Energetic evolution of cellular Transportomes

Energetic evolution of cellular Transportomes Background: Transporter proteins mediate the translocation of substances across the membranes of living cells. Many transport processes are energetically expensive and the cells use 20 to 60% of their energy to power the transportomes. We hypothesized that there may be an evolutionary selection pressure for lower energy transporters. Results: We performed a genome-wide analysis of the compositional reshaping of the transportomes across the kingdoms of bacteria, archaea, and eukarya. We found that the share of ABC transporters is much higher in bacteria and archaea (ca. 27% of the transportome) than in primitive eukaryotes (13%), algae and plants (10%) and in fungi and animals (5–6%). This decrease is compensated by an increased occurrence of secondary transporters and ion channels. The share of ion channels is particularly high in animals (ca. 30% of the transportome) and algae and plants with (ca. 13%), when compared to bacteria and archaea with only 6–7%. Therefore, our results show a move to a preference for the low-energy-demanding transporters (ion channels and carriers) over the more energy-costly transporter classes (ATP-dependent families, and ABCs in particular) as part of the transition from prokaryotes to eukaryotes. The transportome analysis also indicated seven bacterial species, including Neorickettsia risticii and Neorickettsia sennetsu, as likely origins of the mitochondrion in eukaryotes, based on the phylogenetically restricted presence therein of clear homologues of modern mitochondrial solute carriers. Conclusions: The results indicate that the transportomes of eukaryotes evolved strongly towards a higher energetic efficiency, as ATP-dependent transporters diminished and secondary transporters and ion channels proliferated. These changes have likely been important in the development of tissues performing energetically costly cellular functions. Keywords: Energetic efficiency, Evolution, Cellular membrane, Mitochondria, Transporters Background cellular events such as the acquisition of mitochondria by The expansion of life on Earth has involved competition eukaryotes. This enabled an increase of eukaryotic cell size and also cooperation among organisms for the utilisation and complexity due to a more “efficient” generation of the of resources which have been accessible to them [1, 2]. cellular fuel ATP [6, 7]. Cells need to allocate considerable Arguments have been made in favour of growth rate over resources to energize their transportomes. For example, growth efficiency in organisms competing within a specific brain neurons account for approximately 20% of the basal niche [3], which implies a natural selection towards an metabolic rate in humans, mostly for the movement of improved ability to capture and utilize the available free ions across neuronal membranes [8]. In general, a meta- energy sources for survival and reproduction [4, 5]. bolic cost of up to 60% of the total ATP requirement in Darwinian evolutionary theory originally covered only organisms is estimated for the activity of their transpor- phenotypic improvements at the organismal level, but we tomes [9, 10]. Thus, it would be reasonable to imagine nowadays also recognize the importance of molecular and that an improved energetic performance of the transpor- tome has contributed to a higher fitness over the course * Correspondence: dbk@manchester.ac.uk; irbo@biosustain.dtu.dk of evolution. The Novo Nordisk Foundation Center for Biosustainability, Technical Despite the importance of cellular transportomes (also University of Denmark, 2800 Lyngby, Denmark reported as the second largest component of the human Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Darbani et al. BMC Genomics (2018) 19:418 Page 2 of 11 membrane proteome [11]), transporters are surprisingly classes of transporters, i.e., ion channels, secondary trans- understudied [12]. Additionally, the presence of porters, and ATP-dependent transporters. To translocate substrate-binding proteins as the partners of a subset of substrates, ATP-dependent transporters bind and membrane transporters [13] makes the cellular transport hydrolyse ATP [21], ion channels form pores for selective machinery more complicated than if we consider only diffusion of ions and small molecules, and the secondary the transporters themselves. The tightening of porous transporters shuttle substrate molecules across biological and leaky primordial envelopes such that they did not let membranes either through energy independent facilitated in (and could learn to efflux) all kinds of substances [14, diffusion or via exploiting membrane electrochemical poten- 15] has been proposed as a turning point for membrane tial gradients through uniport, symport and antiport [22]. transporters to co-evolve together with lipid bilayer membranes [16]. Different classes of transporters, each in- Results cluding several transporter superfamilies, share a common To study the compositional changes of transportomes, ancestral family of peptides which carry 1–4transmem- we analysed the transportomes of 249 evolutionarily dis- brane domains and form homo- and hetero-oligomer tant species (of which 222 were annotated in this study) channels [17–20]. Intragenic duplication and triplication from archaea, bacteria and eukarya. These included 126 have been the major events promoting the diversification prokaryotic species (from 16 taxonomic phyla and 60 of transporter proteins [18, 20]. Classical evolutionary the- taxonomic orders), 30 primitive eukaryotes (different ory on the basis of natural selection proposed by Charles species from Alveolata, Kinetoplastida and Amoebozoa), Darwin [4, 5] explains how the random variability of the 30 algal and plant species, 30 fungal species, and 33 ani- genome as the diversification force has given the chance mal species (See Additional file 2: Data S1). The trans- for specialisation, improved performance, and adaptation portomes were annotated using the Transporter to the continuously changing biosphere. Here, we anno- Automatic Annotation Pipeline at TransportDB [23]. tated the cellular transportomes of bacteria, archaea and Notably, the species had large differences in the size of eukarya and analysed their composition with a focus on both their genomes and their transportomes (Fig. 1a, b the energetic efficiency. The analyses include all the three and Additional file 2: Data S1). Fig. 1 Transportomes differ in size among species and evolutionarily distant domains of life. (a) The number of membrane transporters per organism in relation to the genome size. (b) The number of membrane transporters per genome in relation to the number of total genes. (c) Percentage of transporter-coding genes in relation to gene density Darbani et al. BMC Genomics (2018) 19:418 Page 3 of 11 We found that the sizes of an organism’s transportome eukaryotic kingdoms along with the transportome enlarge- tends to increase with its genome size, though there are ment (Fig. 2a). Specifically, we found higher intra-genomic considerable intra-kingdom variations (Fig. 1a) (see also frequencies (frequency relative to the total number of genes [24]). In particular, primitive eukaryotes have small in the genome) of ATP-dependent transport classes in transportomes with 100–500 members, relative to their prokaryotes than eukaryotes. An opposing trend was found genome sizes of tens of Mb when compared to the bac- for low-energy-demanding transport classes. This indicates teria with modestly sized genomes (less than 10 Mb). different rates of gene proliferation among the evolved Ion channels, secondary transporters, and primary active transporter classes; low-energy-demanding transporter transporters were found in each of the analysed domains families have expanded at a higher rate. Notably, the trans- of life (See Additional file 2: Data S1). This indicates a portomes of primitive eukaryotes also represent a transition very early appearance for these three classes of trans- state between prokaryotic and higher eukaryotic kingdoms porters, possibly in a common ancestor. (Fig. 2a). In agreement with previous reports [25, 26], the genome We further compared the prevalence of secondary size had a higher rate of enlargement than did the gene transporters, ion channels, and ATP-dependent number, resulting in a decreased gene density over the transporters within the transportomes