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1.  Interkingdom gene fusions 
Genome Biology  2000;1(6):research0013.1-13.13.
Genome comparisons have revealed major lateral gene transfer between the three primary kingdoms of life - Bacteria, Archaea, and Eukarya. Another important evolutionary phenomenon involves the evolutionary mobility of protein domains that form versatile multidomain architectures. We were interested in investigating the possibility of a combination of these phenomena, with an invading gene merging with a pre-existing gene in the recipient genome.
Complete genomes of fifteen bacteria, four archaea and one eukaryote were searched for interkingdom gene fusions (IKFs); that is, genes coding for proteins that apparently consist of domains originating from different primary kingdoms. Phylogenetic analysis supported 37 cases of IKF, each of which includes a 'native' domain and a horizontally acquired 'alien' domain. IKFs could have evolved via lateral transfer of a gene coding for the alien domain (or a larger protein containing this domain) followed by recombination with a native gene. For several IKFs, this scenario is supported by the presence of a gene coding for a second, stand-alone version of the alien domain in the recipient genome. Among the genomes investigated, the greatest number of IKFs has been detected in Mycobacterium tuberculosis, where they are almost always accompanied by a stand-alone alien domain. For most of the IKF cases detected in other genomes, the stand-alone counterpart is missing.
The results of comparative genome analysis show that IKF formation is a real, but relatively rare, evolutionary phenomenon. We hypothesize that IKFs are formed primarily via the proposed two-stage mechanism, but other than in the Actinomycetes, in which IKF generation seems to be an active, ongoing process, most of the stand-alone intermediates have been eliminated, perhaps because of functional redundancy.
PMCID: PMC16144  PMID: 11178267
2.  Towards understanding the first genome sequence of a crenarchaeon by genome annotation using clusters of orthologous groups of proteins (COGs) 
Genome Biology  2000;1(5):research0009.1-research0009.19.
Standard archival sequence databases have not been designed as tools for genome annotation and are far from being optimal for this purpose. We used the database of Clusters of Orthologous Groups of proteins (COGs) to reannotate the genomes of two archaea, Aeropyrum pernix, the first member of the Crenarchaea to be sequenced, and Pyrococcus abyssi.
A. pernix and P. abyssi proteins were assigned to COGs using the COGNITOR program; the results were verified on a case-by-case basis and augmented by additional database searches using the PSI-BLAST and TBLASTN programs. Functions were predicted for over 300 proteins from A. pernix, which could not be assigned a function using conventional methods with a conservative sequence similarity threshold, an approximately 50% increase compared to the original annotation. A. pernix shares most of the conserved core of proteins that were previously identified in the Euryarchaeota. Cluster analysis or distance matrix tree construction based on the co-occurrence of genomes in COGs showed that A. pernix forms a distinct group within the archaea, although grouping with the two species of Pyrococci, indicative of similar repertoires of conserved genes, was observed. No indication of a specific relationship between Crenarchaeota and eukaryotes was obtained in these analyses. Several proteins that are conserved in Euryarchaeota and most bacteria are unexpectedly missing in A. pernix, including the entire set of de novo purine biosynthesis enzymes, the GTPase FtsZ (a key component of the bacterial and euryarchaeal cell-division machinery), and the tRNA-specific pseudouridine synthase, previously considered universal. A. pernix is represented in 48 COGs that do not contain any euryarchaeal members. Many of these proteins are TCA cycle and electron transport chain enzymes, reflecting the aerobic lifestyle of A. pernix.
Special-purpose databases organized on the basis of phylogenetic analysis and carefully curated with respect to known and predicted protein functions provide for a significant improvement in genome annotation. A differential genome display approach helps in a systematic investigation of common and distinct features of gene repertoires and in some cases reveals unexpected connections that may be indicative of functional similarities between phylogenetically distant organisms and of lateral gene exchange.
PMCID: PMC15027  PMID: 11178258
3.  The alpha/beta fold uracil DNA glycosylases: a common origin with diverse fates 
Genome Biology  2000;1(4):research0007.1-research0007.8.
Uracil DNA glycosylases (UDGs) are major repair enzymes that protect DNA from mutational damage caused by uracil incorporated as a result of a polymerase error or deamination of cytosine. Four distinct families of UDGs have been identified, which show very limited sequence similarity to each other, although two of them have been shown to possess the same structural fold. The structural and evolutionary relationships between the rest of the UDGs remain uncertain.
Using sequence profile searches, multiple alignment analysis and protein structure comparisons, we show here that all known UDGs possess the same fold and must have evolved from a common ancestor. Although all UDGs catalyze essentially the same reaction, significant changes in the configuration of the catalytic residues were detected within their common fold, which probably results in differences in the biochemistry of these enzymes. The extreme sequence divergence of the UDGs, which is unusual for enzymes with the same principal activity, is probably due to the major role of the uracil-flipping caused by the conformational strain enacted by the enzyme on uracil-containing DNA, as compared with the catalytic action of individual polar residues. We predict two previously undetected families of UDGs and delineate a hypothetical scenario for their evolution.
UDGs form a single protein superfamily with a distinct structural fold and a common evolutionary origin. Differences in the catalytic mechanism of the different families combined with the construction of the catalytic pocket have, however, resulted in extreme sequence divergence of these enzymes.
PMCID: PMC15025  PMID: 11178247
4.  Holliday junction resolvases and related nucleases: identification of new families, phyletic distribution and evolutionary trajectories 
Nucleic Acids Research  2000;28(18):3417-3432.
