 1999 Oxford University Press Nucleic Acids Research, 1999, Vol. 27, No. 8 1767–1780

SURVEY AND SUMMARY mitochondrial genomes Jeffrey L. Boore*

Department of Biology, University of Michigan, 830 North University Avenue, Ann Arbor, MI 48109-1048, USA

Received November 12, 1998; Revised and Accepted February 15, 1999

ABSTRACT 13 protein subunits of the enzymes of oxidative phosphorylation, the two rRNAs of the mitochondrial ribosome, and the 22 tRNAs Animal mitochondrial DNA is a small, extrachromosomal ∼ necessary for the translation of the proteins encoded by mtDNA. genome, typically 16 kb in size. With few exceptions, For historical reasons, these genes have designations specific to all animal mitochondrial genomes contain the same 37 animal mtDNA; Table 1 lists these along with their synonyms. Downloaded from genes: two for rRNAs, 13 for proteins and 22 for tRNAs. This gene content has been shown to vary only in nematodes The products of these genes, along with RNAs and (9–11), which lack A8, a bivalve (12) which both lacks A8 and proteins imported from the cytoplasm, endow mito- contains an extra tRNA, and cnidarians (13–18), which have lost chondria with their own systems for DNA replication, nearly all tRNA genes and gained one or two additional genes not transcription, mRNA processing and translation of

found so far in other mtDNAs (see below). All of the 37 genes http://nar.oxfordjournals.org/ proteins. The study of these genomes as they function typically found in animal mtDNA have homologs in the mtDNAs in mitochondrial systems—‘mitochondrial genomics’— of plants, fungi and/or protists (19–22). There is also generally a serves as a model for genome evolution. Furthermore, single large non-coding region which, for a few (23), is the comparison of animal mitochondrial gene arrange- known to contain controlling elements for replication and ments has become a very powerful means for inferring transcription. Whether these ‘control regions’ (assumed to be the ancient evolutionary relationships, since rearrange- largest non-coding segment) are homologous between distantly ments appear to be unique, generally rare events that related animals or, alternatively, have arisen from various are unlikely to arise independently in separate evolution- non-coding sequences independently in separate evolutionary ary lineages. Complete mitochondrial gene arrange- at Maastricht University on July 3, 2014 lineages is often unclear since they share no sequence similarity ments have been published for 58 chordate species and 29 non-chordate species, and partial arrangements except among closely related animals. Although the largest for hundreds of other taxa. This review compares and non-coding region is illustrated herein for many of these summarizes these gene arrangements and points out genomes, this is not necessarily to imply homology, and it is some of the questions that may be addressed by noteworthy that many mtDNAs also have other smaller non-coding comparing mitochondrial systems. regions that are not illustrated that may or may not contain controlling elements. In some mtDNAs all genes are transcribed from one strand, INTRODUCTION whereas in others the genes are distributed between the two Mitochondria play a central role in metabolism (1), apoptosis (2), strands. This is indicated in the text and figures by underlining disease (3) and aging (4). They are the site of oxidative right-to-left (as drawn) oriented genes. In the few cases where it has phosphorylation, essential for the production of ATP, as well as been studied, each strand is transcribed as a single large a variety of other biochemical functions. Within these subcellular polycistron which is post-transcriptionally processed into gene- organelles is a genome, separate from the nuclear chromatin, specific messages. Transfer RNA genes, whose secondary referred to as mitochondrial DNA (mtDNA), very commonly structures are thought to signal cleavage (24), punctuate the used in studies of molecular phylogenetics (5). Among multi- polycistron of some mtDNAs, but others have tRNA genes cellular animals this is nearly always a closed-circular molecule; clustered so as to preclude such a mechanism. Although potential only the cnidarian classes Cubozoa, Scyphozoa and Hydrozoa secondary structures have been proposed as substitutes at some of have been found to have linear mtDNA chromosomes (6). these gene junctions, no obvious secondary structures can be In animals, mtDNA is generally a small (15–20 kb) genome identified for most cases. It is possible that the ‘polycistron containing 37 genes. Although much larger mitochondrial model’ may not be appropriate for many of the animals whose genomes have occasionally been found, these are the product of mitochondrial gene expression remains unstudied. Whatever the duplications of portions of the mtDNA rather than variation in mechanisms of gene rearrangement (discussed below), it is clear gene content (7,8). The typical gene complement encodes that a new gene order must preserve, or enable substitutes for,

*Tel: +1 734 763 4375; Fax: +1 734 647 0884; Email: [email protected]

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Table 1. The 13 protein, two ribosomal RNA and 22 tRNA genes typically found in animal mitochondrial genomes