of each spe- course of evolution (Fig. 1c). The transportome enlarge- cies, and averaged these over the larger taxonomic ment was found to be well correlated with the increase in groups (Fig. 2b-d). In general, we observed compo- the gene number (r = 0.937) with the exception of sitional changes that indicate a positive adaptive (Pearson) primitive eukarya, where the transportome-encoding selection of the no- to low-cost-flux equilibrative ion proportion of genes was the lowest (Fig. 1b, c). Of most channels and carriers, and negative selection of the interest, the composition of the transportomes changed energetically more expensive ABC transporters. More from prokaryotes to eukaryotes and also among the specifically, we found significant variations in each Fig. 2 The evolutionary dynamics of transportomes composition. (a) Heat-map representation of the changes in the number of members of the transporter classes. To calculate the intra-genomic frequencies, the numbers of transporter members are normalized to the total number of genes per genome. The heat-map is drawn for each class of ion channels, secondary transporters, and ATP-dependent transporters and therefore colors are not comparable between the classes. (b) The fraction of ATP-dependent transporters in the transportomes. All of the variations of ATP-dependent transporters and ABC superfamily except the difference between bacteria and archaea are significant with a p-value less than 0.001. (c) The fraction of secondary transporters in the transportomes. Only the difference between bacteria and animals is not statistically significant (p =0.635). (d) The fraction of ion channels in the transportomes. All differences, except among fungi, bacteria and archaea, are significant with a p-value less than 0.001. The values on panels b-d are shown as mean +/− t-test based 99% confidence intervals. The variations were also confirmed on the arc sin √x transformed data (See Additional file 2: Data S1). The family names of the transporters can also be found in the Additional file 2: Data S1 Darbani et al. BMC Genomics (2018) 19:418 Page 4 of 11 of the transporter classes (Fig. 2b-d). While 27% of on both transporter classes for the evolution of their all the bacterial and archaeal transporters are ABC transportomes (Fig. 2b-d). For energetically efficient transporters, this fraction decreases to 13% in primi- transportomes, organisms therefore adopted different tive eukaryotes, 10% in algae and plants and a mere strategies, likely due to their specialisations and different 5–6% in fungi and animals (Fig. 2b). On the other requirements. In fact, this recalls cooperative evolution hand, an increased contribution to the cellular at tissue and molecular levels (see also [2, 27]). The transportome was found for secondary transporters trend of expansion of ion channels and secondary in eukaryotes, particularly in fungi (Fig. 2c). Ion transporters at the expense of ATP-dependent trans- channels accounted for only 6–7% of bacterial and porters also holds true for the prokaryotic transportomes archaeal transportomes, but were more abundant in (Fig. 3), even though they did not undergo the kind of algae and plants (≈ 13%) and particularly in animals intensive developmental specialisation as was required in (≈ 30%) (Fig. 2d). During evolution, and in parallel multicellular eukaryotes. with the genome enlargement and gene pool expan- The analyses also indicate family member expansions sion, each of the three classes of transporters had a for secondary transporters (from 60 to 100 in prokaryotes chance to contribute proportionally to the expansion to more than 400 in animals and 600 in plants on average) of transportomes. By contrast, our results show a and ion channels (from 10 members in prokaryotes to preference for the low-energy demanding trans- more than 300 members in animals). To find prokaryotic- porters (ion channels and carriers) over the and eukaryotic-specific families, we further enriched our energy-costly transporter classes (ATP-dependent analysis by including the publicly-available data for the families, and ABCs in particular) in the transition secondary transporters and ion channels of prokaryotes from prokaryotes to eukaryotes. found at TransportDB 2.0 (http://www.membranetran- We defined the energy usage efficiency of a transpor- sport.org/transportDB2/index.html). This extended our tome (EUE) as the average required energy per single prokaryotes to 2637 transportomes (Additional file 1: substrate translocation. We calculated the EUE values Table S1). We also included two eukaryotic transportomes for the transportomes studied (more details in the from diatoms found at TransportDB 2.0 (Additional file 1: Methods section). The EUE describes the overall ener- Table S1). When comparing the organisms for the getic performance of transportomes at organismal level presence of different transporter families, we found and most importantly it does not indicate the total en- that eight secondary transporter families were com- ergy consumption by the cellular transportome, because pletely lost in the passage to eukaryotes (Fig. 4). This the latter depends also on the flux through individual includes the 2-hydroxycarboxylate transporter family, transporters that is largely unknown. In contrast to the the p-aminobenzoyl-glutamate transporter family, the total energy requirements, the EUE is therefore not short chain fatty acid uptake (AtoE) family, the + + subjected to spatiotemporal variations. By comparing the monovalent cation (K or Na ):proton antiporter-3 average EUEs of the transportomes across the different family, the branched chain amino acid:cation sympor- + + domains of life, we found that the EUE has improved in ter family, the NhaB Na :H antiporter family, the eukaryotes by reductions of up to 0.50 ATP in the riboflavin transporter family, and the Na -dependent average ATP consumption per single transport event bicarbonate transporter family (See Additional file 2: mediated by transporters (Table 1). Data S1). Additionally, we found that six new families Furthermore, the data suggest that animals have of secondary transporters had emerged in eukaryotes mainly relied on the diversification of ion channels, fungi (Fig. 4, See also Additional file 2:DataS1).Specifi- on secondary transporters, and finally, algae and plants cally, we did not find any prokaryotic hits in Table 1 Improvement in the energy-usage efficiency (ΔEUE) calculated as changes in the average ATP-usage per single transport cycle Domains of life Bacteria Archaea Primitive eukaryotes Algae and plants Fungi Animals Bacteria 0 Archaea −0.03 0 Primitive eukaryotes −0.16 − 0.14 0 Algae and plants −0.27 −0.25 − 0.11 0 Fungi −0.30 −0.27 − 0.13 −0.02 0 Animals −0.49 −0.46 − 0.32 −0.21 − 0.19 0 The changes (ΔEUE) are calculated as ATP-usage – ATP-usage (see methods) domain of life in the matrix-row domain of life in the matrix-column Negative changes represent the reduction in ATP-usage and improved EUE of transportomes Darbani et al. BMC Genomics (2018) 19:418 Page 5 of 11 Fig. 3 The compositional changes in the transportomes of prokaryotes with different genome sizes. (a) Comparison between the transportome size and total gene number among prokaryotes including bacteria and archaea. All of the 126 studied species are clustered into three groups based on the total number of the genes. (b) The fraction of ATP-dependent transporters in the transportomes. (c) The fraction of secondary transporters in the transportomes. (d) The fraction of ion channels in the transportomes. The values on panels b-d are shown as mean +/− t-test based 99% confidence interval. The variations were also confirmed on the arc sin √x transformed data (See Additional file 2: Data S1). Group I and III differ significantly for all of the transporter classes with a p-value of < 0.001 GenBank for these eukaryotic families, that must have presence of the mitochondrial transporter family members diverged massively [28] from some ancestral genes. indicates that these seven bacterial species are possible or- Our results are mostly in agreement with the igins of the mitochondrion in eukaryotes. The first two intra-family speciation of transporters reported by species are Gram-negative obligatory intracellular bacteria Renand Paulsen[29]. In contrast, we also found that from the order Rickettsiales, an order that in previous ion channels had evolved through both intra-family studies