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Evolutionary history and mode of the amylase multigene family in drosophilaJ Mol Evol (2003) 57:702–709DOI: 10.1007/s00239-003-2521-7 Evolutionary History and Mode of the amylase Multigene Family in Drosophila Ze Zhang,1,2 Nobuyuki Inomata,3 Tsuneyuki Yamazaki,4 Hirohisa Kishino1 1 Laboratory of Biometrics and Bioinformatics, Graduate School of Agriculture and Life Sciences, University of Tokyo,Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan2 Institute for Bioinformatics Research and Development (BIRD), Japan Science and Technology Corporation (JST), Japan3 Department of Biology, Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan4 The Research Institute of Evolutionary Biology, 2-4-28, Kamiyoga, Setagaya-ku, Tokyo 158-0098, Japan Received: 10 March 2003/ Accepted: 4 July 2003 within the montium subgroup species and D. anan- demly repeated members of the amylase (Amy) gene assae. While the tandemly repeated members evolved family evolved in a concerted manner in the mel- in a concerted manner, the two types of diverged Amy anogaster subgroup and in some other species. In this genes in Drosophila experienced frequent gene du- paper, we analyzed all of the 49 active and complete plication, gene loss, and divergent evolution follow- Amy gene sequences in Drosophila, mostly from ing the model of a birth-and-death process.
subgenus Sophophora. Phylogenetic analysis indic-ated that the two types of diverged Amy genes in the Drosophila montium subgroup and Drosophila anan- — Birth-and-death process — Drosophila assae, which are located in distant chromosomal re-gions from each other, originated independently indiﬀerent evolutionary lineages of the melanogaster group after the split of the obscura and melanogastergroups. One of the two clusters was lost after dupli- The formation of new genes by various duplication cation in the melanogaster subgroup. Given the time, events results in the creation of multigene families and 24.9 mya, of divergence between the obscura and the has been long thought to be a major source for the melanogaster groups (Russo et al. 1995), the two origin of evolutionary novelties, including new gene duplication events were estimated to occur at about functions and expression patterns. Thus, the evolution 13.96 ± 1.93 and 12.38 ± 1.76 mya in the montium of multigene families has been extensively studied at subgroup and D. ananassae, respectively. An accel- both the empirical and the theoretical levels (Ohta erated rate of amino acid changes was not observed 1987; Clark 1994; Walsh 1995; Liebhaber et al. 1981; in either lineage after these gene duplications. How- Brown and Ish-Horowicz 1981; Hibner et al. 1991; ever, the G+C contents at the third codon positions Nei et al. 1997; Rooney et al. 2002). It has long been (GC3) decreased signiﬁcantly along one of the two believed that the members of a multigene family do Amy clusters both in the montium subgroup and in D.
not evolve independently but instead evolve together ananassae right after gene duplication. Furthermore, as a unit by means of gene conversion and/or unequal one of the two types of the Amy genes with a lower crossing-over (Smith 1974; Arnheim 1983). This con- GC3content has lost a speciﬁc regulatory element certed evolution was observed in ribosomal and smallnuclear RNA genes and globin genes (Liebhaber et al.
1981; Brown and Ish-Horowicz 1981; Hibner et al.
Correspondence to: Ze Zhang; email: email@example.com.
ac.jp 1991; Liao 1999). On the other hand, Nei and Hughes (1992) proposed a birth-and-death model for evolu- gene duplication, gene loss, and divergence among the tion of multigene families. This model expresses fre- Amy gene members will strengthen our understanding quent duplication and loss of gene copies and assumes of this gene family. Here, we analyzed all of the 49 independent evolution between the members. The active and complete Amy sequences from Sophophora birth-and-death model approximates evolution of subgenus. With this extensive dataset, we were able to large multigene families, such as the major histo- show that the two gene duplication events occurred in compatibility complex (MHC), immunoglobulin (Ig), diﬀerent lineages of the Sophophora subgenus inde- antibacterial ribonuclease genes, and nematode che- pendently and produced distant paralogs. In addition, moreceptor gene families (Nei and Hughes 1992; Ota the melanogaster subgroup was estimated to have lost and Nei 1994; Nei et al. 1997; Robertson 1998), as well one of the two types of the Amy genes. While no sig- as of smaller multigene families such as the ubiquitins niﬁcant change in rate of amino acid replacement was (Nei et al. 2000). It is a matter of concern to charac- observed among the lineages after gene duplications, terize the cases to where the two models apply. We the GC3contents decreased signiﬁcantly along one of could expect that tandemly arrayed members in the the two Amy clusters both in the montium subgroup genome are likely to evolve in a concerted manner, and in D. ananassae right after gene duplication. This while members in diﬀerent genomic environments suggests that the two types of the Amy genes within evolve independently. And also, the members will species undergo a birth-and-death process, whereas have some constraint as a whole in functional level or tendemly repeated Amy members evolve in a con- expression level. In this paper, we report the evidence from the Amy gene family in Drosophila.