For historical reasons these have designations commonly used only for animal systems. To aid comparison with other works, column three lists the synonymous gene labels used for non-animal systems. Downloaded from whatever signals are necessary for transcription and processing of CHORDATA AND HEMICHORDATA RNAs from the rearranged genome. Although animal mitochondrial sequences are known to evolve Of the 87 complete metazoan mtDNA sequences that have been rapidly, their gene arrangements often remain unchanged over published, 58 are from chordates with all but two of these from long periods of evolutionary time. For example, the gene http://nar.oxfordjournals.org/ vertebrates. Table 2 lists these 58 species. There is little variation arrangements of human (25–27) and trout (28) mtDNAs are in gene arrangement; the 44 species listed without asterisks share identical (Table 1). With few exceptions, gene arrangements are an identical arrangement of all 37 genes. Many hundreds of other relatively stable within major groups, but variable between them, vertebrate species that are too numerous to include here have been and comparisons of these gene arrangements have great potential sampled for short regions identical to this common vertebrate for resolving some of the deepest branches of metazoan arrangement (many of these can be found at: www.biology.lsa. (multicellular animal) phylogeny. The great number of potential umich.edu/∼jboore ). gene arrangements makes it very unlikely that different taxa Figure 1A depicts this common vertebrate gene arrangement would independently adopt an identical state, so complex along with that of the primitive cephalochordate Branchiostoma at Maastricht University on July 3, 2014 rearrangements are unlikely to be convergent. Comparisons of (‘amphioxus’) (32,33). The gene arrangement of Branchiostoma mitochondrial gene arrangements have provided convincing varies from the common vertebrate arrangement only in the phylogenies in several cases where all other data were equivocal, location of four tRNA genes: F, G, M and N (marked with an including the relationships among major groups of echinoderms asterisk in Fig. 1A). In order to determine whether the primitive (29) and arthropods (30,31). gene arrangement for Chordata (Vertebrata plus Cephalochordata) is Many aspects of genome evolution (e.g. evolution of gene more like the common vertebrate arrangement or more like that rearrangements, gene regulation, message processing systems of Branchiostoma, one can compare with the arrangements of and replication mechanisms) may be tractable for mitochondrial lesser related taxa. The position of F is similar in the common systems at a level of detail and understanding not currently vertebrate arrangement and in the mtDNAs of echinoderms possible for nuclear systems. Questions that may be addressed by (Fig. 2) and the positions of G and M are identical in the common ‘mitochondrial genomics’ include: What are the patterns of arrangement and in the mtDNA of many arthropods (Fig. 3), so evolution of gene expression mechanisms? Which types of genes the most parsimonious interpretation is that the primitive rearrange most often? What aspects of genomic variation are arrangement of these tRNA genes for Chordata is the same as in correlated with aspects of physiology, molecular mechanisms or the common vertebrate arrangement, with later, independent life history? How do interacting molecular factors coevolve? Is rate translocations resulting in their positions in Branchiostoma of sequence evolution correlated with rate of gene rearrangements mtDNA. Since the position of N in Branchiostoma mtDNA is within a lineage? identical to that of the hemichordate Balanoglossus mtDNA (34), Comparisons of mitochondrial genomes may result in significant this must be the chordate primitive state, with its translocation insights into the evolution both of organisms and of genomes. Other from N-W-A-C-Y to W-A-N-C-Y occurring at the base of recent reviews summarize information about the mitochondrial Vertebrata (32). genomes of plants (20), protists (21) and fungi (22), and address As noted with asterisks in Table 2 and depicted in Figure 1, issues of the genetics and molecular biology of mitochondrial small-scale rearrangements have been found in several chordate systems (18,20,23). This summary of animal mitochondrial gene lineages. In each of these cases where a gene (i.e. other than the arrangements is given largely in the hope of stimulating further non-coding region, see below) rearrangement is shared it is a expansion of this data set, of encouraging broad phylogenetic valid marker of evolutionary relationships, although these comparisons of the basic molecular biology of mitochondrial particular relationships are not generally controversial. systems, and of advocating the development of better techniques The sea lamprey (35) has a translocation of E-Cytb and changes for comparison and analysis. in the locations of the non-coding regions. It was initially unclear 1769

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Table 2. Chordates for which the complete mitochondrial gene arrangement has been determined Downloaded from http://nar.oxfordjournals.org/

All the species share an identical arrangement of the 37 mitochondrial genes except those 14 marked with an asterisk. Database accession numbers are in parentheses. See Figure 1 for the specific deviations. if this arrangement could be the primitive state for vertebrates, but was accompanied by a duplication of the large non-coding region.