was proposed (based on different evidence) as expansions and the substantial appearance of new the most likely origin of the mitochondrion in families. While there were only seven ion channel families eukaryotes [28, 30–35]. The present findings add specific to the prokaryotes, there are 18 eukarya-specific significant evidence to this proposal. families (Fig. 4, See also Additional file 2: Data S1). Inter- estingly, the mitochondria-specific solute carriers, i.e., sol- Discussion ute carrier family SLC25 [30, 31], are absent from the Our genome-wide analysis on the compositional reshap- transportomes of all 143 archaeal species (See Additional ing of the transportomes across the kingdoms of bac- file 1: Table S1 for the list of organisms). Among the bac- teria, archaea, and eukarya suggests an evolutionary teria, including 259 alpha-proteobacteria, of which 69 preference for energetically efficient transportomes. Our belonged to the order Rickettsiales, we found only seven analyses also mapped some ancestral mitochodrial car- bacterial genomes that encoded members of the rier members of SLC25 into the bacterial genomes and mitochondrial transporter family. These are Neorickettsia excluded the archaeal species. These ancesters include risticii, Neorickettsia sennetsu, Legionella pneumophila, two bacteria from the order Rickettsiales. Rickettsiales Legionella longbeachae, Acidaminococcus intestini, Cardi- are considered to be the mitochodrial origin [32–35]. It nium endosymbiont and Butyrivibrio proteoclasticus.The seems the eukaryotic members of the SLC25 family, all Darbani et al. BMC Genomics (2018) 19:418 Page 6 of 11 Fig. 4 Number of transporter families that are shared between or are specific for prokaryotes and eukaryotes with 6 transmembrane domains, have diverged massively nitrogen. Marine microorganisms faced with low levels from their bacterial ancesters with 4–5 transmembrane of nitrogen show reduced levels of nitrogen in amino domains. In agreement with Calvo et al. [36], the ab- acid sequences, especially in highly expressed proteins, sence of SLC25 homologues in the genome of Rickettsia which reduces the total cellular nitrogen budget by up to prowazekii, a species from the Rickettsiales, was also 10% [41]. There are also observations on the energetic confirmed in this study; we did not find any ancestral evolution at a phenotypic level. For example, an SLC25 coding genes among the 10 different strains of energetic trade-off between maximum population dens- Rickettsia prowazekii that were included in the analysis. ity and body size has been reported in [42]. Energetic A higher ratio of secondary transporters to primary constraints have also been proposed for the number of ATP-driven transporters was previously reported for neurons, which determines the brain size [43]. At a yeast when compared to prokaryotes [37]. This is add- molecular level, although both the solute carrier SLC2 itionally complemented by a relatively large genomic family of facilitated glucose transporters and the SLC5 survey on 141 species, of which 9 species were family of energy-dependent sodium/glucose cotranspor- eukaryotic [29]. Our results on the general compos- ters participate in glucose uptake, the human brain has itional changes of transportomes are in agreement with largely been dependent on SLC2 transporters for the en- the findings of Ren and Poulsen [29]. The publication by ergetically free supply of glucose [44]. Positive selection Ren and Poulsen, however, did not report the energetics and gene expression adjustments, such that they allocate of transportomes or the detailed analysis of transporter higher energy fluxes to the brain, have been reported for classes. Resource depletion and inadequate nutrition the SLC2 members in the human branch that has a affect survival but can also increase energetic efficiency, larger brain compared to the chimpanzees and macaques that is fitness, in the course of evolution [38]. For ex- [45]. This indicates the importance of the energetic ample, the adaptation to chronic energy stress has been evolution of membrane transporters, even at the single hypothesized to be partly responsible for the general family level, and highlights the possibly huge impacts of capacity of archaea to out-compete bacteria [39]. In the energetic evolution of the entire transportomes on addition, energetic evolution of gene expression has also organismal adaptation and speciation. On the other been discussed by addressing the preference for major hand, the higher dependency of bacterial and archaeal codons in highly expressed genes, which alleviates the species on the ATP-driven transporters is also interest- costly processes of proofreading and removal of dysfunc- ing. It could be related to the higher affinities of ATP tional proteins [40]. Another environmental stress transporters that allowed the cells to capture rare reported to affect codon usage is the low availability of substrates more efficiently. It is also possible that ATP Darbani et al. BMC Genomics (2018) 19:418 Page 7 of 11 transporters have diversified from the early ATP transportomes during the course of evolution, a very synthases and this partly explains why they are therefore significant finding. so abundant in bacteria and archaea. All of the eight prokarya-specific secondary transporter Conclusions families (Additional file 2: Data S1) were energy-dependent, The present inter-kingdom comparison of transportomes i.e., dependent on a proton or sodium gradient, or utilizing a provides genome-scale molecular evidence for their evolu- combination of electro- and chemical potential of the mem- tion towards an improved energetic efficiency. This has brane [46–51]. A surprising insight here was related to the likely been very influential due to the high energy demand six evolutionarily younger secondary transporter families of the cellular transport machinery and also for the found only in eukaryotes (See Additional file 2:DataS1):four development of tissues performing energetically costly of these, about which we have experimental information, functions. The present data also strengthen members of were energy-independent and low-energy-demanding trans- the previously reported bacterial order Rickettsiales as the porter families for bile acid, choline, silicate, and vitamin A. origin of the mitochondrion by recognising Neorickettsia The last two belong to the 4 TMS multidrug endosomal risticii and Neorickettsia sennetsu as the sole species in transporter and chloroplast maltose exporter families. The this order whose genomes harbor putative choline transporter-like family is involved in choline influx mitochondria-specific solute carrier (SLC25) coding genes. [52]. The ‘birth’ of a cheap and sodium-independent trans- Since other evidence had also suggested Rickettsiales as porter for choline is important because of the broad cellular candidates for this, our transoportome findings strengthen usage of choline. Choline is an essential precursor for mem- considerably the case for such a lineage. branes and for the neuromodulator acetylcholine [53, 54]. Another recently evolved transport family was the organic Methods solute transporter family, which is involed in the facilitated The publicly-available membrane transporter data on ion diffusion of bile acids from enterocytes into the blood [55]. channels and secondary transporters were extracted from The silicon transporter family is also energetically cheap and TransportDB (http://www.membranetransport.org/trans- has a silicate:sodium symport stoichiometry of 1:1 [56]. Fi- portDB2/)[23].The transportomes of 126prokaryotic nally, the animal-specific vitamin A receptor/transporter species (78 bacteria and 48 archaea) and 96 eukaryotic (STRA6) mediates costless influx and efflux of vitamin A de- species (22 primitive eukaryotes, 24 algae and plants, 23 rivatives by a mechanism not seen in any other transporter fungi, and 27 animals) (See Additional file 2:Data S1) class [57, 58]. Of particular interest, the animal visual were annotated using the Transporter Automatic Annota- system is dependent on vitamin A and has a tion Pipeline at TransportDB [23]. We also included 27 substantial energetic cost, e.g., up to 15% of resting eukaryotic species including the transportomes of 8 primi- metabolism in the Mexican fish Astyanax mexicanus tive eukaryotes, 6 algae and plants, 7 fungi, and 6 animals [59, 60]. Such photo-detection involves the