Overlapping genes of Aedes aegypti: evolutionary implications from comparison with orthologs of Anopheles gambiae and other insects
© Behura and Severson; licensee BioMed Central Ltd. 2013
Received: 18 October 2012
Accepted: 12 June 2013
Published: 18 June 2013
Although gene overlapping is a common feature of prokaryote and mitochondria genomes, such genes have also been identified in many eukaryotes. The overlapping genes in eukaryotes are extensively rearranged even between closely related species. In this study, we investigated retention and rearrangement of positionally overlapping genes between the mosquitoes Aedes aegypti (dengue virus vector) and Anopheles gambiae (malaria vector). The overlapping gene pairs of A. aegypti were further compared with orthologs of other selected insects to conduct several hypothesis driven investigations relating to the evolution and rearrangement of overlapping genes.
The results show that as much as ~10% of the predicted genes of A. aegypti and A. gambiae are localized in positional overlapping manner. Furthermore, the study shows that differential abundance of introns and simple sequence repeats have significant association with positional rearrangement of overlapping genes between the two species. Gene expression analysis further suggests that antisense transcripts generated from the oppositely oriented overlapping genes are differentially regulated and may have important regulatory functions in these mosquitoes. Our data further shows that synonymous and non-synonymous mutations have differential but non-significant effect on overlapping localization of orthologous genes in other insect genomes.
Gene overlapping in insects may be a species-specific evolutionary process as evident from non-dependency of gene overlapping with species phylogeny. Based on the results, our study suggests that overlapping genes may have played an important role in genome evolution of insects.
Gene rearrangement is one of the necessary ingredients of genome evolution. Several well studied mechanisms such as chromosomal inversions, translocations, duplications and transpositions are known to have important roles in genomic rearrangement events [1–4]. Reshuffling of genomic DNA by gross chromosomal rearrangements generally involves a number of genes that undergo positional relocation in the genome. In addition to such large scale genomic rearrangements, genomic rearrangements at small scale levels facilitate relocation of genes which are otherwise positionally overlapping in a genome . It has been suggested that transposition mechanisms may contribute to such gene arrangements [1, 2, 6, 7], but the functional and evolutionary significance of such events is largely unknown.
Positional overlapping between genes is a common structural feature of prokaryote and mitochondria genomes [8–10]. However, overlapping genes have also been identified from whole genome sequences of several eukaryotes such as fruit fly, zebrafish, human, chimpanzee, orangutan, marmoset, rhesus, cow, dog, mouse, rat and chicken [11–13]. Studies show that overlapping genes in eukaryotes are extensively rearranged even between closely related species [5, 12, 14–16]. Bhutkar et al. 2007  compared overlapping genes of Drosophila melanogaster and Anopheles gambiae with Apis mellifera (honey bee) and suggested that relocalization of overlapping genes may have played a significant role in genome evolution of these insects. Although several other insect genome sequences are now available, overlapping genes of most of these insects have not been studied.
The present study is an effort to investigate overlapping genes of Aedes aegypti, the primary global vector of dengue virus, in a comparative manner with those of A. gambiae, a major vector of malaria in subSaharan Africa. Understanding genome structure of these mosquitoes has become one of the major interests among insect vector biologists. At present, the draft genome sequences for three mosquito species have been completed [17–19]. These projects (http://www.vectorbase.org) have provided new insights on structure, function and evolution of mosquito genes, thus furthering our ability to study mosquito-parasite or mosquito-virus interactions at the molecular level [20–23].
We identified positional overlapping of genes at the whole genome level in A. aegypti and studied structural differences and evolutionary features by comparisons with orthologous genes of A. gambiae and other selected arthropod genomes. The primary aim was to test several common hypotheses relating to rearrangement of overlapping genes and determine factors that may have a role in relocalization of overlapping genes in insects. The results of our investigation show that positional overlapping among genes is a species specific evolutionary process as evident from non-dependency of gene overlapping with species phylogeny, and also show that specific factors, such as introns and repeat sequences, are significantly associated with retention/rearrangement of overlapping genes in mosquitoes. Based on these results, our study suggests that overlapping genes may have played an important role in genome evolution among insects.