further outgroup comparisons convincingly demonstrate that it is, Random loss of one or the other of these non-coding regions at Maastricht University on July 3, 2014 rather, derived for the sea lamprey (see above). Several marsupials could then have produced either of the states found among birds. (36–38) also have a small scale change, a shared, derived Supporting this model is the commonality of duplicate non-coding rearrangement of W-A-N-C-Y to A-C-W-N-Y. This is not found in regions [e.g. in mtDNAs of Tuatara (45) and of several snakes a monotreme (39) or in eutherian mammals. (40,55,56)] and the presence of a secondary non-coding region Several reptiles have small scale, unique rearrangements. The between E and F in birds having gene order C (the location of the Texas blind snake (40), has a translocation of Q not shared by single non-coding region of gene order B). Although the authors other studied reptiles. An amphisbaenian reptile, Bipes, has an designate this as ‘nc’ for ‘non-coding’ to differentiate it from the independent duplication of T-P followed by the degeneration of ‘control region’, it may be more correct to view this as the one of these tRNAs into a pseudogene (see more below) (41). degenerating vestige of a duplicate control region; Figure 1 Several acrodont and agamid reptiles share an exchange of therefore designates it as a pseudo-control region. This view is position between I and Q (42,43). An alligator (44) and a reinforced by noting that the two species from which sequence of saltwater crocodile (45) share an exchange of the non-coding this region has been determined show no interspecies similarity region and F and this alligator shares with a crocodile, caiman (as though they result from independent paths of degeneration) and (40) and several squamate reptiles (40) an exchange in position that, in one of the cases (Smithornis), there is substantial sequence of S(AGY) and H. similarity between the designated ‘nc’ and ‘control region’. Many birds share an exchange of position between the blocks Although their nearest outgroup relative, the crocodile, does Cytb-T-P and ND6-E (46–53) (Table 2; Fig. 1A). In addition, a not share this rearrangement (45), the tuatara has two large recent study (54) identified two arrangements of bird mtDNAs non-coding regions, one in the same relative position as in birds (termed ‘gene order B’ and ‘gene order C’) differing in the and the other in the same relative position as in the common location of the large non-coding region. This is based on five vertebrate arrangement (45,57). This may be a retained primitive complete mtDNA sequences (Rhea, Aythya and Vidua having feature of the original rearrangement that occurred prior to the gene order B and Falco and Smithornis having gene order C) and divergence of birds from reptiles, or it may have occurred a sampling of short fragments of many species representing convergently in these independent lineages. 16 orders. When these two gene arrangements are plotted on a In the most commonly invoked model of mitochondrial gene phylogenetic tree derived from other types of data, it is apparent rearrangement (5,58), a segment of the mtDNA containing two that there must have been several convergent, independent origins or more genes is duplicated, perhaps through slipped-strand of gene order C. This suggests the model proposed in Figure 1C, mispairing during replication, or perhaps due to imprecise where the original translocation between Cytb-T-P and ND6-E termination during replication of this circular molecule (such that

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Figure 1. (A) The mitochondrial gene arrangement for the hemichordate Balanoglossus (34), the cephalochordate Branchiostoma (32,33), that inferred to be the primitive arrangement for Chordata, the commonly found vertebrate arrangement, and all identified deviations. Genomes are graphically linearized at the arbitrarily chosen COI gene. Although not depicted in their entirety, the following animals have completely determined mitochondrial gene arrangements that are identical to the common vertebrate arrangement except for the deviations shown [marked with (C)]: seven birds (48,52–54) (with two arrangements differing in the location of the non-coding region) (54), akamata (snake) (55), two marsupials (37,38), alligator (44) and sea lamprey (35). Partial mtDNA sequences of other birds (46,47,49–51,54) and marsupials (36) show that they share these deviations. For all other taxa (40–43,45,56,57,59,144) in this figure, all known gene arrangements are shown. Genes are not drawn to scale and are abbreviated as in the text except for the tRNA designations of the two serine and two leucine tRNAs, which are differentiated by the codon recognized: S(AGN), S(UCN), L(CUN) and L(UUR) are designated S1, S2, L1 and L2, respectively. In the cases of unconnected blocks of genes it is unknown if these are their actual relative locations. Shaded boxes are significant non-coding sequences with OL indicating cases inferred to be the origin of ‘light-strand’ (i.e. second-strand) replication. All genes are transcribed from left-to-right except those underlined to indicate opposite orientation. Asterisks for Branchiostoma mark the four genes whose locations differ from the common vertebrate arrangement (see text). (B) Partial gene arrangements of five snakes along with the common vertebrate arrangement. This shows how all these gene arrangement variations could be accounted for by a primitive duplication and translocation of the block P-(non-coding region)-F-L(UUR) (hypothetical intermediate) followed by random loss of the ‘extra’ genes (see text). Shaded boxes are non-coding regions of various sizes with scaling being arbitrary to aid alignment of homologous genes. (C) Model accounting for the apparently convergent translocation of the large non-coding region in bird mtDNAs (54) (see text). The two differing arrangements (gene orders B and C) can be derived from that commonly found among vertebrates through a hypothetical intermediate with duplicated non-coding regions. The non-coding region between E and F is designated Ψ to recognise it as a degenerating pseudogene of the ‘control region’. 1771

