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On page 133 of this issue, Andersson etal.1 report the complete genomesequence (1,111,523 base pairs) of

Rickettsia prowazekii, the causative agent oflouse-borne typhus. This bacterium and itsrelatives represent one of biologys great

ironies. On the one hand, the historicalancestors ofR.prowazekiiprecipitated someof the greatest plagues to afflict the humanrace (see box overleaf). On the other hand, anevolutionary antecedent ofR.prowazekiipar-ticipated in one of the seminal events in theevolution of eukaryotic (nucleus-contain-ing) cells the formation of mitochondria2,cellular organelles that contain their ownDNA and, during oxidative breakdown ofglucose, produce the ATP that powers thesecells. With the complete genome sequence ofR. prowazekii, we can now examine this

important genetic blueprint for clues both asto what makes R. prowazekii such a greatkiller, and what allowed one of its ancestors tocontribute so fundamentally to the emer-gence of eukaryotic cells in the first place.

R.prowazekiiis an obligate intracellular

parasite that is, it can only live withinother cells. Its gene content, like that of otherparasitic eubacteria, has been reduced andtailored to suit its dependent lifestyle.Andersson et al.1 have found that the R.

prowazekii genome encodes 834 completeopen reading frames, DNA sequences thatspecify protein sequences. This number is farless than the 4,288 protein-coding genesfound in the fourfold larger genome ofEscherichiacoli, its free-living cousin3. How-ever, R. prowazekii contains ten times asmany genes as the most bacteria-like

NATURE | VOL 396 | 12 NOVEMBER 1998 | www.nature.com 109

mitochondrial genome described to date,the 69,034-bp mitochondrial (mt)DNA ofthe freshwater protozoon Reclinomonasamericana4. Surprisingly, the R. prowazekiigenome also contains the highest fraction ofnon-coding DNA (24%) found in anymicrobial genome so far, much of which mayrepresent inactive genes that have beendegraded by mutation, but have not yet been

eliminated from the genome.By comparing the sequences of bacterialand mitochondrial genes, we get the best evi-dence that Rickettsia and mitochondria arespecific evolutionary relatives. Evolutionarytrees based on small-subunit ribosomalRNA (SSU rRNA) originally pinpointedmembers of the -division of the so-calledpurple bacteria (proteobacteria) as the clos-est contemporary bacterial relatives of mito-chondria5. More recent SSU rRNA treesdivide the-proteobacteria into two groups,with the rickettsial sub-division (to which R.

prowazekiibelongs) the one that is specifical-ly affiliated with mitochondria2 (Fig. 1).

The same result is seen with evolutionarytrees based on mitochondrial proteinsencoded by the nuclear genome6. Suchnuclear genes are assumed to have beentransferred from mitochondria during thedrastic down-sizing that characterized evo-lution of the mitochondrial genome after itwas acquired by the eukaryotic cell2. In theiranalysis, Andersson et al.1 constructed evo-lutionary trees comparing the amino-acidsequences encoded by mitochondrial andbacterial genes involved in energy metabo-lism (subunits of NADH dehydrogenase)and genetic processes (ribosomal proteins).

True to expectation, these results show thatR. prowazekii is more closely related tomitochondria than is any other bacteriumwhose genome has been investigated at thislevel of detail.

Andersson and colleagues rightly pointout that the DNAs of Rickettsiaand mito-chondria are stunning examples of highlyderived genomes, the products of severalmodes of reductive evolution. Both lackgenes for metabolizing sugars in the absenceof oxygen (anaerobic glycolysis), as well as allor most of the genes involved in synthesizingamino acids and nucleotides. However, theR. prowazekiigenome contains a complete

set of genes encoding components of the tri-carboxyclic acid cycle, a metabolic pathwayinvolved in respiration, and respiratory-chain complexes. A subset of the same genesis found in mtDNA, with the remainder inthe nuclear genome. The functional profilesofRickettsiaand mitochondria are strikinglysimilar, with production of ATP occurring inbasically the same way in the two systems.

Do these similarities mean that mito-chondria evolved directly from a Rickettsia-like organism that was already highlyreduced? The answer is almost certainly no.If one compares the organization of the same

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Rickettsia, typhusand themitochondrial

connectionMichael W. GrayThe genome sequence of Rickettsia prowazekii, the agent that causestyphus, has been determined. What emerges is a snapshot of genome re-tailoring in a parasitic bacterium, and a new look at the evolutionaryconnection between Rickettsiaand mitochondria.

