020_6873_MOESM3_ESM.txt (216KB, txt)

Additional file 3. ABCalin.txt: Aligned and trimmed ABC sequences employed in evolutionary analyses.

12864_2020_6873_MOESM4_ESM.txt (8.9KB, txt)

Additional file 4. ABC.unrooted.txt: Unrooted maximum likelihood phylogenetic tree of the ABC gene family.

Data Availability Statement

The datasets analysed during the current study are available in the GenBank and VectorBase repositories. All accession numbers were listed in Tables 1 and 2.

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