Nucleic AcidsAcids Research,Research, 1994, 1999, Vol. Vol. 22, 27, No. No. 1 8 1771 the nascent strand overruns its origin). Subsequent random loss of the crinoid mtDNA or whether these rearrangements occurred of the now supernumerary genes may (or may not) result in within that lineage. Within the remaining four classes (jointly exchange of position. This model may explain the rearrangements comprising the Eleutheria), there is a large inversion of the region found in five snakes: the akamata (55), western rattlesnake, boa, bounded by P and lrRNA separating the gene arrangement shared python and Japanese pit viper (56) (Fig. 1B). All share a by three echinoids (sea urchins) and a holothuroid (sea cucumber) translocation of L(UUR) from upstream of ND1 to a position from that shared by five asteroids (sea stars) and an ophiuroid adjacent to Q accompanied by a second large non-coding region (brittle stars). Cladistic analysis, using the gene arrangement inserted here. In the cases of the rattlesnake and pit viper P is here typical of vertebrates as an outgroup, supports the view of a as well and in the case of akamata there is a P pseudogene; however, monophyletic Asterozoa (Asteroidea plus Ophiuroidea), leaving no vestige of P is apparent in the python or boa. This tRNA is undetermined whether the more basal Echinozoa (Echinoidea missing from its primitive location in the rattlesnake and is a plus Holothuroidea) is monophyletic or paraphyletic (Fig. 2B). In pseudogene here in the pit viper, but this region has not been studied addition, several independent tRNA gene translocations can be for the python or boa. The pit viper also has a duplicated F, one in seen in both the ophiuroid and holothuroid mtDNAs. the primitive position and the other adjacent to the repositioned The best example of an intermediate in the duplication-random L(UUR). It is tempting to speculate that the primitive rearrangement loss model of gene rearrangement (see section above) is in the here began as the duplication of the segment P-(non-coding mtDNA of the sea cucumber Cucumaria (69) (Fig. 2C). As can region)-F and its movement, along with L(UUR), to between I and be seen in Figure 2A, all other echinoderms have a similar or Q. All of these five snake arrangements would then be derived from identical cluster of many tRNA genes. Because of the conservation this by subsequent losses of the supernumerary genes. of this arrangement and the nearly complete determination of the Downloaded from Another possible example of an intermediate for this duplication- order of these genes in another holothuroid, Parastichopus, the random loss model is in the mtDNA of the amphisbaenian reptile primitive holothuroid arrangement can be confidently inferred. In Bipes biporus (41). In this mtDNA T-P is duplicated between the mtDNA of Cucumaria these same tRNAs are distributed Cytb and the large non-coding region and one of the tRNAs between two regions, one between srRNA and ND1 (as is appears to have become non-functional. However, in this case, primitive), the other between COI and ND4L. These tRNA genes are loss of either of the remaining P genes would restore the original widely spaced in each case, separated by the presumed disintegrating http://nar.oxfordjournals.org/ arrangement rather than lead to an exchange. vestiges of tRNA pseudogenes rendered supernumerary by an The rearrangements of bullfrog (59) and rice frog (42) are not earlier duplication of the entire cluster [or perhaps of the cluster found in Xenopus mtDNA (60). Each has a similar translocation minus D, Y, G and L(UUR)]. It is noteworthy that this duplication of the large non-coding region and movement of L(CUN) to a also includes the large non-coding region, presumably containing nearby position, although the arrangements are not identical. The the origin of replication, and that these duplicated non-coding rice frog has L(CUN) positioned adjacent to F where the regions retain significant sequence similarity. non-coding region is primitively located. Both frogs share a new location for the non-coding region, which is flanked by L(CUN) at Maastricht University on July 3, 2014 in the bullfrog and a pseudogene for L(CUN) in the rice frog. ARTHROPODA Considering the frequent implication of the non-coding region in gene translocations, one reconstruction of the rearrangement Next to chordates, arthropods are the best studied phylum for would be the translocation of L(CUN) to a position adjacent to the mtDNA (Fig. 3). The sequence of Drosophila mtDNA (70,71) non-coding region, followed (or accompanied) by the duplication was the first among invertebrates to be determined and has a gene and translocation of the non-coding region and L(CUN) together, arrangement differing from that of the chelicerate Limulus then the random loss of L(CUN) genes, with only rice frog mtDNA polyphemus (72) by only a single tRNA translocation, that of retaining the pseudogene and bullfrog losing the gene entirely. L(UUR), from the arrangement lrRNA-L(CUN)-L(UUR)-ND1 to All observed rearrangements among chordate mtDNAs fall COI-L(UUR)-COII (this included its movement to the opposite into three categories: exchange in position of nearest neighbor DNA strand). This translocation occurred at the base of an genes or segments; changes near to one or the other origin of insect-crustacean clade and is a strong indicator of the close replication, sometimes with an accompanying duplication of relationship of these groups to the exclusion of myriapods, non-coding sequences; or changes near the region that is chelicerates, tardigrades and onychophorans (30,31). primitively I-Q-M. While the significance is not obvious, the Generally, few rearrangements have been observed in arthropod I-Q-M region also appears to be one of the most mobile in mtDNAs and, other than in one group of ticks (73,74) (see arthropod mtDNAs (see below), where it is adjacent to the large below), all have been translocations of only tRNA genes. The non-coding region. Could this signal some primitive functional crustacean Artemia (75) has a translocation of I-Q, apparently significance to sequences near this region for chordates which derived for this lineage since another branchiopod, Daphnia (76), might be implicated in these rearrangements? has these genes in the same arrangement as both Limulus and Drosophila. Three mosquitoes share derived tRNA rearrangements ECHINODERMATA of R, A and S(AGN) (77–79). The mitochondrial gene arrangement of the hymenopteran Apis (80) requires a minimum of eight tRNA All published mitochondrial gene arrangements of echinoderms translocations to relate it to that of Drosophila. One of these are shown in Figure 2 (29,61–69). Of the five extant echinoderm translocations, a nearest neighbor exchange of D and K, it shares classes, crinoids are believed to be the most primitive. Although with two orthopterans (81,82). Short sequences have been several rearrangements separate the crinoid gene order from those published for many other insects that have gene arrangements shared by other echinoderms, it cannot be reliably discerned identical to those of Drosophila; many of these references can be whether the primitive echinoderm arrangement is more like that found at: www.biology.lsa.umich.edu/∼jboore .