The a-amylase enzyme is one of the most important enzymes for eukaryotic organisms, especially animals, because it is essential for digestive processes in which food starch is hydrolyzed into maltose and glucose. InDrosophila, the members of the Amy gene family vary Forty-nine complete Amy gene sequences were retrieved from from two to seven among species (Doane et al. 1987; GenBank. Their accession numbers, GC contents at all positions of Brown et al. 1990; Shibata and Yamazaki 1995; Da coding region, and codon usage bias indices (the scaled chi-square) Lage et al. 1996, 2000; Popadic et al. 1996; Inomata, are shown in Table 1. Although pseudogenes are part of the evo- Tachida and Yamazaki 1997; Steinemann and Stein- lutionary history of multigene families, they have very diﬀerent emann 1999; Inomata and Yamazaki 2000). The du- evolutionary rates compared with functional genes and may con-tort attempts to date duplication events. Therefore, we used only plicated Amy genes in the melanogaster species the available complete DNA sequences of functional Amy genes.
subgroup (Shibata and Yamazaki 1995) and inD. pseudoobscura (Brown et al. 1990; Popadic et al.
1996) are respectively, inverted and tandem repeats.
They have been shown to evolve in a concerted Sequences were ﬁrst aligned at the amino acid level using CLU- manner (Hickey et al. 1991; Shibata and Yamazaki STALX (Thompson et al. 1997). The Amy genes code 494 amino 1995; Popadic et al. 1996). Recently, however, Ino- acid residues (1482 nucleotides), including the signal peptide, which mata and Yamazaki (2000) found that D. kikkawai encompasses the ﬁrst 18 amino acid residues. The only Amy4N and and its sibling species have two types of highly di- Amyi5 genes in D. ananassae have an additional amino acid (Arg)in the signal peptide (Da Lage et al. 2000). After removing this vergent, paralogous Amy genes with diﬀerent GC additional amino acid, the length of sequences analyzed in this contents at the third codon positions (GC3) at dif- ferent chromosomal locations. They encode active a- To reconstruct phylogenetic trees, we used the neighbor-joining method in MEGA 2.0 (NJ; Saitou and Nei 1987), the maximum patterns. Furthermore, two such types of divergent likelihood (ML) method in PHYLIP 3.6a3 (Felsenstein 2002), andthe maximum parsimony (MP) method (Branch-and-Bound search) Amy gene duplicates appear to be common in the in PAUP* 4.0 (Swoﬀord 1998). The JC69 (Jukes and Cantor 1969), montium subgroup, to which D. kikkawai and its sib- K80 (Kimura 1980), and TN (Tamura and Nei 1993) distance ling species belong (Zhang et al. 2003). Similar ob- measures were used for the NJ tree reconstruction to examine their servations were reported in D. ananassae (Da Lage et eﬀects on topological stability. The precision of the tree topology al. 2000). Importantly, the two types of the paralo- was assessed by bootstrap analysis, with 1000 resampling replicatesfor the MP and NJ methods and 100 replicates for the ML method.
gous Amy genes reside in chromosomal regions that To assess the signiﬁcance of diﬀerences in evolutionary rate are very distant from each other (Inomata and among gene clusters, the ML method, as implemented in the Yamazaki 2000; Da Lage et al. 2000).
DNAML and DNAMLK programs in PHYLIP 3.6a3 was used.
Although the evolution of paralogous Amy genes Since base composition at the third codon position varies among Amy has been studied previously (Inomata and Yamazaki sequences, we used Galtier and Gouy’s (1998) maximum likelihoodmethod as implemented in the EVAL_NH program (NHML pack- 2000; Da Lage et al. 2000; Zhang et al. 2002), their age). This method is based on a nonhomogeneous, nonstationary origins in Drosophila remain to be resolved. Further- model of DNA sequence evolution, to estimate base compositional more, inference on an evolutionary history such as change in evolutionary course of the Amy genes in Drosophila.