publicly available at TransportDB (See Additional file 2: single-photon-triggered isomerization of 11-cis-retinal Data S1). To study the compositional changes of transpor- to all-trans-retinal, which must be recycled back tomes, we did not include any transportomes from pro- through efflux and influx steps of these isomers be- karyotes publicly available at the TransportDB. This is due tween the retinal pigmented epithelial and photo- to the incomplete information on the ABC transporters. receptor cells [57, 61–63]. Thus, the evolved The majority of ABC transporters in prokaryotes are energy-independent membrane translocation of the coded by different genes of an operon, where each gene vitamin A isomers seems to be an adaptive trait for codes for different subunits [66], and these should be ex- higher energetic performance. This is in line with the cluded from the data and considered as single transporters positive selection reported for STRA6 in different in our analyses on the transportome composition. mammalian phyla [64]. Additionally, we found a However, this information on the ABC coding genes and higher representation of ion channels in the animal operons is not provided for the publicly-available trans- kingdom when compared to the other domains of life portomes of prokaryotes. (Fig. 2d). The membrane transport of ions is im- To predict the transportomes, the proteomes of organ- portant for highly energy-demanding sensory tissues isms were downloaded from the Genbank and Ensembl [8, 65] and it can therefore be hypothesized that the databases (http://www.ensembl.org/index.html, http:// extensive diversification of ion channels and the cost- fungi.ensembl.org/index.html, http://protists.ensem- less transport of vitamin A in animals are trade-offs bl.org/index.html, http://plants.ensembl.org/index.html) between the benefits of the evolved nervous and [67]. All proteins with fewer than 100 amino acids were visual systems and their high energy requirements. excluded. Taken together, we analysed 78 bacterial, 48 Overall, our findings demonstrate a clear and archaeal, 30 primitive eukaryotes, 30 algal and plant, 30 unequivocal change in the energetic efficiency of fungal, and 33 animal transportomes, each representing Darbani et al. BMC Genomics (2018) 19:418 Page 8 of 11 one independent biological replicate (per species). The secondary transporters, and ion-channels, respectively. list of organisms with their genome size and total num- The F/V/A-type ATPases and ATP synthases were ber of transporters is shown in Additional file 2: Data S1 excluded from the ATP-dependent transporters. This is and Additional file 1: Table S1. The annotated transpor- because they provide the energy as ATP or membrane tomes were manually filtered for multi-prediction hits as electrochemical potential for the rest of the transporters. well as the alternative isoforms of transport proteins It is worthy of note that the efficiency of energy usage before the analysis. Taken together, our analyses on the indicates the average energy demand per unit of action. transporter families included all of the 15 So the expression and activity levels of transporters are ATP-dependent transporter families, 51 ion channel not taken into the account when calculating the EUE. A families, and 90 secondary transporter families which more general example would compare two organisms were present in the studied organisms. We used Stu- with exactly the same transportome but with differences dent’s t-test to examine the possible differences among in the expression levels of transportome members the samples, i.e., domains of life. The data were in the among them. Here, the EUE of transportome machine- format of counts and percentages. Therefore, to exclude ries of the two organisms are equal since they use a possible divergence from normality, we also performed exactly same transportome machinery. This is thus the analyses on the arc sin √x transformed data. All the irrespective of the differences in activity levels of trans- analyses can be found in Additional file 2: Data S1. porters, which define the total energy demand for the To make an approximation of the energetic perform- given transportome. ance of the cellular transportomes, we calculated the inter-transportome changes in energy-usage efficiency Additional files (EUE), which we defined as the average free energy Additional file 1: Table S1. The list of organisms with publicly-available demand for a single transport event. The following as- data on the ion channels and secondary transporters. (DOCX 168 kb) sumptions were made when calculating EUE values. Equil- Additional file 2: Data S1. Genomic and transportome data on the ibrative ion channels require no free energy for the organisms included in the study. (XLSX 255 kb) transport action. While some of the secondary trans- porters also act in an energy-independent manner known Abbreviations as equilibrative transport or facilitated diffusion, others ex- ADT: ATP-dependent transporters; EUE: energy-usage efficiency; IC: ion- ploit the electrochemical potential established by ATPases channels; ST: secondary transporters across membranes [14, 22, 68–70]. For active transport, Acknowledgements secondary transporters are considered to use membrane The authors thank Dr. Gavin H. Thomas from the University of York for electrochemical potential gradients, coupled to a varying discussions and advice. Shahin Noeparvar from the Aarhus University is acknowledged for discussions and participation into the genomic data stoichiometry (0.5 to 3) of ions per turnover [69, 71–92]. processing. Considering the stoichiometry of ≈ 2–3ionspumpedper ATP hydrolysed by ATPases [93–102], even concentrative Funding B.D. and I.B. acknowledge the financial support by the Novo Nordisk secondary transporters would not use more than 0.5 ATP Foundation (grant number NNF10CC1016517). The project has received equivalent per substrate translocation across a membrane funding from the European Research Council (ERC) under the European on average. The average of two substrates per ATP tends, Union’s Horizon 2020 research and innovation programme (Grant Agreement no. 757384). D.B.K. thanks the Biotechnology and Biological therefore, to be conservative for secondary transporters Sciences Research Council (grants BB/M006891/1, BB/M017702/1 and BB/ and a higher rate of substrate translocation can also be P009042/1) for financial support. expected. In contrast, the ATP-dependent members belonging to the ABC superfamily, and also the mitochon- Availability of data and materials All data generated or analysed during this study are included in this drial protein translocase, the type III secretory pathway, published article and its supplementary information files (Additional file the chloroplast envelope protein translocase, and the 2: Data S1 and Additional file 1: Table S1). The raw genomic data are arsenite-antimonite efflux families, generally show a 1:2 publicly-available at http://www.ensembl.org/index.html, http://fungi.en- sembl.org/index.html, http://protists.ensembl.org/index.html,and http:// stoichiometry of substrate:ATP hydrolysis [103–109]. To plants.ensembl.org/index.html. calculate the inter-transportome variations in the energy-usage efficiency (ΔEUE), we therefore applied the Authors’ contributions BD, DBK, and IB conceived the study. BD performed the analyses by equation: consulting DBK and IB. BD, DBK, and IB wrote the manuscript. All authors read and approved the final manuscript. ΔEUEðÞ ΔATP−usage per single transport cycle Ethics approval and consent to participate ¼½2  Δ%ADT þ 0:5  Δ%ST ATP ATP Not applicable. þ0:0  Δ%IC=100; ATP Competing interests where ADT, ST, and IC are ATP-dependent transporters, The authors declare that they have no competing interests. Darbani et al. BMC Genomics (2018) 19:418 Page 9 of 11 Publisher’sNote 25. Lynch M, Conery JS. The origins of genome complexity. Science. 2003; Springer Nature remains neutral with regard to jurisdictional claims in 302:1401–4. published maps and institutional affiliations. 26. Hou Y, Lin S. Distinct gene number-genome size relationships for eukaryotes and non-eukaryotes: gene content estimation for dinoflagellate Author details genomes. PLoS ONE. 2009;4:e6978. The Novo Nordisk Foundation Center for Biosustainability, Technical 27. Frank SA. 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Energetic evolution of cellular Transportomes

