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COMMENTARY

Secondary loss of in trypanosomes

William Martin*† and Piet Borst‡ *Institute of Botany III, Universita¨t Du¨ sseldorf, Universita¨tstrasse 1, D-40225 Du¨sseldorf, Germany; and ‡Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, NL-1066 CX Amsterdam, The Netherlands

n page 1067 in this issue of matid genes is that encoding sedoheptu- long known to contain an enigmatic or- PNAS, Hannaert et al. (1) lose-1,7-bisphosphatase (SPBase), an ganelle in their cytosol, called the hohl- present evidence for the idea enzyme specific to the Calvin cycle in zylinder. In 1984, a 35-kb circular DNA that trypanosomes once pos- chloroplasts. In terms of both se- molecule was found in Toxoplasma (8), Osessed a that they lost some quence similarities and its enzymatic and Ian Wilson and colleagues later time in their distant evolutionary past. It properties, this enzyme is specific to showed that this DNA is a highly re- would probably be going overboard to , because cyanobacteria use a side duced chloroplast genome (9), whereas call trypanosomes in disguise, but Geoff McFadden and colleagues discov- for a protozoan parasite without any ered that the hohlzylinder itself is in trace of chloroplast remnants, the try- It would fact a highly reduced (10). These panosome is now shown to possess a insights led to the discovery that some remarkable number of enzymes of probably be going compounds that inhibit plant-specific plant-related origin. This finding ad- pathways, much the way that herbicides vances our understanding of trypano- overboard to call do, also kill apicomplexan parasites, some biology and could even help ef- opening up new opportunities for the forts to discover drugs to treat trypanosomes development of treatments for apicom- trypanosomatid-caused diseases. plexan-caused maladies (11). Typanosomatids are unicellular eu- algae in disguise. Yet in contrast to the apicomplexans, karyotes belonging to the order of Kin- the trypanosomatids have retained etoplastidae; they are among the most no detectable trace of a membrane- versatile parasites in nature, infecting activity of their highly distinct fructose- bounded that might represent mammals, fish, and plants, and are usu- 1,6-bisphosphatase for the correspond- a plastid relict: the plastid compartment ally transmitted by insect vectors. Major ing reaction and lack a specific SPBase has been reduced to the point that it has human diseases caused by - altogether. disappeared entirely (Fig. 1). All that tids are leishmaniases ( spe- These new findings raise an obvious remains are a number of genes in the cies), sleeping sickness (Trypanosoma evolutionary question: What photosyn- nucleus that were transferred from the brucei variants), and Chagas’ disease thetic lineage was the source of these symbiont’s genome, the unmistakable (). Drugs for treating plant-like traits and genes? Hannaert et imprint of endosymbiosis. How many these diseases are few and toxic, and al. point to the , which contain algal genes might the trypanosomatid resistance is on the rise (2, 3). Because numerous photosynthetic members in- lineage have acquired during its prior these diseases predominantly affect poor cluding gracilis. On the basis of life as an alga? In Arabidopsis, as much people in (sub)tropical developing coun- comparative cytology and morphology, as 18% of all nuclear genes seem to be tries, development of new drugs is not a taxonomists have traditionally placed the acquisitions from the genome of their high priority of the pharmaceutical in- trypanosomatids and the euglenids in a primary plastid (12). Complete genome dustry. Yet academic labs are hunting well-circumscribed common group, the data will be forthcoming for Leishmania for new drug targets, so the discovery of . They share many unusual and possibly for other trypanosomatids plant-like enzymes in T. brucei is good and defining molecular traits as well, news indeed. in the course of 2003 (3). This finding including the unusual base ‘‘J’’ (␤-D- The evidence for secondary loss of will permit a more detailed analysis of glucosyl-hydroxymethyluracil) in their in trypanosomes stems from the the numbers and kinds of genes that nuclear DNA (6). The plastids of the genome sequencing programs that are these organisms acquired from their euglenids are surrounded by three mem- now well underway for Leishmania, T. plastid. brucei, and T. cruzi.§ Hints for the pres- branes, which is the sure sign of second- A flood of recent papers indicates ence of plant- and plastid-derived genes ary endosymbiosis, that is, Euglena ac- that the acquisition of genes from or- in trypanosomatids came from analyses quired its plastid through engulfment of ganelles has been a major force in the of two enzymes involved in the hexose a eukaryotic green alga, rather than evolution of unicellular (13). phosphate shunt (4) and of trypanoso- through engulfment of a cyanobacterium Wholesale incorporation of genes and matid peroxidases (5). Hannaert et al. (primary symbiosis) (7). Hannaert et al. genomes acquired via endosymbiosis was (1) now report a substantial number of suggest, as the most reasonable and sim- at least as important, if not more so, to plant-like trypanosomatid genes, most of plest of all possible explanations, that genome evolution in these organisms which are involved in core carbohydrate trypanosomatids and euglenids pos- than the laborious route of gene dupli- metabolism. For many of these genes, sessed one and the same green second- cation and genetic drift among endoge- the sequence comparisons reveal a spe- ary plastid, which was retained in the nously generated surplus copies. ‘‘You cific evolutionary affinity between the euglenids but lost through reduction in the trypanosomatid lineage. trypanosome gene and a higher plant, See companion article on page 1067. algal, or cyanobacterial homolog, indi- The new findings by Hannaert et al. cating that at some time in the evolu- are reminiscent of the malaria parasite †To whom correspondence should be addressed. E-mail: [email protected]. tionary past, some photosynthetic cell story. Two major apicomplexan para- § ࿝ sites, falciparum, the infec- For T. brucei, see www.sanger.ac.uk/Projects/T brucei/ and donated quite a few genes into the www.tigr.org/tdb/mdb/tbdb/index.shtml; for L. major, see trypanosomatid lineage. One of the tious agent of malaria, and Toxoplasma www.sanger.ac.uk/Projects/L࿝major/; for T. cruzi, see www. most conclusive of the green trypanoso- gondii, which causes toxoplasmosis, were tigr.org/tdb/e2k1/tca1.