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Figure 2. (A) Mitochondrial gene arrangements of echinoderms (29,61–69) emphasizing the large inversion separating the gene orders of Echinozoa (Holothuroidea plus Echinoidea) from that of Asterozoa (Asteroidea plus Ophiuroidea). (B) By omitting tRNA genes from the analysis and comparing to the common gene arrangement found in vertebrates, it can be seen that a lesser number of rearrangements would be required to describe a Vertebrata–Echinozoa–Asterozoa transition than a Vertebrata–Asterozoa–Echinozoa transition (29). (C) The cluster of tRNAs inferred to be in the primitive arrangement for Holothuroidea along with the duplicated cluster found in Cucumaria (69). Shaded boxes represent unassigned nucleotides of various length, presumably vestiges of tRNA genes from the original duplication (see text). Box sizes vary to aid alignment of homologous genes. The 1030 nt marked for one of the boxes is an estimated size based on fragment size of a region containing multiple repeated sequence elements. Genes are depicted and labeled as in Figure 1.

The complete mtDNA sequence of the prostriate tick Ixodes (73) larger size is due to a greatly expanded non-coding region demonstrates a gene arrangement identical to that of another containing multiple repeat units (7). chelicerate Limulus. However, the metastriate tick Rhiphicephalus It seems that the most common changes in arthropods are of (73) has a translocation of a seven-gene block bounded by the genes genes near the large non-coding region or of the tRNAs of the ND1 and Q (along with other tRNA translocations). A broad region that is A-R-N-S(AGN)-E-F in Drosophila. This points to a sampling of gene boundaries (73,74) finds that all sampled role for the origins of replication in gene order translocation and, metastriates share this rearrangement, whereas it is not found among perhaps, suggests that a closer look be taken for a second-strand prostriates. origin in arthropod mtDNA near the A-R-N-S(AGN)-E-F region. Three species of bark weevil, Pissodes nemorensis, Pissodes strobi and Pissodes terminalis, have been shown by Southern hybridization to Drosophila mtDNA probes to have a gene arrangement typical of insects. Otherwise, these genomes are The mitochondrial gene arrangement of Mytilus (12) was the first much larger than those of other studied arthropods, up to 36 kb, among mollusks to be determined (Fig. 4A). It has several highly and vary greatly in size both between and within individuals. This unusual features: the gene arrangement is remarkably unlike that 1773