A list of Drosophila species and Amy sequences used in this study, GC content, codon usage bias, and accession number Note: Scaled chi-square computed using Yates’ correction. G + C3s: G + C content at (synonymous) third codon positions. G + Cc: G +C content at coding positions.
reduce the eﬀects of compositional bias on phylo-genetic reconstruction, the only ﬁrst and second co- don positions were used for phylogenetic analyses.
Because topologies of NJ trees constructed by K80 Previous studies indicate that there is great hetero- distances (Kimura 1980; Saitou and Nei 1987), JC geneity in GC3content among the Amy genes even distances (Jukes and Cantor 1969), and TN distance within species (Inomata and Yamazaki 2000; Da (Tamura and Nei 1993), and of MP (Swoﬀord 1998) Lage et al. 2000; Zhang et al. 2002). Therefore, to and ML (Felsenstein 2002) trees were almost the Gene NJ tree reconstructed by ﬁrst and second codon positions and Kimura’s two-parameter distances. The numbers near the nodes refer to bootstrap probabilities and the boldface underlined numbers refer to GC3contents of the corresponding ancestral nodes.
same, we show only the NJ tree constructed by K80 melanogaster group formed a monophyletic group distances (Fig. 1). Using the Amy sequences of D.
with very high bootstrap probability (96%). The Amy virilis and S. lebanonensis as outgroups, the Amy genes of the ananassae subgroup diverged ﬁrst from genes of the obscura group ﬁrst diverged from the the other Amy genes of the melanogaster and montium other lineages. Furthermore, the Amy genes of the subgroups, followed by those of the montium sub- group. All Amy genes in the subgroups and groups their standard deviations, A and B (Fig. 1), for the (except for the montium subgroup) formed mono- mon-clusters 1 and 2 and for the ana-clusters 1 and 2, phyletic clusters, although some clusters do not have respectively. Using the 24.9-mya divergence time of high bootstrap probabilities. These results are con- the obscura and melanogaster groups as a calibration sistent with previous studies (Russo et al. 1995; Ino- point (Russo et al. 1995), the duplication time be- mata et al. 1997). Another important observation in tween mon-cluster 1 and mon-cluster 2 was estimated Fig. 1 is that there are two gene clusters with high at about 13.96 ± 1.93 mya and the duplication time bootstrap probabilities within the montium subgroup between ana-cluster 1 and ana-cluster 2 was estimated species and D. ananassae. For the montium subgroup, at about 12.38 ± 1.76 mya. These results indicate we refer to the Amy paralog cluster including the that the two gene duplication events occurred inde- Amy1 and Amy2 genes as ‘‘mon-cluster 1’’ and the pendently and relatively recently, after the split of the Amy paralog cluster including the Amy3and Amy4 ananassae subgroup and the montium and melano- genes as ‘‘mon-cluster 2.’’ Similarly, we refer to the gaster subgroups. The calibration time used in the Amy paralog cluster including the Amy58 and Amy35 present study is considerably conservative. The esti- genes as ‘‘ana-cluster 1’’ and the Amy paralog cluster mate of the divergence time for the split of the obs- including Amy4N and Amyi5 genes as ‘‘ana-cluster 2’’ immunological distance data (Beverley and Wilson Figure 1 clearly suggests that one duplication 1984) is about 46 mya, twice the estimate obtained by event, which resulted in two gene clusters in the Adh sequence data (Russo et al. 1995). Thus, the es- montium lineage, predated the split of the melano- timates of the duplication time in present study gaster and montium subgroups and that another du- should be regarded as the minimum ones.
ananassae lineage after the split of the ananassae Birth-and-Death Process Versus Concerted Evolution subgroup and the montium and melanogaster sub-groups. Since the melanogaster subgroup species have Since there is great heterogeneity in GC3content only one gene cluster, they are likely to have lost one among the paralogous Amy gene clusters (Table 1), of the two homologous gene clusters in the montium the method of Galtier and Gouy (1998) was used to subgroup. This inference on gene duplication/loss estimate the ancestral GC3contents. The numbers events is further supported by comparison of their underlined in Fig. 1 show the estimates of the cor- gene arrangements in genomes. For instance, Fig. 2 responding ancestral node GC3contents. Our results shows that the two gene clusters are located on dif- indicate that the common ancestor of Sophophora ferent regions of the same chromosome in the mon- species had an elevated GC3content, which is con- tium subgroup species but on diﬀerent chromosomes sistent with at least one other study (Rodriguez-Tre- in D. ananassae (Inomata and Yamazaki 2000; Da lles et al. 2000). The GC3content of the common Lage et al. 2000). The most likely scenario is that the ancestor of mon-clusters 1 and 2 was 91.4%, whereas two gene duplication events occurred independently the GC3contents of the ancestral nodes of mon- in two diﬀerent lineages and that the melanogaster clusters 1 and 2 are 90.4 and 76.5%, respectively. The subgroup species might have lost the corresponding diﬀerence in GC3content between the ancestral paralogous Amy cluster 2 (Figs. 1 and 2).