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Abstract

Background: Transporter proteins mediate the translocation of substances across the membranes of living cells. Many transport processes are energetically expensive and the cells use 20 to 60% of their energy to power the transportomes. We hypothesized that there may be an evolutionary selection pressure for lower energy transporters. Results: We performed a genome-wide analysis of the compositional reshaping of the transportomes across the kingdoms of bacteria, archaea, and eukarya. We found that the share of ABC transporters is much higher in bacteria and archaea (ca. 27% of the transportome) than in primitive eukaryotes (13%), algae and plants (10%) and in fungi and animals (5–6%). This decrease is compensated by an increased occurrence of secondary transporters and ion channels. The share of ion channels is particularly high in animals (ca. 30% of the transportome) and algae and plants with (ca. 13%), when compared to bacteria and archaea with only 6–7%. Therefore, our results show a move to a preference for the low-energy-demanding transporters (ion channels and carriers) over the more energy-costly transporter classes (ATP-dependent families, and ABCs in particular) as part of the transition from prokaryotes to eukaryotes. The transportome analysis also indicated seven bacterial species, including Neorickettsia risticii and Neorickettsia sennetsu, as likely origins of the mitochondrion in eukaryotes, based on the phylogenetically restricted presence therein of clear homologues of modern mitochondrial solute carriers. Conclusions: The results indicate that the transportomes of eukaryotes evolved strongly towards a higher energetic efficiency, as ATP-dependent transporters diminished and secondary transporters and ion channels proliferated. These changes have likely been important in the development of tissues performing energetically costly cellular functions. Keywords: Energetic efficiency, Evolution, Cellular membrane, Mitochondria, Transporters Background cellular events such as the acquisition of mitochondria by The expansion of life on Earth has involved competition eukaryotes. This enabled an increase of eukaryotic cell size and also cooperation among organisms for the utilisation and complexity due to a more “efficient” generation of the of resources which have been accessible to them [1, 2]. cellular fuel ATP [6, 7]. Cells need to allocate considerable Arguments have been made in favour of growth rate over resources to energize their transportomes. For example, growth efficiency in organisms competing within a specific brain neurons account for approximately 20% of the basal niche [3], which implies a natural selection towards an metabolic rate in humans, mostly for the movement of improved ability to capture and utilize the available free ions across neuronal membranes [8]. In general, a meta- energy sources for survival and reproduction [4, 5]. bolic cost of up to 60% of the total ATP requirement in Darwinian evolutionary theory originally covered only organisms is estimated for the activity of their transpor- phenotypic improvements at the organismal level, but we tomes [9, 10]. Thus, it would be reasonable to imagine nowadays also recognize the importance of molecular and that an improved energetic performance of the transpor- tome has contributed to a higher fitness over the course * Correspondence: dbk@manchester.ac.uk; irbo@biosustain.dtu.dk of evolution. The Novo Nordisk Foundation Center for Biosustainability, Technical Despite the importance of cellular transportomes (also University of Denmark, 2800 Lyngby, Denmark reported as the second largest component of the human Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Darbani et al. BMC Genomics (2018) 19:418 Page 2 of 11 membrane proteome [11]), transporters are surprisingly classes of transporters, i.e., ion channels, secondary trans- understudied [12]. Additionally, the presence of porters, and ATP-dependent transporters. To translocate substrate-binding proteins as the partners of a subset of substrates, ATP-dependent transporters bind and membrane transporters [13] makes the cellular transport hydrolyse ATP [21], ion channels form pores for selective machinery more complicated than if we consider only diffusion of ions and small molecules, and the secondary the transporters themselves. The tightening of porous transporters shuttle substrate molecules across biological and leaky primordial envelopes such that they did not let membranes either through energy independent facilitated in (and could learn to efflux) all kinds of substances [14, diffusion or via exploiting membrane electrochemical poten- 15] has been proposed as a turning point for membrane tial gradients through uniport, symport and antiport [22]. transporters to co-evolve together with lipid bilayer membranes [16]. Different classes of transporters, each in- Results cluding several transporter superfamilies, share a common To study the compositional changes of transportomes, ancestral family of peptides which carry 1–4transmem- we analysed the transportomes of 249 evolutionarily dis- brane domains and form homo- and hetero-oligomer tant species (of which 222 were annotated in this study) channels [17–20]. Intragenic duplication and triplication from archaea, bacteria and eukarya. These included 126 have been the major events promoting the diversification prokaryotic species (from 16 taxonomic phyla and 60 of transporter proteins [18, 20]. Classical evolutionary the- taxonomic orders), 30 primitive eukaryotes (different ory on the basis of natural selection proposed by Charles species from Alveolata, Kinetoplastida and Amoebozoa), Darwin [4, 5] explains how the random variability of the 30 algal and plant species, 30 fungal species, and 33 ani- genome as the diversification force has given the chance mal species (See Additional file 2: Data S1). The trans- for specialisation, improved performance, and adaptation portomes were annotated using the Transporter to the continuously changing biosphere. Here, we anno- Automatic Annotation Pipeline at TransportDB [23]. tated the cellular transportomes of bacteria, archaea and Notably, the species had large differences in the size of eukarya and analysed their composition with a focus on both their genomes and their transportomes (Fig. 1a, b the energetic efficiency. The analyses include all the three and Additional file 2: Data S1). Fig. 1 Transportomes differ in size among species and evolutionarily distant domains of life. (a) The number of membrane transporters per organism in relation to the genome size. (b) The number of membrane transporters per genome in relation to the number of total genes. (c) Percentage of transporter-coding genes in relation to gene density Darbani et al. BMC Genomics (2018) 19:418 Page 3 of 11 We found that the sizes of an organism’s transportome eukaryotic kingdoms along with the transportome enlarge- tends to increase with its genome size, though there are ment (Fig. 2a). Specifically, we found higher intra-genomic considerable intra-kingdom variations (Fig. 1a) (see also frequencies (frequency relative to the total number of genes [24]). In particular, primitive eukaryotes have small in the genome) of ATP-dependent transport classes in transportomes with 100–500 members, relative to their prokaryotes than eukaryotes. An opposing trend was found genome sizes of tens of Mb when compared to the bac- for low-energy-demanding transport classes. This indicates teria with modestly sized genomes (less than 10 Mb). different rates of gene proliferation among the evolved Ion channels, secondary transporters, and primary active transporter classes; low-energy-demanding transporter transporters were found in each of the analysed domains families have expanded at a higher rate. Notably, the trans- of life (See Additional file 2: Data S1). This indicates a portomes of primitive eukaryotes also represent a transition very early appearance for these three classes of trans- state between prokaryotic and higher eukaryotic kingdoms porters, possibly in a common ancestor. (Fig. 2a). In agreement with previous reports [25, 26], the genome We further compared the prevalence of secondary size had a higher rate of enlargement than did the gene transporters, ion channels, and ATP-dependent number, resulting in a decreased gene density over the transporters within the transportomes of each spe- course of evolution (Fig. 