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Figure 3. Mitochondrial gene arrangements of arthropods plus small segments of an onychophoran and a tardigrade (30–31,70–82,146–149). Metastriate ticks have a rearrangement of a seven-gene block bounded by ND1 and Q; this is marked by a line connecting this block to the homologous genes of other chelicerates. Otherwise, only rearrangements of tRNA genes have been observed. Asterisks mark all tRNA genes differing in location from the arrangement found in Limulus polyphemus, which has been inferred to be primitive for Arthropoda (30,31,72). In a few cases, i.e. an exchange of nearest neighbor genes, the choice of which tRNA to mark is arbitrary. In the cases of unconnected blocks of genes it is unknown if these are their actual relative locations; depiction is aligned with other corresponding genes for clarity only. Genes are depicted and labeled as in Figure 1. found for other mtDNAs; several genes deviate significantly in protein initiation while the other functions only in elongation. length from their homologs; there is an unusual number of However, both the codons ATA and ATG are used in both initiator non-coding nucleotides; and no gene for A8 can be found. and internal positions, so if each of these codons were to pair most Whether A8 moved to the nucleus, became dispensable entirely, efficiently with the TAT and CAT anticodons, respectively, of or had its function co-opted by one of the other ATPase subunits these tRNAs, there would be no such division of roles. However, is unknown. The normally small size (∼150 nt) of A8 and its rapid mitochondrial tRNAs are known to have post-transcriptionally rate of sequence change make it unlikely that it could be found in modified nucleotides and the mechanisms by which an initiation the nuclear genome by heterologous probe hybridization. Mytilus codon normally discriminates in favor of a formyl-methionine mtDNA also contains an extra gene for an additional methionine charged tRNA are unknown. tRNA. This leads to speculation that only one of these methionine It is unclear whether these unusual mitochondrial features are tRNAs might be charged with formyl-methionine to be used for related in any way to the unusual mode of inheritance that has

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Figure 4. (A) Mitochondrial gene arrangements of Mollusca (12,19,90–93,95,96). S2 of Mytilus is shown here in a different place from the original publication; recent studies comparing sequences of several Mytilus species and performing northern blot analysis of tRNA expression have demonstrated that the sequence originally proposed as S2 is not detected as a tRNA-sized message and that the location depicted here is of the actual S2 (D.Wolstenholme, personal communication). (B) Complete mitochondrial gene arrangement of the oligochaete annelid Lumbricus (97) along with published, small segments of the polychaete annelid Platynereis, the hirudinid annelid Helobdella, the pogonophoran Galatheolinum, and the echiuran Urechis (31). (C) Mitochondrial gene arrangements of Nematoda (9–11). (D) Mitochondrial gene arrangement of a platyhelminth (101). (E) Mitochondrial gene arrangements of Cnidaria (13–18). Genes are depicted and labeled as in Figure 1 with a few additions. Mytilus mtDNA has two tRNA genes for methionine: M1 has the anticodon TAT; M2 has the anticodon CAT. Two of the cnidarians also contain a gene homologous to the bacterial mismatch repair gene mutS. Metridium mtDNA contains two introns, each of which contain other genes (see text); these two halves of the intron-containing genes are designated COI-5′/COI-3′ and ND5-5′/ND5-3′. been described for Mytilus mtDNA, termed ‘doubly uniparental’ individual animal (84). Opportunities to test this are available since inheritance (83), and of its consequence of heteroplasmy of two this appears to be the mode of inheritance in other bivalves as well very different mitochondrial haplotypes in the tissues of an (85,86), although no gene arrangement information is yet available. 1775