Official gene sets and extraction of overlapping gene pairs
The overlapping gene pairs of A. aegypti and A. gambiae were identified in a genome-wide manner based on the coordinates of gene boundaries of official gene sets annotated from the genome assemblies. The other mosquito genome sequence for Culex quinquefasciatus was not used for this purpose because of differences in gene annotation of this species compared to A. aegypti or A. gambiae. That is, while nearly equally percentages (~60%) of the official gene sets of A. aegypti as well as A. gambiae have been annotated for gene boundaries that incorporated the 5’ and 3’ untranslated regions, only 15% of the C. quinquefasciatus genes have been annotated in this manner. Thus, incorporating C. quinquefasciatus could have produced biased results in the genome-wide comparison of overlapping gene pairs between A. aegypti and A. gambiae. However, we have used orthologs of A. aegypti overlapping gene pairs in C. quinquefasciatus and other selected insect species such as Drosophila melanogaster, Apis mellifera, Pediculus humanus, Bombyx mori and Acyrthosiphon pisum to determine if they are also localized in overlapping positions in the respective genomes. For genome-wide comparison of overlapping genes, the predicted gene sets of A. aegypti (AaegL1.1) and A. gambiae (AgamP3.4) along with coordinates of genes in the reference genome were downloaded from VectorBase (http://www.vectorbase.org/GetData/). The one-to-one orthologous genes (OrthoDB5; http://cegg.unige.ch/orthodb5) were compared to determine if they were also present in overlapping gene pairs across multiple genomes. To determine the relative position of the orthologous genes, the official gene lists along with their start and end positions in the genome sequences of the other six insects (C. quinquefasciatus: CpipJ1, D. melanogaster: BDGP 5, A. mellifera: Amel_2.0, P. humanus: PhumU1, B. mori: SilkDB V2.0 and A. pisum: Acyr2) were downloaded from either VectorBase (http://www.vectorbase.org/) or the SilkDB database (http://www.silkdb.org) or the ‘Ensembl Metazoa 10’ data sets at http://www.biomart.org.
To determine if introns have an association with overlapping between genes, orthologous genes were categorized as intronless and intron-containing genes for overlapping and non-overlapping pairs in the A. aegypti and A. gambiae genomes. The exon structures predicted for A. aegypti and A. gambiae genes (obtained from Biomart.org) were used to classify genes into single exon genes (intronless) and multi exon genes (intron-containing). The number of introns in each gene was determined from the number of exons annotated in the genes. The 2x2 contingency analysis of counts of the intronless and intron-containing genes of both categories (overlapping/ non-overlapping) was performed using Yates Chi square tests to determine significance of association between introns and gene overlapping.
Transcriptional analysis of overlapping genes
The expressed sequence tags (EST) of A. aegypti and A. gambiae mosquitoes used in this study were largely generated in conjunction with the individual genome sequencing projects (http://www.vectorbase.org). These ESTs were used to assist in the annotation of the official gene sets of the two mosquitoes. We used these ESTs to investigate expression patterns associated with the overlapping gene pairs. To further confirm correspondence of ESTs with overlapping gene pairs, we performed reciprocal BLAST analyses described as follows. The EST sequences were used to generate a local BLAST database and then searched by BLASTN with the sequences of overlapping genes. The EST ‘hits’ that had an e-value = 0 were used again as queries in another BLASTN search against all predicted gene sequences. If the reciprocal hits matched the same gene that was used as a query in the first BLAST, it was considered that the EST corresponded to that gene. Apart from analyzing the EST data, we also analyzed previously performed microarray expression data of A. aegypti to determine expression patterns of the overlapping gene pairs. The A. gambiae microarray expression data was obtained from Baker et al. 2011 study . The expression data of these studies [23, 24] are publicly available with Gene Expression Omnibus (GEO) accession # GSE16563 and GSE21689 at http://www.ncbi.nlm.nih.gov/geo/. The Spearman’s rank correlation test was conducted to ascertain whether the overlapping gene pairs had significantly correlated expression levels throughout the genome.
Identification of microsatellites in overlapping genes
In order to determine if there is a significant association of microsatellites with retention or rearrangement of overlapping gene structures between A. aegypti and A. gambiae, we identified microsatellite sequences within the gene pairs in both genomes. SciRoKo, a simple sequence repeat (SSR) identification program , was used to detect both perfect and imperfect mono-, di-, tri-, tetra- and hexa-nucleotide repeats using the default parameters (mismatch, fixed penalty = 5). The repeats with more than 3 consecutive mismatch sites were excluded. The genes where one or more sites were ambiguous nucleotides (such as ‘N’s) were not used to report microsatellites. The length of orthologous genes may vary (primarily because of introns) that may contribute to varying amounts of microsatellite sequences in the orthologous gene copies. So, instead of comparing the absolute amounts of microsatellite sequences, their relative amounts were compared. The relative amounts were obtained from the total amount of microsatellites of genes normalized with the alignment length (common DNA sequences) of the orthologous genes between A. aegypti and A. gambiae.
