Potential genomic determinants of hyperthermophilyCOG1318 - a hyperthermophile-specific transcriptional regulator?COG2250 and COG1895 - putative molecular chaperones important for hyperthermophilyConclusionsReferencesWhy are the genomes of endosymbiotic bacteria so stable?linkage analysis in families recruited through 2 asthmatic sibs.Collaborative Study on the Genetics of Asthma (CSGA). J. AllergyClin. Immunol. 102, 436–4429 Mathias, R.A. et al. (2001) Genome-wide linkage analyses of totalserum IgE using variance components analysis in asthmatic families.Genet. Epidemiol. 20, 340 –35510 Dizier, M.H. et al. (2000) Genome screen for asthma and relatedphenotypes in the French EGEA study. Am. J. Respir. Crit. Care Med.162, 1812 –181811 Laitinen, T. et al. (2001) A susceptibility locus for asthma-related traitson chromosome 7 revealed by genome-wide scan in a founderpopulation. Nat. Genet. 28, 87–9112 Hakonarson, H. et al. (2002) A major susceptibility gene for asthmamaps to chromosome 14q24. Am. J. Hum. Genet. 71, 483– 49113 Koppelman, G.H. et al. (2002) Genome-wide search for atopysusceptibility genes in Dutch families with asthma. J. Allergy Clin.Immunol. 109, 498– 50614 Haagerup, A. et al. (2002) Asthma and atopy – a total genome scan forsusceptibility genes. Allergy 57, 680– 68615 Libert, F. et al. (1998) The Dccr5 mutation conferring protectionagainst HIV-1 in Caucasian populations has a single and recent originin Northeastern Europe. Hum. Mol. Genet. 7, 399–40616 Suarez, B.K. et al. (1994) Problems of replicating linkage claims inpsychiatry. Genetic Approaches to Mental Disorders (Gershorn, E.S.,Cloninger, C.R., et al. eds), pp. 23 –46, American Psychiatric Press17 Ober, C. et al. (1998) Genome-wide search for asthma susceptibility lociin a founder population. The Collaborative Study on the Genetics ofAsthma. Hum. Mol. Genet. 7, 1393– 139818 Cookson, W.O. et al. (2001) Genetic linkage of childhood atopicdermatitis to psoriasis susceptibility loci. Nat. Genet. 27, 372–37319 Nair, R. et al. (1997) Evidence for two psoriasis susceptibility loci (HLAand 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum. Mol. Genet. 6, 1349 –135620 Tosh, K. et al. (2002) A region of chromosome 20 is linked to leprosysusceptibility in a South Indian population. J. Infect. Dis. 186,1190–119321 Drazen, J.M. and Weiss, S.T. (2002) Genetics: inherit the wheeze.Nature 418, 383–38422 Risch, N.J. (2000) Searching for genetic determinants in the newmillennium. Nature 405, 847 –85623 Abecasis, G.R. et al. (2001) Extent and distribution of linkagedisequilibrium in three genomic regions. Am. J. Hum. Genet. 68,191– 19724 Patil, N. et al. (2001) Blocks of limited haplotype diversity revealed byhigh-resolution scanning of human chromosome 21. Science 294,1719– 172325 Lander, E. and Kruglyak, L. (1995) Genetic dissection of complextraits: guidelines for interpreting and reporting linkage results. Nat.Genet. 11, 241 – 24726 Stone, A.L. et al. (1999) Structure– function analysis of the ADAMfamily of disintegrin-like and metalloproteinase-containing proteins.J. Protein Chem. 18, 447–4650168-9525/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.doi:10.1016/S0168-9525(03)00025-8|Genome AnalysisPotential genomic determinants of hyperthermophilyKira S. Makarova, Yuri I. Wolf and Eugene V. KooninNational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USAWe searched for genes that could be important forhyperthermophily using a flexible approach to phyleticpattern analysis. We identified 290 clusters of ortholo-gous groups of proteins (COGs) that are preferentiallypresent in archaeal and bacterial hyperthermophiles. Ofthese, 58 COGs include proteins from at least one bac-terium and two archaea, and these were considered tobe the best candidates for a specific association withthe hyperthermophilic phenotype. Detailed sequenceand genome-context analysis of these COGs led to func-tional predictions for several previously uncharacterizedprotein families, including a novel group of putativemolecular chaperones and a unique transcriptionalregulator.The molecular basis of the hyperthermophilic phenotype ofnumerous prokaryotes remains unclear, althoughcomparisons of orthologous proteins from hyperthermo-philes and mesophiles pointed to potential adaptations tothe hyperthermophilic environments; in particular, excessof electrostatic interactions [1,2]. Complete genomesequences of 11 hyperthermophiles were available as ofAugust 1, 2002, including eight archaea from six distinctlineages, and three bacteria from diverse phyla.(Hyperthermophiles are defined as organisms with opti-mal growth temperature . 758C; thermophiles are thosewith optimal growth temperature of 55–758C.) With thisamount of data at hand, it is tempting to pursue a differentavenue of search for potential determinants of this uniquephenotype, namely comparative-genomic analysis aimedat the identification of genes that occur exclusively orprimarily in hyperthemophiles.Recent analysis of phyletic patterns (Box 1) in thedatabase of clusters of orthologous groups of proteins(COGs) [3] showed that the only protein encoded in thegenomes of all hyperthermophiles, and not in any othergenomes, is reverse gyrase [4]. Reverse gyrase consists of ahelicase and a Type I topoisomerase, and it introducespositive supercoiling into circular DNA, thus preventingexcess local unwinding of the double helix at hightemperatures [5]. Although reverse gyrase is, in alllikelihood, necessary for hyperthermophily, it is hard toimagine that it alone could account for this phenotype [4].The absence of other strictly hyperthermophile-specificCOGs is not particularly unexpected in view of thesubstantial horizontal gene flow between thermophilesand mesophiles [6,7] and numerous non-orthologous genedisplacements [8], which result in scattered phyleticpatterns for most orthologous sets ([3,9]; Box 1). Here,we describe an attempt to search for potential genomicCorresponding author: Eugene V. Koonin ([email protected]).Update TRENDS in Genetics Vol.19 No.4 April 2003172http://tigs.trends.comdeterminants of hyperthermophily using a flexible strat-egy of phyletic pattern analysis.Recently, using a combination of detailed sequenceanalysis, structure prediction and gene order comparison,we predicted a previously undetected