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Furthermore, other bivalves, the scallops Pecten (87), Patinopecten In several respects Lumbricus mtDNA is quite conventional: (88) and Placopecten (89), have very unusual mtDNA structures, only ATG is used as an initiation codon, whereas most mtDNAs with extensive regions of repetitive DNA and, in some cases, use a variety of alternatives (18); the tRNAs have uncommonly extreme variations in size, even among conspecific individuals. The uniform potential secondary structures; nucleotide composition is mode of mtDNA inheritance in scallops is unknown. more balanced than for most mtDNAs; and non-coding nucleotides The complete mtDNA sequences of three land snails, Euhadra are very few. One unusual feature, however, is that A8 and A6 are herklotsi (90), Cepaea nemoralis (91) and Albinaria coerulea separated by ∼2700 nt. In nearly all animal mtDNAs A8 and A6 (92), and the partial sequence of Albinaria turrita (93), have been are adjacent, often overlapping in alternate reading frames. In published. These pulmonates share a nearly identical gene mammals, A8 and A6 are translated from a bicistronic transcript, arrangement that is highly divergent from those of any other with translation initiating alternatively at the 5′ end of the mRNA for animals. Reported in (90) as ‘unpublished data’ is that the gene A8 or at an internal start codon for A6 (98). It is unknown whether arrangement of the opisthobranch Pupa also has an identical gene this is also the mode of translation of these two genes in other arrangement. These shared gene arrangements, then, unite these organisms, although, if so, it could explain their nearly universal two classes of to the exclusion of the prosobranch juxtaposition. Other than A8 being missing from the mtDNAs of gastropod Plicopurpura (30), since partial gene arrangement data nematodes (see below), all exceptions to this are members of phyla for this animal show several genes in the same order as many assigned to the group ‘Eutrochozoa’ (99). A8 is missing from the outgroups to Gastropoda. Initially, based on gene sequence, it mtDNA of Mytilus (Mollusca) (12) and these two genes are appeared that the tRNAs of pulmonate snails had aberrant separated in the mtDNAs of Lumbricus (Annelida), Helobdella structures, but it has been now shown that several undergo and Platynereis (Annelida; unpublished); three pulmonate snails Downloaded from post-transcriptional processing to restore base pairing of their (Mollusca) (90), Dentalium and Nautilus (Mollusca; unpub- aminoacyl acceptor stem (94). lished);Urechis (Echiura; unpublished), Galatheolinum (Pogono- In contrast to these highly rearranged mollusk mitochondrial phora; unpublished); Phascolopsis (Sipuncula; unpublished); and genomes, that of the chiton Katharina tunicata (95) can be related Terebratalia (Brachiopoda; unpublished). It may be that loss of to those of Drosophila or vertebrates by a moderate number of co-translation of this bicistron is a derived feature of the Eutro- rearrangements. It is less clear how much rearrangement has chozoa; this could be studied in members that retain A8 adjacent to http://nar.oxfordjournals.org/ occurred in the fourth class of Mollusca that has been sampled, A6, such as the polyplacophoran mollusk Katharina (95). Cephalopoda. This class is represented by only a single partial sequence of squid mtDNA (96) containing 15 genes. There are two blocks of genes in similar arrangement to Katharina, but NEMATODA several other genes are differently located. Nowhere is it more clear than in the phylum Mollusca that there is no ‘molecular clock’ of gene rearrangements. Rather, the data Complete mtDNA sequence has been published for two members indicate periods of stasis and of saltatory rearrangements. For of the family Rhabditidae, Ascaris and Caenorhabditis (11). These at Maastricht University on July 3, 2014 example, after the opisthobranch-pulmonate clade split from the two animals share an identical gene arrangement (Fig. 4C), although ancestral mollusk, there must have been rearrangements involv- there is a large non-coding region in differing relative locations. Two ing nearly every gene to generate their shared but highly derived other members of this class Secernentea, Meloidogyne (10) and gene order. Then, during the long period of evolution since these Onchocerca (9), have unique gene arrangements; the three gene two gastropod classes split, there have been only very few arrangements of these four nematodes differ at nearly every gene rearrangements in either lineage. For deriving phylogeny from boundary from all other mtDNAs. This has established the view that this type of data, there seems to be no accurate a priori estimation nematodes are characterized by very rapid rates of mitochondrial possible of the level of relationship likely to be characterized by gene rearrangement. However, this may more properly be a gene rearrangement. considered a trait of the Secernentea; Trichinella, a representative of the other nematode class, Adenophorea, has a mitochondrial gene arrangement easily related to those of protostomes by a moderate ANNELIDA number of changes (unpublished). One other adenophorean, the mosquito parasite Romanomermis culicivorax, has been shown to Only one complete annelid mtDNA sequence has been determined, have a much larger mitochondrial genome (∼26–32 kb) resulting that of the oligochaete Lumbricus terrestris (97); small portions from a large number of repeated sequences, although no gene have been published of two other annelids, Platynereis and arrangements are known except for a very small amount within Helobdella, and of the related taxa Galatheolinum (phylum the repeat unit (100). Multiple, unrelated repeated sequences are Pogonophora) and Urechis (phylum Echiura) (31) (Fig. 4B). also present in Meloidogyne mtDNA. Unlike most studied mtDNAs, all Lumbricus mitochondrial genes are encoded on the same strand. One speculates that there could be a ‘ratchet’ effect to such a set of rearrangements. That is, if rearrangements were to place all genes on one strand, it PLATYHELMINTHES would be expected that transcription of the other strand would soon cease, since presumably selection would not maintain the The only gene arrangement known of any flatworm is from a necessary signaling elements and the futile transcription would be 3.5 kb segment of Fasciola hepatica mtDNA (101) (Fig. 4D). All an energetic burden. This would then constitute an effective 11 of these Fasciola genes are transcribed from the same strand. barrier to further inversions which would place a gene on the Part of this is similar to the Lumbricus gene arrangement, non-transcribed strand unless that inversion also carried with it ND1-N-P-I-K-ND3-S(AGN) versus ND1-I-K-ND3-S(AGN), but the necessary sequence elements to resume its expression. it is not clear whether this is of any phylogenetic significance.