Statistical and computational analyses
All statistical analyses were performed using the R statistical program. The p-value < 0.05 was considered statistical significance in all tests unless stated otherwise. Cluster analyses of gene pairs based on overlapping or non-overlapping structures across genomes were based on average correlation of city-block distance estimated using the Cluster3 program . The phylogenetic analyses were performed by neighbor-joining method using MEGA4 . The evolutionary distances were in the units of the number of base substitutions per site; and they were calculated using the Maximum Composite Likelihood method . The Mantel procedure  was used to perform linear regression between matrices where the dependent matrix (representing 0 for non-overlapping and 1 for overlapping) was permutated 1000 times to test significance of the observed correlation with the independent matrix (that represented presence or absence of orthologs of overlapping gene pairs of A. aegypti) in the genomes used for comparison. The multi Mantel procedure was performed using an algorithm developed by Dr. Liam J. Revell (URL: http://anolis.oeb.harvard.edu/~liam/programs/). Maximum likelihood methods described elsewhere [30, 31] were used to estimate the log likelihoods of models assuming either dependency or non-dependency of gene phylogeny with the discrete variation of gene traits (i.e. overlapping or non-overlapping localization in the respective genomes). The likelihood ratio tests were conducted to infer statistical significance of these two models. A binary logit model was developed to test marginal effects of the rates of synonymous (dS) and non-synonymous (dN) mutations in the orthologous gene pairs between A. aegypti and other select insect genomes (A. gambiae, C. quinquefasciatus, D. melanogaster and P. humanus). While each of the gene pairs (n =19) were localized in an overlapping manner in the A. aegypti genome, the orthologous genes showed variation in relative localization (overlapping = 1or non-overlapping = 0) in other species. The dN and dS values of orthologous genes were obtained from metazoan genes database at http://www.Biomart.org. A generalized linear model (described in detail in results section), fitting the dependent variable (0 or 1) and independent variables (dN and dS values for both genes), was used in R to estimate the logit coefficients.
Results and discussion
Identification of overlapping genes
A total of 761 and 565 overlapping gene pairs were identified in the assembled genomes of A. aegypti and A. gambiae, respectively (Additional file 1). They represent 8-10% of the annotated genes of the two mosquitoes. The frequencies of overlapping genes of A. aegypti and A. gambiae mosquitoes are within the range of overlapping gene frequencies reported in other eukaryotes [32, 33]. More than two genes (overlapping gene clusters) were also found in overlapping locations in both genomes, with the majority of these overlapping gene clusters containing no more than three genes (21 clusters in A. aegypti and 19 in A. gambiae). These overlapping clustered genes constituted only a minor portion (less than 3%) of the total number of overlapping genes in either of the two genomes. Because of low frequency and also for simplicity of analysis, we have not included the gene clusters in our investigation. All the analyses performed in this study were based on overlapping gene pairs.
Orthology of overlapping genes between A. aegypti and A. gambiae
Rearrangement of overlapping genes
Number of one-to-one orthologous gene pairs which are localized either in overlapping or non-overlapping manner relative to each other between the A. aegypti and A. gambiae genomes
Number of gene pairs
E/H in both A. aegypti and A. gambiae
P/O in both A. aegypti and A. gambiae
E/H in A. aegypti but P/O in A. gambiae
P/O in A. aegypti but E/H in A. gambiae
E/H in A. aegypti but non-overlapping in A. gambiae
P/O in A. aegypti but non-overlapping in A. gambiae
Non-overlapping in A. aegypti but E/H in A. gambiae
Non-overlapping in A. aegypti but P/O in A. gambiae
Gene overlapping is phylogeny independent
Positional overlapping/non-overlapping patterns of orthologs of A. aegypti gene pairs in 7 other insect species were compared with species phylogeny
Orthologs of gene pairs
Log likelihood difference
By comparisons with predicted orthologous genes among sequenced arthropod genomes (OrthoDB5, http://cegg.unige.ch/orthodb5), we identified a total of 196 overlapping gene pairs of A. aegypti where at least one gene of each pair was also present among the other seven insect species. But only 19 of these gene pairs in A. aegypti had both the genes present as orthologs in all the other seven species (Additional file 4). To further confirm that overlapping or non-overlapping localization of genes has no correspondence with presence or absence of orthologs across genomes, we performed hierarchal cluster analysis among the above 19 orthologous gene pairs across the eight species (Additional file 5). The potential for correlation between gene orthology and gene positional overlapping was assessed for statistical significance by Mantel test (see Methods). The correlation was evaluated between binary data of orthologous genes in matrix forms (presence or absence of overlap) with the presence or absence of orthology of the gene pairs. The results showed non-significant correlation between the two (p > 0.8) suggesting that gene orthology has no relationship with overlapping localization of genes across species.