Figure 1 Relationship between the R.prowazekiigenome and mitochondrial DNA. The tree shown is

the -proteobacterial/mitochondrial (MT) por tion of a eubacterial/organellar small-subunit (SSU)

ribosomal RNA tree. Extreme differences in the rate of mitochondrial sequence divergence are

responsible for the separation of mitochondria into short-branch (plants, Reclinomonas americana)

and long-branch groups. (The analysis used an aligned data set of 275 published eubacterial and

organellar SSU rRNA sequences, and the tree was generated using DNADIST from Phylip version 3.5

(ref. 9) with the ML option and default parameters2. Courtesy of D. F. Spencer, Dalhousie University.)

Rickettsia rickettsiiRickettsia prowazekiiRickettsia belliiRickettsia typhiRickettsia canadaOrientia tsutsugamushi

Wolbachia pipientisCowdria ruminantiumEhrlichia chaffeensis

Anaplasma marginaleEhrlichia risticiiNeorickettsia helminthoeca

Arabidopsis thalianaMTMarchantia polymorphaMTReclinomonas americanaMT

Saccharomyces cerevisiaeMTTetrahymena pyriformisMT

Paramecium tetraureliaMT

Allomyces macrogynusMTMetridium senileMT

Xenopus laevisMT

Chondrus crispusMT

Acanthamoeba castellaniiMTPrototheca wickerharniiMT

Other -proteobacteria

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genes in the R.prowazekii1, E. coli3 and Recli-nomonasmitochondrial4 genomes, vestiges

of bacterial operon organization (gene clus-tering) are still clearly seen in the Recli-nomonas mtDNA. However, the Recli-nomonas mitochondrial and R. prowazekiigenomes do not specifically share anyderived characteristics of gene organization;indeed, certain gene clusters are uniquelyrearranged in the Rickettsiagenome, relativeto what was probably the ancestral bacterialorder. These comparisons emphasize thatthe Rickettsiaand mitochondrial genomesindependently descended from an -pro-teobacteria-like ancestor, each undergoing aseparate process of reductive evolution. The

observed congruence in the functional pro-files of Rickettsia and mitochondria is cer-tainly intriguing, but it remains to be seenwhether this seeming example of convergentevolution is more than a coincidence.

By examining other rickettsial genomeswe should learn more about genome reduc-tion in bacterial parasites, a challengingquestion in its own right. However, suchstudies are unlikely to provide more infor-mation about the nature of the genome in themost recent common ancestor of mitochon-dria and the Rickettsiae. While the searchcontinues for organisms with mtDNAs thatare even more ancestral than in Recli-

nomonas, it will be important to identify andexplore the genomes of those minimallydiverged, free-living -proteobacteria thatare specific but more distant relatives ofboth the Rickettsiae and mitochondria.Such genomes should yield additional cluesrelevant to the origin and evolution ofmitochondria, a process that is central tothe emergence of eukaryotic life7,8.Michael W. Gray is at the Program in Evolutionary

Biology, Canadian Institute for Advanced Research,

Department of Biochemistry, Dalhousie University,

Halifax, Nova Scotia B3H 4H7, Canada.

e-mail: M.W.Gray@Dal.Ca

1. Andersson, S. G. E. et al. Nature396, 133140 (1998).

2. Gray, M. W. & Spencer, D. F. inEvolution of Microbial Life(eds

Roberts, D. McL., Sharp, P., Alderson, G. & Collins, M.)

109126 (Cambridge Univ. Press, 1996).

3. Blattner, F. R. et al. Science277, 14531471 (1997).

4. Lang, B. F. et al. Nature387, 493497 (1997).

5. Yang, D. et al. Proc. Natl Acad. Sci. USA 82, 44434447 (1985).

6. Viale, A. M. & Arakaki, A. K. FEBS Lett. 341, 146151 (1994).

7. Margulis, L. Origin of Eukaryotic Cells(Yale Univ. Press, New

Haven, Connecticut, 1970).

been made for the origin of this unusual

behaviour, called the paramagnetic Meissnereffect (PME) or the Wohlleben effect.It seems fairly certain that the PME is a

property of the granular structure of thesesuperconductors with grains of mesoscop-ic size their scale is in between that of themicroscopic crystal structure and that ofbulk samples. Some theories of the PME arebased on the unconventional symmetry ofthe superconducting state in high-tempera-ture superconductors.