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CNIDARIA be possible in these cases to release full-length RNAs of each overlapping message from the same transcript. Further, those The complete mitochondrial gene arrangements of three cnidarians arranged with clustered tRNA genes and without compensatory have been published, those of the anthozoans Metridium senile intergenic secondary structures must somehow produce gene- (15,18), Renilla kolikeri (13) and Sarcophyton glaucum (16,17) specific messages. Vertebrates (and perhaps other animals with nearly adjacent rRNA genes) use a ‘transcriptional attenuator’ (Fig. 4E). These mtDNAs are unique in several respects, ∼ including in Metridium the presence of introns in the COI and system to regulate the production of rRNA to yield an 50-fold ND5 genes (14). Introns have been found in animal mtDNA only excess of rRNA to the products of other genes (103), yet many here and in two other species of the same order, Actiniaria, and animals have now been found with widely separated rRNA genes are known to be absent from these genes in the mtDNAs of a or that do not have non-coding sequences immediately upstream number of other cnidarians (14). The intron in COI contains an of the rRNA genes (suggesting that transcription may not ORF similar to some intron-encoded endonucleases that are originate there); how do they meet their need for large amounts active in their transposition. The intron within ND5 contains the of rRNA? Aspects of genome evolution, including changes in rate genes for ND1 and ND3 whose mRNAs are liberated as a and modes of transcription, message processing, regulation of bicistron during intron processing. replication, interactions among various molecular factors, the These mtDNAs have only one or two tRNA genes. Presumably role of selection on base composition in determining gene the other necessary tRNAs are imported nuclear products. All evolution, changes in the secondary structures of tRNAs and have a tRNA for methionine, which may be necessary to provide rRNAs, changes in the genetic code—all are especially tractable in mitochondrial systems. the formyl-methionine which initiates mitochondrial proteins Downloaded from (102) (but not nuclear proteins, so the cytoplasm may not contain Comparison of mitochondrial genome arrangements has prom- such a tRNA). Metridium mtDNA also contains a tRNA gene for ise for resolving some of the controversial evolutionary relation- tryptophan, perhaps to accommodate a variation in the genetic ships among major animal groups. Obviously, only a minority of code common in mitochondria. The more closely related pair, phylogenetic relationships will be addressed using this type of Renilla and Sarcophyton (both in the group Octocorallia), have an comparison. No rearrangements may have occurred during a period identical mitochondrial gene arrangement, and also share having of shared history or subsequent rearrangements may have eroded the http://nar.oxfordjournals.org/ an extra gene not otherwise found in animal mtDNAs, a homolog shared features. The greatest advantage of this data set is that there to the bacterial mismatch repair gene mutS. All of the genes other is significant confidence in evolutionary branches characterized by than mutS and the ORF within the Metridium COI intron have complex shared rearrangements. As a corollary to this, one might homologs in the mtDNAs of plants, fungi and/or protists (19–22) wisely view as less significant rearrangements that are simple, and so are unambiguously homologous among animals, this especially an exchange in position of nearest neighbor genes, a reduced set having been achieved early in the evolution of the movement of a non-coding region, or rearrangements of genes Metazoa. This paucity of tRNA genes is certainly derived for the adjacent to the origin of replication. These types of changes appear

Anthozoa or for a larger, subsuming clade, rather than the to be more common than others and are explained by relatively at Maastricht University on July 3, 2014 primitive state for multicellular animals. simple mechanisms, so are less likely to be unique events. There are three other cnidarian classes: Cubozoa, Scyphozoa Methods for computer reconstructions of gene rearrangements and Hydrozoa. Each of these has been found to have linear are being developed and debated (104,105), but no algorithm yet mtDNA chromosomes (6), a unique feature among animal exists which will exhaustively search all possible solutions and mitochondrial genomes. Linear mtDNA appears to have evolved guarantee an exact, most parsimonious reconstruction. Further- a single time in their common ancestor, indicating a shared more, little is known about the molecular processes that lead to evolutionary history to the exclusion of the remaining class, rearrangement, making unclear the relative likelihood of inversions, Anthozoa, which retains the primitive (for Cnidaria) condition of translocations or duplications with subsequent random gene loss circular mtDNA. No information on the gene content of these linear (5,58) as mechanisms of change. Ultimately the most accurate mitochondrial chromosomes is yet available, nor have any studies models for reconstructing mitochondrial genome rearrangements addressed the unique molecular feature of linear animal mtDNA, must integrate information on molecular mechanisms. such as mechanisms for replicating the chromosome ends. So far, only a small sample of the Metazoa has been studied for mtDNA sequences, gene arrangements and molecular mechanisms. Mitochondrial genomics has great potential for resolving ancient patterns of evolutionary history and for serving as a model of CONCLUSIONS genome evolution. Many patterns of evolution, both of organisms and of genomes, may in the near future be better understood The molecular biology of mitochondrial systems has been studied through the comparison of mitochondrial genomic systems. for only a few model organisms, with nearly all information being from mammals or Drosophila. Many of the views that have become nearly axiomatic are challenged by newly determined mtDNA sequences. For example, the view that animal mtDNAs ACKNOWLEDGEMENTS are selected for extreme economy of size, while apparent in some cases, is refuted by mitochondrial genomes with very large amounts of non-coding sequence, as has been found in some Many thanks to Susan Fuerstenberg, Kevin Helfenbein and Alan arthropods, mollusks and nematodes (7,8,87–89,100). Overlapping Wolf for helpful comments on the manuscript. This work was genes found among many mtDNAs leads to speculation that the supported by NSF grant DEB9807100. More information can be ∼ ‘polycistron model’ may not universally apply, since it would not found at: www.biology.lsa.umich.edu/ jboore 1777

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