Role of selection on rearrangement of overlapping genes
Binary logit regression coefficients of rate of synonymous (dS) and non-synonymous (dN) mutations between A. aegypti overlapping genes and their 1-to-1 orthologs in other selected insects (A. gambiae, C. quinquefasciatus, D. melanogaster and P. humanus)
Association of microsatellites with gene overlapping
Role of introns in positional overlapping of genes
Significant association of introns with rearrangement of overlapping gene pairs between A. aegypti (Aaeg) and A. gambiae (Agam)
Gene pair structure
Aaeg Gene1 + Gene2
Agam Gene1 + Gene2
Yates Chi square
Two tailed p-value
Non-overlapping in Aaeg but E/H in Agam
p < 0.0001
E/H in Aaeg but non-overlapping in Agam
P/O in Aaeg but non-overlapping in Agam
p < 0.0001
Non-overlapping in Aaeg but P/O in Agam
Expression of overlapping genes
Overlapping expression of more than one gene is well known in eukaryotes , . We analyzed the expressed sequence tags (ESTs) datasets of A. aegypti and A. gambiae to determine if overlapping gene pairs may have overlapping transcripts. Using reciprocal BLASTN searches, we identified several ESTs of A. aegypti that represented the likely transcription product of overlapping gene pairs (Additional file 7). Although many of these gene pairs are oriented in opposite direction to each other, ESTs were also observed for gene pairs oriented in same direction. Whether these gene pairs are co-transcribed or co-regulated by common upstream/downstream sequences  are not known from this study. However, identification of ESTs of overlapping gene sequences clearly shows that these sequences are expressed. Moreover, we show that the annotation of overlapping genes is unaffected whether good evidence of expression (such as EST evidence) is available or not. The dataset of overlapping genes was also analyzed based on availability or non-availability of EST evidence. We found no significant difference in the number of genes that localized in positionally overlapping manner between the two groups (Additional file 8). In A. gambiae, the EST dataset didn’t reveal such transcripts except for a single gene pair. Although transcripts of overlapping genes were not available in the EST collections of A. gambiae, we found evidence of expression of these genes (Additional file 9) from published microarray data .
Generally, overlapping transcripts are processed by post-transcriptional events to produce individual transcripts of the genes . To assess the expression level of individual gene transcripts of overlapping gene pairs, we examined the microarray expression data of A. aegypti. Because overlapping genes are predominantly localized in opposite orientation to each other in the genome (Figure 1), we compared expression level of gene pairs (E/H genes) which are either oppositely oriented or oriented in same direction to each other. It was found that the expression levels of overlapping genes in opposite orientation lack significant correlation, whereas the overlapping genes which are oriented in the same direction to each other show statistically significant correlation (p < 0.01) (Additional file 10). Most of these genes code for known proteins and have been annotated with start and stop codons suggesting that these genes are not annotation artifacts, although a few genes were annotated as hypothetical proteins. Nevertheless, these results suggested that when the two genes are localized in overlapping manner and also oriented in the same direction, their expression may be co-regulated leading to similar transcription levels. On the other hand, when the two genes are localized in overlapping manner, but oriented in the opposite direction, their transcripts may have differential regulation. In fact, it is well documented that overlapping genes when transcribed in the opposite directions, give rise to sense-antisense transcript pairs which are differentially regulated to play a role in a variety of processes, including mRNA splicing and stability, RNA editing, genomic imprinting and control of translation [33 and references therein].
The results from this study provide insight into the common prevailing theories of origin and evolution of positionally overlapping genes. These are particularly important for better understanding of distribution and structure of overlapping genes in the genomes of A. aegypti and A. gambiae. The genome sequences of both A. gambiae and A. aegypti contain gaps that could affect our estimates of overlapping genes in the genome assemblies, but we find this unlikely based on our observation that the overlapping genes are distributed throughout the genome in each species without any bias to specific chromosomal region of A. gambiae or specific supercontigs of A. aegypti (data not shown). Furthermore, our estimated frequencies of overlapping genes in mosquitoes are within the range of overlapping gene frequencies reported in other eukaryotes [32, 33]. Thus, it is unlikely that there may be large numbers of genes missing because of gaps in sequencing that are positionally overlapping. Nevertheless, the dynamic patterns of positional rearrangement of overlapping genes suggest that these genes may have important roles in genome evolution of vector mosquitoes. Importantly, the information from this investigation may help us in further studies pertaining to evolution and functional characterization of antisense transcripts among overlapping genes in mosquitoes.
Availability of supporting data
The manuscript is accompanied with the following listed Additional files in the form of supporting data for this study.
SKB is a Research Assistant Professor in the Department of Biological Sciences and the Eck Institute for Global Health at the University of Notre Dame, Indiana. He has a broad interest in insect genomics and evolution with emphasis on disease transmitting vector species. DWS is a Professor of Biological Sciences and the Director of Eck Institute for Global Health at the University of Notre Dame, Indiana. His work focuses on genetic and genomic analysis of mosquito vector competence to various pathogens as well as on development and application of molecular tools to investigate population biology of mosquitoes.
This work was supported, in part, by grants AI059342 and AI079125 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).
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