Holliday junction resolvases (HJRs) are key enzymes of DNA recombination. A detailed computer analysis of the structural and evolutionary relationships of HJRs and related nucleases suggests that the HJR function has evolved independently from at least four distinct structural folds, namely RNase H, endonuclease, endonuclease VII–colicin E and RusA. The endonuclease fold, whose structural prototypes are the phage λ exonuclease, the very short patch repair nuclease (Vsr) and type II restriction enzymes, is shown to encompass by far a greater diversity of nucleases than previously suspected. This fold unifies archaeal HJRs, repair nucleases such as RecB and Vsr, restriction enzymes and a variety of predicted nucleases whose specific activities remain to be determined. Within the RNase H fold a new family of predicted HJRs, which is nearly ubiquitous in bacteria, was discovered, in addition to the previously characterized RuvC family. The proteins of this family, typified by Escherichia coli YqgF, are likely to function as an alternative to RuvC in most bacteria, but could be the principal HJRs in low-GC Gram-positive bacteria and Aquifex. Endonuclease VII of phage T4 is shown to serve as a structural template for many nucleases, including McrA and other type II restriction enzymes. Together with colicin E7, endonuclease VII defines a distinct metal-dependent nuclease fold. As a result of this analysis, the principal HJRs are now known or confidently predicted for all bacteria and archaea whose genomes have been completely sequenced, with many species encoding multiple potential HJRs. Horizontal gene transfer, lineage-specific gene loss and gene family expansion, and non-orthologous gene displacement seem to have been major forces in the evolution of HJRs and related nucleases. A remarkable case of displacement is seen in the Lyme disease spirochete Borrelia burgdorferi, which does not possess any of the typical HJRs, but instead encodes, in its chromosome and each of the linear plasmids, members of the λ exonuclease family predicted to function as HJRs. The diversity of HJRs and related nucleases in bacteria and archaea contrasts with their near absence in eukaryotes. The few detected eukaryotic representatives of the endonuclease fold and the RNase H fold have probably been acquired from bacteria via horizontal gene transfer. The identity of the principal HJR(s) involved in recombination in eukaryotes remains uncertain; this function could be performed by topoisomerase IB or by a novel, so far undetected, class of enzymes. Likely HJRs and related nucleases were identified in the genomes of numerous bacterial and eukaryotic DNA viruses. Gene flow between viral and cellular genomes has probably played a major role in the evolution of this class of enzymes. This analysis resulted in the prediction of numerous previously unnoticed nucleases, some of which are likely to be new restriction enzymes.
PMCID: PMC110722  PMID: 10982859
5.  Comparative Genome Analysis of the Pathogenic Spirochetes Borrelia burgdorferi and Treponema pallidum 
Infection and Immunity  2000;68(3):1633-1648.
A comparative analysis of the predicted protein sequences encoded in the complete genomes of Borrelia burgdorferi and Treponema pallidum provides a number of insights into evolutionary trends and adaptive strategies of the two spirochetes. A measure of orthologous relationships between gene sets, termed the orthology coefficient (OC), was developed. The overall OC value for the gene sets of the two spirochetes is about 0.43, which means that less than one-half of the genes show readily detectable orthologous relationships. This emphasizes significant divergence between the two spirochetes, apparently driven by different biological niches. Different functional categories of proteins as well as different protein families show a broad distribution of OC values, from near 1 (a perfect, one-to-one correspondence) to near 0. The proteins involved in core biological functions, such as genome replication and expression, typically show high OC values. In contrast, marked variability is seen among proteins that are involved in specific processes, such as nutrient transport, metabolism, gene-specific transcription regulation, signal transduction, and host response. Differences in the gene complements encoded in the two spirochete genomes suggest active adaptive evolution for their distinct niches. Comparative analysis of the spirochete genomes produced evidence of gene exchanges with other bacteria, archaea, and eukaryotic hosts that seem to have occurred at different points in the evolution of the spirochetes. Examples are presented of the use of sequence profile analysis to predict proteins that are likely to play a role in pathogenesis, including secreted proteins that contain specific protein-protein interaction domains, such as von Willebrand A, YWTD, TPR, and PR1, some of which hitherto have been reported only in eukaryotes. We tentatively reconstruct the likely evolutionary process that has led to the divergence of the two spirochete lineages; this reconstruction seems to point to an ancestral state resembling the symbiotic spirochetes found in insect guts.
PMCID: PMC97324  PMID: 10678983
6.  The COG database: a tool for genome-scale analysis of protein functions and evolution 
Nucleic Acids Research  2000;28(1):33-36.
Rational classification of proteins encoded in sequenced genomes is critical for making the genome sequences maximally useful for functional and evolutionary studies. The database of Clusters of Orthologous Groups of proteins (COGs) is an attempt on a phylogenetic classification of the proteins encoded in 21 complete genomes of bacteria, archaea and eukaryotes ( ). The COGs were constructed by applying the criterion of consistency of genome-specific best hits to the results of an exhaustive comparison of all protein sequences from these genomes. The database comprises 2091 COGs that include 56–83% of the gene products from each of the complete bacterial and archaeal genomes and ~35% of those from the yeast Saccharomyces cerevisiae genome. The COG database is accompanied by the COGNITOR program that is used to fit new proteins into the COGs and can be applied to functional and phylogenetic annotation of newly sequenced genomes.
PMCID: PMC102395  PMID: 10592175

Results 1-6 (6)