1c). The transportome enlarge- cies, and averaged these over the larger taxonomic ment was found to be well correlated with the increase in groups (Fig. 2b-d). In general, we observed compo- the gene number (r = 0.937) with the exception of sitional changes that indicate a positive adaptive (Pearson) primitive eukarya, where the transportome-encoding selection of the no- to low-cost-flux equilibrative ion proportion of genes was the lowest (Fig. 1b, c). Of most channels and carriers, and negative selection of the interest, the composition of the transportomes changed energetically more expensive ABC transporters. More from prokaryotes to eukaryotes and also among the specifically, we found significant variations in each Fig. 2 The evolutionary dynamics of transportomes composition. (a) Heat-map representation of the changes in the number of members of the transporter classes. To calculate the intra-genomic frequencies, the numbers of transporter members are normalized to the total number of genes per genome. The heat-map is drawn for each class of ion channels, secondary transporters, and ATP-dependent transporters and therefore colors are not comparable between the classes. (b) The fraction of ATP-dependent transporters in the transportomes. All of the variations of ATP-dependent transporters and ABC superfamily except the difference between bacteria and archaea are significant with a p-value less than 0.001. (c) The fraction of secondary transporters in the transportomes. Only the difference between bacteria and animals is not statistically significant (p =0.635). (d) The fraction of ion channels in the transportomes. All differences, except among fungi, bacteria and archaea, are significant with a p-value less than 0.001. The values on panels b-d are shown as mean +/− t-test based 99% confidence intervals. The variations were also confirmed on the arc sin √x transformed data (See Additional file 2: Data S1). The family names of the transporters can also be found in the Additional file 2: Data S1 Darbani et al. BMC Genomics (2018) 19:418 Page 4 of 11 of the transporter classes (Fig. 2b-d). While 27% of on both transporter classes for the evolution of their all the bacterial and archaeal transporters are ABC transportomes (Fig. 2b-d). For energetically efficient transporters, this fraction decreases to 13% in primi- transportomes, organisms therefore adopted different tive eukaryotes, 10% in algae and plants and a mere strategies, likely due to their specialisations and different 5–6% in fungi and animals (Fig. 2b). On the other requirements. In fact, this recalls cooperative evolution hand, an increased contribution to the cellular at tissue and molecular levels (see also [2, 27]). The transportome was found for secondary transporters trend of expansion of ion channels and secondary in eukaryotes, particularly in fungi (Fig. 2c). Ion transporters at the expense of ATP-dependent trans- channels accounted for only 6–7% of bacterial and porters also holds true for the prokaryotic transportomes archaeal transportomes, but were more abundant in (Fig. 3), even though they did not undergo the kind of algae and plants (≈ 13%) and particularly in animals intensive developmental specialisation as was required in (≈ 30%) (Fig. 2d). During evolution, and in parallel multicellular eukaryotes. with the genome enlargement and gene pool expan- The analyses also indicate family member expansions sion, each of the three classes of transporters had a for secondary transporters (from 60 to 100 in prokaryotes chance to contribute proportionally to the expansion to more than 400 in animals and 600 in plants on average) of transportomes. By contrast, our results show a and ion channels (from 10 members in prokaryotes to preference for the low-energy demanding trans- more than 300 members in animals). To find prokaryotic- porters (ion channels and carriers) over the and eukaryotic-specific families, we further enriched our energy-costly transporter classes (ATP-dependent analysis by including the publicly-available data for the families, and ABCs in particular) in the transition secondary transporters and ion channels of prokaryotes from prokaryotes to eukaryotes. found at TransportDB 2.0 (http://www.membranetran- We defined the energy usage efficiency of a transpor- sport.org/transportDB2/index.html). This extended our tome (EUE) as the average required energy per single prokaryotes to 2637 transportomes (Additional file 1: substrate translocation. We calculated the EUE values Table S1). We also included two eukaryotic transportomes for the transportomes studied (more details in the from diatoms found at TransportDB 2.0 (Additional file 1: Methods section). The EUE describes the overall ener- Table S1). When comparing the organisms for the getic performance of transportomes at organismal level presence of different transporter families, we found and most importantly it does not indicate the total en- that eight secondary transporter families were com- ergy consumption by the cellular transportome, because pletely lost in the passage to eukaryotes (Fig. 4). This the latter depends also on the flux through individual includes the 2-hydroxycarboxylate transporter family, transporters that is largely unknown. In contrast to the the p-aminobenzoyl-glutamate transporter family, the total energy requirements, the EUE is therefore not short chain fatty acid uptake (AtoE) family, the + + subjected to spatiotemporal variations. By comparing the monovalent cation (K or Na ):proton antiporter-3 average EUEs of the transportomes across the different family, the branched chain amino acid:cation sympor- + + domains of life, we found that the EUE has improved in ter family, the NhaB Na :H antiporter family, the eukaryotes by reductions of up to 0.50 ATP in the riboflavin transporter family, and the Na -dependent average ATP consumption per single transport event bicarbonate transporter family (See Additional file 2: mediated by transporters (Table 1). Data S1). Additionally, we found that six new families Furthermore, the data suggest that animals have of secondary transporters had emerged in eukaryotes mainly relied on the diversification of ion channels, fungi (Fig. 4, See also Additional file 2:DataS1).Specifi- on secondary transporters, and finally, algae and plants cally, we did not find any prokaryotic hits in Table 1 Improvement in the energy-usage efficiency (ΔEUE) calculated as changes in the average ATP-usage per single transport cycle Domains of life Bacteria Archaea Primitive eukaryotes Algae and plants Fungi Animals Bacteria 0 Archaea −0.03 0 Primitive eukaryotes −0.16 − 0.14 0 Algae and plants −0.27 −0.25 − 0.11 0 Fungi −0.30 −0.27 − 0.13 −0.02 0 Animals −0.49 −0.46 − 0.32 −0.21 − 0.19 0 The changes (ΔEUE) are calculated as ATP-usage – ATP-usage (see methods) domain of life in the matrix-row domain of life in the matrix-column Negative changes represent the reduction in ATP-usage and improved EUE of transportomes Darbani et al. BMC Genomics (2018) 19:418 Page 5 of 11 Fig. 3 The compositional changes in the transportomes of prokaryotes with different genome sizes. (a) Comparison between the transportome size and total gene number among prokaryotes including bacteria and archaea. All of the 126 studied species are clustered into three groups based on the total number of the genes. (b) The fraction of ATP-dependent transporters in the transportomes. (c) The fraction of secondary transporters in the transportomes. (d) The fraction of ion channels in the transportomes. The values on panels b-d are shown as mean +/− t-test based 99% confidence interval. The variations were also confirmed on the arc sin √x transformed data (See Additional file 2: Data S1). Group I and III differ significantly for all of the transporter classes with a p-value of < 0.001 GenBank for these eukaryotic families, that must have presence of the mitochondrial transporter family members diverged massively [28] from some ancestral genes. indicates that these seven bacterial species are possible or- Our results are mostly in agreement with the igins of the mitochondrion in eukaryotes. The first two intra-family speciation of transporters reported by species are Gram-negative obligatory intracellular bacteria Renand Paulsen[29]. In contrast, we also found that from the order Rickettsiales, an order that in previous ion channels had evolved through both intra-family studies was proposed (based on different evidence) as