nodes of mon-clusters 1 and 2 was 13.9%. The To test the hypothesis of molecular clock at the standard error was estimated by a bootstrap method ﬁrst and second codon positions, we compared the with 100 resampling replicates. The estimated diﬀer- likelihoods of the phylogenies assuming a constant ence was statistically signiﬁcant (Z = 3.69, p < 0.01).
rate and without assuming a clock (DNAMLK vs.
For D. ananassae, the GC3content of the common DNAML in PHYLIP 3.6 [Felsenstein 2002]). Both ancestor of ana-clusters 1 and 2 was 92.8%, whereas models resulted in the same topologies. The log the GC3contents of the ancestral nodes of ana- likelihood under the assumption of a molecular clock clusters 1 and 2 are 74.2 and 63.6%, respectively. The was l0 = )4144.23, whereas the log likelihood under ancestral node of ana-cluster 1 has a signiﬁcantly the assumption of no clock was l0 = )4121.26.
higher GC3content than does that of ana-cluster 2 Comparison of twice the log-likelihood diﬀerence, 2dl (Z = 4.54, p < 0.01). These results consistently = 2 · ()4121.26 ) ()4144.23)) = 45.94, with the chi- suggest divergent evolution between the two gene square distribution (df = 47, p = 0.516). The dif- ference between the two models was not signiﬁcant, Figures 1 and 2 imply that the melanogaster sub- indicating that the molecular clock holds at the ﬁrst group species might have lost one Amy cluster ho- and second codon positions. Therefore, the outputs mologous to mon-cluster 2 with a lower GC3content.
of maximum likelihood analysis under a molecular clock and bootstrap resampling with 100 replicates D. ananassae retain cluster 2, the gene cluster has lost were used to estimate the gene duplication times and some speciﬁc regulatory elements compared with the gene clusters in D. melanogaster,D. pseudoobscura ST, D. kikkawai, andD. ananassae. Open circles refer tocentromeres of chromosomes. Orienta-tions of the Amy genes are indicated byarrows if they are known. Open rec-tangles indicate a pseudogene or partialsequence available. Genes in gray donot have signiﬁcant expression infor-mation available or are Amyrel genes.
The D. melanogaster arrangement istaken from Boer and Hickey (1986),D. pseudoobscura ST from Brown et al.
(1990), D. kikkawai from Inomata andYamazaki (2000), and D. ananassaefrom Da Lage et al. (2000). The ﬁgureshows just the organization of theAmy gene clusters, not the real sizes anddistances between genes.
corresponding cluster 1’s (Inomata and Yamazaki plication but of frequent gene conversions in the 2000; Da Lage et al. 2000; Zhang et al. 2002). All the coding region. Concerted evolution of the tandemly above observations suggest that the two Amy clusters duplicated genes was also reported in a study on the within species have experienced frequent duplication, Amy genes in D. kikkawai and its sibling species gene and regulatory losses, and divergent evolution.
(Inomata and Yamazaki 2000). The phylogenetic tree This appears to be consistent with a birth-and-death in Fig. 1 shows that the mon-cluster 1 has a branching pattern very similar to that of the melanogaster sub- On the other hand, on the basis of the observations group Amy cluster and that the tandemly repeated of the electrophoretic polymorphism of amylases and members within species group by cluster. Further- southern hybridization of a molecular probe speciﬁc more, the head-to-head gene arrangements of the two for the a-amylase coding region in the melanogaster tandemly repeated members are conserved for mon- subgroup species, Dainou et al. (1987) and Payant et cluster 1 of D. kikkawai and Amy (p) and Amy (d) of al. (1988) demonstrated that duplication of the tan- D. melanogaster (Fig. 2). All of these results suggest demly repeated Amy members predated the speciation that concerted evolution holds for the members within events within the melanogaster species subgroup.