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0437776100 PNAS ͉ February 4, 2003 ͉ vol. 100 ͉ no. 3 ͉ 765–767 Downloaded by guest on September 28, 2021 nated by the that need not be encoded in the organelle). The trypanosomatids have gone one step further: They have kept the bath water (the acquired genes) but have tossed out the baby (the plastid). The trypanosomatids are by no means the only organisms to have lost a plas- tid. In fact, plastid loss is turning out to be a surprisingly common theme in cell evolution (22), particularly among para- sites. A striking example concerns the oomycetes, a group of -like pro- tists that have cell walls of cellulose (rather than chitin, as is typical of fungi) and that contains many important agri- cultural pathogens of crop plants, among them the agent of potato blight, Phytophthora infestans. Molecular studies have revealed that the oomycetes are not fungi at all, but rather are derived from algae that became secondarily non- photosynthetic through loss of their plastids (22, 23). Moreover, secondary loss of or- ganelles is not restricted to plastids, either. Mitochondria can be lost, or ‘‘lost and found’’ as well, as newer findings have shown. A prime example here is Entamoeba histolytica,anim- portant intestinal pathogen of humans, which was long thought to be without mitochondria (amitochondriate) and which obtains all of its ATP through a cytosolic pathway called extended gly- colysis (24). However, a small highly Fig. 1. Schematic diagram indicating how trypanosomes may have come to acquire their plant-like reduced relict mitochondrion was re- genes. The common ancestry indicated here for the and trypanosome plastid is the simplest of several possibilities to account for the current findings. Electron micrograph courtesy of Keith Vickermann. cently discovered in Entamoeba, and this apparently has no function in core ATP production (25, 26). One suspi- are what you eat,’’ wrote Doolittle (14), chromosome 2 (17, 18), and in rice, a cion is that such relict mitochondria when it comes to gene donations from contiguous 33-kb fragment of the chlo- might be retained because they are . When organelles lyse, a roplast genome, 99.7% identical to the needed for the assembly of iron–sulfur whole organelle-genome’s worth of organelle copy, can be found on nuclear clusters, an essential function present DNA is suddenly in the cytosol, just chromosome 10 (19). Such transfer in mitochondria (27) and in hydro- waiting to get into the nuclear chromo- events are likely to have been as preva- genosomes (28), anaerobic H2-produc- somes via illegitimate recombination. lent in the past as they are today, and ing forms of mitochondria found When host cells lyse, on the other hand, the encoded proteins can be targeted to among many that inhabit the result is not transfer to the or- organelles other than the ones from niches too poor in oxygen to support typical respiration (24). ganelle, but cell . This one-way which the genes were donated (12), in Another striking example of second- street will inexorably drive the integra- line with the newer findings from try- ary loss involves the microsporidia, tion of organelle genes into the chromo- panosomes (1). which cause secondary infection in somes of their host (14). For function- When a host cell acquires an endo- AIDS patients. These protists were long ally equivalent genes, the intruding symbiont, the latter must have a genome thought to be amitochondriate and fur- genes may have an advantage for fixa- complete enough to support a free-liv- thermore to be one of the earliest- tion as long as a copy remains in the ing lifestyle, but contemporary organelle branching eukaryotic lineages based on organelle, because if one integration genomes are the most highly reduced their position in the rRNA tree. Recent does not lead to fixation, the next one genomes known. Only a few percent of genome-based work has, however, can, or the next, and so forth. the genes that were once present in the shown that they are in fact highly modi- Newer findings suggest that the main genomes of ancestral chloroplasts and fied fungi (29) and, perhaps even more mechanism of organelle-to-nucleus mitochondria are still retained in these remarkably, that they have not com- transfer is in fact the direct integration organelles today (20). The remainder pletely lost their mitochondrion after all of bulk DNA from organelles, probably was either discarded or put to new use (30). Furthermore, there is the case of lysed ones (15, 16). In Arabidopsis, for in the host. As Palenik (21) put it in a intestinalis. This pathogen of example, a copy of the entire 367-kb recent commentary in these pages: the human intestinal tract has yet to mitochondrial genome, 99% identical to Hosts keep the baby (the plastid) and reveal cytological evidence for a mito- the organelle copy, can be found on the bath water (additional genes do- chondrion-derived organelle, but it pos-