expansions and the substantial appearance of new the most likely origin of the mitochondrion in families. While there were only seven ion channel families eukaryotes [28, 30–35]. The present findings add specific to the prokaryotes, there are 18 eukarya-specific significant evidence to this proposal. families (Fig. 4, See also Additional file 2: Data S1). Inter- estingly, the mitochondria-specific solute carriers, i.e., sol- Discussion ute carrier family SLC25 [30, 31], are absent from the Our genome-wide analysis on the compositional reshap- transportomes of all 143 archaeal species (See Additional ing of the transportomes across the kingdoms of bac- file 1: Table S1 for the list of organisms). Among the bac- teria, archaea, and eukarya suggests an evolutionary teria, including 259 alpha-proteobacteria, of which 69 preference for energetically efficient transportomes. Our belonged to the order Rickettsiales, we found only seven analyses also mapped some ancestral mitochodrial car- bacterial genomes that encoded members of the rier members of SLC25 into the bacterial genomes and mitochondrial transporter family. These are Neorickettsia excluded the archaeal species. These ancesters include risticii, Neorickettsia sennetsu, Legionella pneumophila, two bacteria from the order Rickettsiales. Rickettsiales Legionella longbeachae, Acidaminococcus intestini, Cardi- are considered to be the mitochodrial origin [32–35]. It nium endosymbiont and Butyrivibrio proteoclasticus.The seems the eukaryotic members of the SLC25 family, all Darbani et al. BMC Genomics (2018) 19:418 Page 6 of 11 Fig. 4 Number of transporter families that are shared between or are specific for prokaryotes and eukaryotes with 6 transmembrane domains, have diverged massively nitrogen. Marine microorganisms faced with low levels from their bacterial ancesters with 4–5 transmembrane of nitrogen show reduced levels of nitrogen in amino domains. In agreement with Calvo et al. [36], the ab- acid sequences, especially in highly expressed proteins, sence of SLC25 homologues in the genome of Rickettsia which reduces the total cellular nitrogen budget by up to prowazekii, a species from the Rickettsiales, was also 10% [41]. There are also observations on the energetic confirmed in this study; we did not find any ancestral evolution at a phenotypic level. For example, an SLC25 coding genes among the 10 different strains of energetic trade-off between maximum population dens- Rickettsia prowazekii that were included in the analysis. ity and body size has been reported in [42]. Energetic A higher ratio of secondary transporters to primary constraints have also been proposed for the number of ATP-driven transporters was previously reported for neurons, which determines the brain size [43]. At a yeast when compared to prokaryotes [37]. This is add- molecular level, although both the solute carrier SLC2 itionally complemented by a relatively large genomic family of facilitated glucose transporters and the SLC5 survey on 141 species, of which 9 species were family of energy-dependent sodium/glucose cotranspor- eukaryotic [29]. Our results on the general compos- ters participate in glucose uptake, the human brain has itional changes of transportomes are in agreement with largely been dependent on SLC2 transporters for the en- the findings of Ren and Poulsen [29]. The publication by ergetically free supply of glucose [44]. Positive selection Ren and Poulsen, however, did not report the energetics and gene expression adjustments, such that they allocate of transportomes or the detailed analysis of transporter higher energy fluxes to the brain, have been reported for classes. Resource depletion and inadequate nutrition the SLC2 members in the human branch that has a affect survival but can also increase energetic efficiency, larger brain compared to the chimpanzees and macaques that is fitness, in the course of evolution [38]. For ex- [45]. This indicates the importance of the energetic ample, the adaptation to chronic energy stress has been evolution of membrane transporters, even at the single hypothesized to be partly responsible for the general family level, and highlights the possibly huge impacts of capacity of archaea to out-compete bacteria [39]. In the energetic evolution of the entire transportomes on addition, energetic evolution of gene expression has also organismal adaptation and speciation. On the other been discussed by addressing the preference for major hand, the higher dependency of bacterial and archaeal codons in highly expressed genes, which alleviates the species on the ATP-driven transporters is also interest- costly processes of proofreading and removal of dysfunc- ing. It could be related to the higher affinities of ATP tional proteins [40]. Another environmental stress transporters that allowed the cells to capture rare reported to affect codon usage is the low availability of substrates more efficiently. It is also possible that ATP Darbani et al. BMC Genomics (2018) 19:418 Page 7 of 11 transporters have diversified from the early ATP transportomes during the course of evolution, a very synthases and this partly explains why they are therefore significant finding. so abundant in bacteria and archaea. All of the eight prokarya-specific secondary transporter Conclusions families (Additional file 2: Data S1) were energy-dependent, The present inter-kingdom comparison of transportomes i.e., dependent on a proton or sodium gradient, or utilizing a provides genome-scale molecular evidence for their evolu- combination of electro- and chemical potential of the mem- tion towards an improved energetic efficiency. This has brane [46–51]. A surprising insight here was related to the likely been very influential due to the high energy demand six evolutionarily younger secondary transporter families of the cellular transport machinery and also for the found only in eukaryotes (See Additional file 2:DataS1):four development of tissues performing energetically costly of these, about which we have experimental information, functions. The present data also strengthen members of were energy-independent and low-energy-demanding trans- the previously reported bacterial order Rickettsiales as the porter families for bile acid, choline, silicate, and vitamin A. origin of the mitochondrion by recognising Neorickettsia The last two belong to the 4 TMS multidrug endosomal risticii and Neorickettsia sennetsu as the sole species in transporter and chloroplast maltose exporter families. The this order whose genomes harbor putative choline transporter-like family is involved in choline influx mitochondria-specific solute carrier (SLC25) coding genes. [52]. The ‘birth’ of a cheap and sodium-independent trans- Since other evidence had also suggested Rickettsiales as porter for choline is important because of the broad cellular candidates for this, our transoportome findings strengthen usage of choline. Choline is an essential precursor for mem- considerably the case for such a lineage. branes and for the neuromodulator acetylcholine [53, 54]. Another recently evolved transport family was the organic Methods solute transporter family, which is involed in the facilitated The publicly-available membrane transporter data on ion diffusion of bile acids from enterocytes into the blood [55]. channels and secondary transporters were extracted from The silicon transporter family is also energetically cheap and TransportDB (http://www.membranetransport.org/trans- has a silicate:sodium symport stoichiometry of 1:1 [56]. Fi- portDB2/)[23].The transportomes of 126prokaryotic nally, the animal-specific vitamin A receptor/transporter species (78 bacteria and 48 archaea) and 96 eukaryotic (STRA6) mediates costless influx and efflux of vitamin A de- species (22 primitive eukaryotes, 24 algae and plants, 23 rivatives by a mechanism not seen in any other transporter fungi, and 27 animals) (See Additional file 2:Data S1) class [57, 58]. Of particular interest, the animal visual were annotated using the Transporter Automatic Annota- system is dependent on vitamin A and has a tion Pipeline at TransportDB [23]. We also included 27 substantial energetic cost, e.g., up to 15% of resting eukaryotic species including the transportomes of 8 primi- metabolism in the Mexican fish Astyanax mexicanus tive eukaryotes, 6 algae and plants, 7 fungi, and 6 animals [59, 60]. Such photo-detection involves the publicly available at TransportDB (See Additional