To test this idea, the IBM research groupof Kirtley, Tsuei and co-workers made minia-ture loops (about 50 m across) of varioushigh-temperature superconductors5 (Fig. 1).

These were designed to frustrate the phaseof the quantum-mechanical wavefunctionthat describes the superconducting electronpairs that is, to prevent the phase fromremaining constant, usually the most stablesituation. This only works in superconduc-tors with an unconventional electron-pair-ing symmetry (so-called d-wave pairing, incontrast to the s-wave pairing of standardsuperconductors such as niobium, lead andaluminium).

Kirtleyet al. found that the frustrationled to spontaneous supercurrents runningwithout dissipation around the loop. These

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O

n page 144 of this issue1, Geim and

colleagues present measurementsmade on superconducting alumini-um discs as small as 0.3 m across. Theyshow that some superconductors have apeculiar attraction for magnetic fields.

When metals become superconducting,not only does their resistance drop to zero,but their magnetic properties also changemarkedly: magnetic fields are expelled fromthe materials interior. Often this phenom-enon is more readily measurable and morerevealing about the nature of superconduc-tivity than a materials electrical properties.Magnetic fields may still penetrate into so-called type-II superconductors, in vortices of

circulating supercurrent (the resistance-freecurrent carried by paired electrons). Never-theless, the magnetic field is always dimin-ished inside a superconductor relative to theexternal field that is, superconductors arediamagnetic2.

So it came as a surprise when highlydisordered granular Bi2Sr2CaCu2O8 one ofthe most prominent high-temperature super-conductors was found to have a paramag-netic response to a small external field3,4. Inthis case the applied magnetic field is notexpelled: on the contrary it is increased in thesuperconducting state. Several proposals have

Superconductors

Mesoscopic magnetismManfred Sigrist

8. Doolittle, W. F. inEvolution of Microbial Life(eds Roberts, D.

McL., Sharp, P., Alderson, G. & Collins, M.) 121 (Cambridge

Univ. Press, 1996).9. Felsenstein, J. Phylip (Phylogeny Inference Package) Version

3.5c (Univ. Washington, Seattle, 1993).

10.Zinsser, H. Rats, Lice and History(Little, Brown, Boston, 1935).

11.Snyder, J. C. in Cecil-Loeb Textbook of Medicine11th edn (eds

Beeson, P. B. & McDermott, W.) 121136 (W. B. Saunders,

Pennsylvania, 1963).

12.Gross, L. Proc. Natl Acad. Sci. USA 93, 1053910540 (1996).

The Rickettsiae are obligate

bacterial parasites they

multiply only within the cells

of susceptible animals.

They are responsible for a

variety of insect-borne

human diseasescharacterized by acute

onset, fever, delirium and

skin rash. Rickettsia

prowazekii, the causative

agent of louse-borne

epidemic typhus, is named

after H. T. Ricketts and S. J.

M. Prowazek, both of whom

died of typhus while

studying rickettsial diseases

early this century. Charles

Nicolle fared rather better,

receiving the Nobel prize in

1928 for his discovery that

epidemic typhus is

transmitted by lice.

Although the plague of

Athens in 430 BC wasprobably a typhus epidemic,

an accurate medical

description of the disease

did not appear until the mid-

1600s. The word typhus

(from the Greek typhos,

meaning smoky or hazy, and

used by Hippocratesto

describe a confused state

of intellect with a tendency

to stupor) was not applied

to typhus fever itself until

1760; moreover, typhus was

not clearly distinguished

from typhoid fever until the

mid-1800s.

Typhus ranks as one

of the main epidemicdiseases of human history, a

truly apocalyptic pestilence

that follows in the wake of

wars, famine and other

human misfortune. It has

been estimated that

between 1918 and 1922,

the typhus epidemics in

eastern Europe and Russia

resulted in 2030 million

cases and at least 3 million

deaths. Medical personnel

have been prominent as

victims of this disease: in

the 1915 Serbian epidemic,

nearly all of that countrys

400 doctors contracted

typhus and more than aquarter of them died. Often,

typhus determined the

outcome of military

campaigns more effectively

than the actual battles

themselves. In 1741, for

example, Prague was

surrendered to the French

army because 30,000 of

the opposing Austrians died

of typhus. M. W. G.

Rickettsiain medicine and history1012