766 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0437776100 Martin and Borst Downloaded by guest on September 28, 2021 sesses mitochondrion-derived genes in counterparts in peroxisomes of other model predicts that trypanosomes and its genome, indicating the past presence eukaryotes. Furthermore, import of euglenids possessed one and the same of a mitochondrion that was secondarily proteins into requires the plastid, but other more complicated lost (31, 32), much like the case of the same targeting signals as in peroxi- scenarios cannot be excluded. For ex- trypanosomatid plastid. somes. Thus, it seems that some en- ample, the trypanosome lineage might In one respect, the trypanosomatids zymes that were ‘‘abandoned’’ by their have already possessed a primary plas- differ from all other parasites that disappearing chloroplast have found a tid (35) before the euglenid lineage have lost an endosymbiotically derived new home inside the (1). acquired a secondary plastid. The anal- organelle: They have invented a new The evolutionary Odyssey of genes ysis of homologues from the Euglena organelle not present in any other eu- encoding the enzymes reported by genome should clarify such questions. karyotic group, the glycosome. Glyco- Hannaert et al. is sketched in Fig. 1. For parasitologists, the disappearing somes are specialized microbodies that Several of these genes entered into the plastid opens up new avenues for under- contain most of the enzymes of the eukaryotic cell through the (primary) standing trypanosomatids and combat- glycolytic pathway (33, 34). Interest- cyanobacterial ancestor of the chloro- ing the diseases that they cause. For ingly, some of these glycolytic enzymes plast and were transferred to the nu- evolutionary biologists, these findings now turn out to have a plastid-related cleus during the evolution of the green are a reminder that, fortunately or un- origin, which does not mean that the algae lineage. When a green alga was fortunately, things are rarely as simple glycosome is a withered evolutionary engulfed to give rise to the secondary as they seem. With genome projects of remnant of a plastid (1). The glyco- plastid of the euglenids and trypanoso- other now ongoing, data ana- some is an undisputed member of the matids, genes were transferred once lysts should be on the lookout for fur- peroxisome family; it is bounded by a again, this time from the nucleus of ther unexpected genes of cyanobacterial single membrane that contains proteins the eukaryotic endosymbiont to the or algal origin and the tell-tale trace of that are clearly homologous to their nucleus of the eukaryotic host. This organelles long gone.

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