file 2: single-photon-triggered isomerization of 11-cis-retinal Data S1). To study the compositional changes of transpor- to all-trans-retinal, which must be recycled back tomes, we did not include any transportomes from pro- through efflux and influx steps of these isomers be- karyotes publicly available at the TransportDB. This is due tween the retinal pigmented epithelial and photo- to the incomplete information on the ABC transporters. receptor cells [57, 61–63]. Thus, the evolved The majority of ABC transporters in prokaryotes are energy-independent membrane translocation of the coded by different genes of an operon, where each gene vitamin A isomers seems to be an adaptive trait for codes for different subunits [66], and these should be ex- higher energetic performance. This is in line with the cluded from the data and considered as single transporters positive selection reported for STRA6 in different in our analyses on the transportome composition. mammalian phyla [64]. Additionally, we found a However, this information on the ABC coding genes and higher representation of ion channels in the animal operons is not provided for the publicly-available trans- kingdom when compared to the other domains of life portomes of prokaryotes. (Fig. 2d). The membrane transport of ions is im- To predict the transportomes, the proteomes of organ- portant for highly energy-demanding sensory tissues isms were downloaded from the Genbank and Ensembl [8, 65] and it can therefore be hypothesized that the databases (http://www.ensembl.org/index.html, http:// extensive diversification of ion channels and the cost- fungi.ensembl.org/index.html, http://protists.ensem- less transport of vitamin A in animals are trade-offs bl.org/index.html, http://plants.ensembl.org/index.html) between the benefits of the evolved nervous and [67]. All proteins with fewer than 100 amino acids were visual systems and their high energy requirements. excluded. Taken together, we analysed 78 bacterial, 48 Overall, our findings demonstrate a clear and archaeal, 30 primitive eukaryotes, 30 algal and plant, 30 unequivocal change in the energetic efficiency of fungal, and 33 animal transportomes, each representing Darbani et al. BMC Genomics (2018) 19:418 Page 8 of 11 one independent biological replicate (per species). The secondary transporters, and ion-channels, respectively. list of organisms with their genome size and total num- The F/V/A-type ATPases and ATP synthases were ber of transporters is shown in Additional file 2: Data S1 excluded from the ATP-dependent transporters. This is and Additional file 1: Table S1. The annotated transpor- because they provide the energy as ATP or membrane tomes were manually filtered for multi-prediction hits as electrochemical potential for the rest of the transporters. well as the alternative isoforms of transport proteins It is worthy of note that the efficiency of energy usage before the analysis. Taken together, our analyses on the indicates the average energy demand per unit of action. transporter families included all of the 15 So the expression and activity levels of transporters are ATP-dependent transporter families, 51 ion channel not taken into the account when calculating the EUE. A families, and 90 secondary transporter families which more general example would compare two organisms were present in the studied organisms. We used Stu- with exactly the same transportome but with differences dent’s t-test to examine the possible differences among in the expression levels of transportome members the samples, i.e., domains of life. The data were in the among them. Here, the EUE of transportome machine- format of counts and percentages. Therefore, to exclude ries of the two organisms are equal since they use a possible divergence from normality, we also performed exactly same transportome machinery. This is thus the analyses on the arc sin √x transformed data. All the irrespective of the differences in activity levels of trans- analyses can be found in Additional file 2: Data S1. porters, which define the total energy demand for the To make an approximation of the energetic perform- given transportome. ance of the cellular transportomes, we calculated the inter-transportome changes in energy-usage efficiency Additional files (EUE), which we defined as the average free energy Additional file 1: Table S1. The list of organisms with publicly-available demand for a single transport event. The following as- data on the ion channels and secondary transporters. (DOCX 168 kb) sumptions were made when calculating EUE values. Equil- Additional file 2: Data S1. Genomic and transportome data on the ibrative ion channels require no free energy for the organisms included in the study. (XLSX 255 kb) transport action. While some of the secondary trans- porters also act in an energy-independent manner known Abbreviations as equilibrative transport or facilitated diffusion, others ex- ADT: ATP-dependent transporters; EUE: energy-usage efficiency; IC: ion- ploit the electrochemical potential established by ATPases channels; ST: secondary transporters across membranes [14, 22, 68–70]. For active transport, Acknowledgements secondary transporters are considered to use membrane The authors thank Dr. Gavin H. Thomas from the University of York for electrochemical potential gradients, coupled to a varying discussions and advice. Shahin Noeparvar from the Aarhus University is acknowledged for discussions and participation into the genomic data stoichiometry (0.5 to 3) of ions per turnover [69, 71–92]. processing. Considering the stoichiometry of ≈ 2–3ionspumpedper ATP hydrolysed by ATPases [93–102], even concentrative Funding B.D. and I.B. acknowledge the financial support by the Novo Nordisk secondary transporters would not use more than 0.5 ATP Foundation (grant number NNF10CC1016517). The project has received equivalent per substrate translocation across a membrane funding from the European Research Council (ERC) under the European on average. The average of two substrates per ATP tends, Union’s Horizon 2020 research and innovation programme (Grant Agreement no. 757384). D.B.K. thanks the Biotechnology and Biological therefore, to be conservative for secondary transporters Sciences Research Council (grants BB/M006891/1, BB/M017702/1 and BB/ and a higher rate of substrate translocation can also be P009042/1) for financial support. expected. In contrast, the ATP-dependent members belonging to the ABC superfamily, and also the mitochon- Availability of data and materials All data generated or analysed during this study are included in this drial protein translocase, the type III secretory pathway, published article and its supplementary information files (Additional file the chloroplast envelope protein translocase, and the 2: Data S1 and Additional file 1: Table S1). The raw genomic data are arsenite-antimonite efflux families, generally show a 1:2 publicly-available at http://www.ensembl.org/index.html, http://fungi.en- sembl.org/index.html, http://protists.ensembl.org/index.html,and http:// stoichiometry of substrate:ATP hydrolysis [103–109]. To plants.ensembl.org/index.html. calculate the inter-transportome variations in the energy-usage efficiency (ΔEUE), we therefore applied the Authors’ contributions BD, DBK, and IB conceived the study. BD performed the analyses by equation: consulting DBK and IB. BD, DBK, and IB wrote the manuscript. All authors read and approved the final manuscript. ΔEUEðÞ ΔATP−usage per single transport cycle Ethics approval and consent to participate ¼½2  Δ%ADT þ 0:5  Δ%ST ATP ATP Not applicable. þ0:0  Δ%IC=100; ATP Competing interests where ADT, ST, and IC are ATP-dependent transporters, The authors declare that they have no competing interests. Darbani et al. BMC Genomics (2018) 19:418 Page 9 of 11 Publisher’sNote 25. Lynch M, Conery JS. The origins of genome complexity. Science. 2003; Springer Nature remains neutral with regard to jurisdictional claims in 302:1401–4. published maps and institutional affiliations. 26. Hou Y, Lin S. Distinct gene number-genome size relationships for eukaryotes and non-eukaryotes: gene content estimation for dinoflagellate Author details genomes. PLoS ONE. 2009;4:e6978. The Novo Nordisk Foundation Center for Biosustainability, Technical 27. Frank SA. 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BMC GenomicsSpringer Journals

Published: May 30, 2018

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