Furthermore, Hickey et al. (1991) found that the 50-ﬂanking and 30-ﬂanking region sequences are highly divergent between the two tandemly repeated Amymembers in D. melanogaster and D. erecta, while the The Amy gene family in Drosophila is a relatively coding region of the two genes in D. melanogaster had small multigene family. The melanogaster subgroup extreme similarity compared with the homologous species and some other species have one gene cluster sequence in D. erecta. This suggests that the two with two or three tandemly arrayed members. They copies were not the consequence of very recent du- have been shown to be subject to concerted evolution (Hickey et al. 1991; Shibata and Yamazaki 1995; a structural basis for divergent evolution. That is, the Popadic et al. 1996). We also observed that the Amy nontandemly arrayed members of this gene family genes within the cluster evolved in a concerted man- most likely evolved independently of each other and ner (Table 1 and Fig. 1). Since the Amy genes within have little probability for gene conversion and unequal the cluster are tandemly repeated (Fig. 2), concerted crossing-over. However, strong purifying selection evolution is the expected result. However, for the two maintains sequence homogeneity at amino acid level.
types of Amy genes with a genomic organization of This scenario also explains the recent observation that nontandem repeats of each other, they evolve inde- the nontandemly repeated histone 3genes evolve in- pendently and divergently. In this sense, members dependently and retain amino acid sequence homoge- with diﬀerent genomic organizations, even if in the neity under strong purifying selection (Rooney et al.
same gene family, may exhibit diﬀerent evolutionary 2002). It must be pointed out that our postulation on modes. In other words, the diﬀerent genomic organ- conservative syntenic groups of Amy genes in the izations of a gene family may determine the evolu- montium subgroup species should be plausible, because the montium subgroup species used in this study are We have shown that two duplication events oc- closely related and their two types of Amy genes exhibit curred independently and relatively recently in dif- very similar expression and phylogenetic patterns ferent Drosophila lineages, resulting in two types of Amy genes in these species. The two types of Amy Finally, it should be pointed out that a decisive ar- genes cluster by type and not by species (Fig. 1).
gument for a common origin of the Amy clusters and Furthermore, it is most likely that the melanogaster the subsequent loss of one Amy cluster in only the subgroup lost one of the two types of Amy genes (Fig.
melanogaster subgroup will require examination of the 1). The shared evolutionary rate at the ﬁrst and sec- cluster structure of the Amy genes in related species at a ond codon positions of the paralogs suggests strong phylogenetic (taxonomic) level intermediate between purifying selection at the amino acid level. On the the melanogaster and the montium subgroups, that is, other hand, one cluster, which is located close to the species belonging to the so-called oriental subgroups centromere, experienced a signiﬁcant decrease in GC3 (Ashburner 1989), such as D. elegans and D. takahashi.
content, while the other maintained it (see Fig. 1 and This leaves open future experimental research. How- Table 1). Comparing with Figs. 1 and 2, we would ever, the occurrence in D. eugracilis, another species expect that the melanogaster subgroup species lost the belonging to the oriental subgroups, of an electroph- Amy cluster 2 with a lower GC3content in the past oretic pattern of two very distinct groups of variants after duplication. In the preceding work, we found similar to that of D. kikkawai (Inomata et al. 1995) that the Amy gene cluster 2 with a lower GC3content suggests that they are encoded by two sets of duplicated lost some cis-regulatory elements compared with gene Amy genes. This seems to be a good indication of a cluster 1 in the montium subgroup species (Inomata structure similar to that of mon-clusters 1 and 2.
and Yamazaki 2000; Zhang et al. 2002). Similarly, D.
ananasse Amyi5, with a lower GC3content, also lost We are grateful to Drs. J.L. Thorne and D.
a putative midgut regulatory element, whereas other Lachaise for helpful discussions and to two anonymous reviewers copies maintain it in this species (Da Lage et al.
for helpful comments that improved our manuscript. This work has 2000). These observations suggest that a decrease in been supported by BIRD of the Japan Science and Technology GC3content is coupled with gene and regulatory Corporation (JST) and the Japan Society for Promotion of Science(JSPS to H.K.).
element loss after duplication. This also implies thatone of the two types of Amy genes is undergoing afunctional decay process. All the above observations suggested that the two types of Amy genes experi-enced relatively recent gene duplications, gene loss, Arnheim N (1983) Concerted evolution of multigene families. In: and divergent evolution and are consistent with a Nei M, Koehn RK (eds) Evolution of genes and proteins. Si- birth-and-death process with strong purifying selec- Ashburner MD (1989) Drosophila. A laboratory handbook. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY Previous studies indicate that in D. kikkawai species, Beverley SM, Wilson AC (1984) Molecular evolution in Drosophila the two Amy clusters reside in diﬀerent genomic loca- and the higher Diptera. II. A time scale for ﬂy evolution. J Mol tions on the same chromosome at a considerable dis- tance from each other (Inomata and Yamazaki 2000).
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