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European Studies Find Unexpected Complexity in Compact Bacterial Genome

NEW YORK (GenomeWeb News) – A trio of papers in this week's issue of Science are revealing the surprising genomic, proteomic, and metabolomic complexity that can exist in a bacterium with a miniscule genome.

Research groups from the European Molecular Biology Laboratory, Spain's Centre de Regulacio Genòmica, and elsewhere characterized the protein complexes, metabolic patterns, and expressed transcripts in a pathogenic bacterial species called Mycoplasma pneumoniae, which has one of the smallest known genomes among free-living organisms. Their results suggest that M. pneumoniae is actually quite complicated, using regulated, multifunctional processes to maximize its miniscule genome.

"At all three levels, we found M. pneumoniae was more complex than we expected," one of the project leaders, Luis Serrano, said in a statement. Serrano was previously a researcher at EMBL and is now head of the Systems Biology Department at the Centre de Regulacio Genòmica.

M. pneumoniae causes atypical pneumonia (sometimes called "walking pneumonia"). Although it's capable of living on its own, the bacterium has a genome that's just 816,000 bases or so — far smaller than the Escherichia coli or Bacillus subtilis genomes, which each contain more than four million bases. Consequently, the researchers decided M. pneumoniae would make a good model for systems biology research on a "minimal" bacterial cell.

In the first study, EMBL researchers Peer Bork and Anne-Claude Gavin led a team of researchers who characterized the M. pneumoniae proteome, using tandem affinity purification mass spectrometry, or TAP-MS, to find protein complexes in the M. pneumoniae strain M129.

The team cloned 617 of the bacteria's 689 protein-coding genes and used transposon expression systems to make 456 strains containing TAP fusions.

Using this TAP-mass spec approach, they detected 411 proteins — an estimated 85 percent of the bug's predicted soluble protein set — as well as 62 homomultimeric complexes (containing more than one copy of the same protein) and 116 heteromultimeric complexes (involving more than one soluble protein).

Based on these results, combined with protein structure model, electron microscopy, and other data, the team developed a set of proteins that they believe represents the bug's minimal proteome.

"Our genome-scale screen for soluble complexes in a bacterium provides a valuable resource for the functional annotation of many genes whose biological roles in prokaryotic or parasitic cells are elusive," Bork, Gavin, and co-authors wrote. "The study allows estimation of unanticipated proteome complexity for an apparently minimal organism that could not be directly inferred from its genome composition and organization or from extensive transcriptional analysis."

In a second paper focused on the bug's metabolic patterns, researchers integrated metabolic information from the Kyoto Encyclopedia of Genes and Genomes with genome sequence and structure data and results from labeled glucose and growth experiments.

In so doing, they pinpointed 129 enzymes involved in 189 catalytic reactions. These and other findings suggest many of the enzymes can pull double duty, functioning in more than one type of enzymatic reaction.

Based on metabolic data, the researchers also developed a minimal M. pneumoniae growth medium containing only 19 nutrients, which they used in a variety of growth experiments.

Their subsequent experiments suggest the cells can quickly tweak their metabolism to suit growth conditions — consistent with other types of evidence showing that M. pneumoniae cells are precisely regulated and capable of adapting rapidly — though its overall growth rate is slower than that observed for other bacterial species.

"Despite its apparent simplicity, we have shown that M. pneumoniae shows metabolic responses and adaptation similar to more complex bacteria," the researchers concluded, "providing hints that other, unknown regulatory mechanisms might exist."

Finally, for a third paper, members of the team used transcriptome sequencing, tiling, and spotted arrays to catalog the transcripts expressed by M. pneumoniae under a range of conditions.

Overall, the team detected and characterized 341 operons and 447 smaller transcriptional units. They also found 117 transcripts not detected previously. Many of these new transcripts appear to be non-coding and 89 were antisense to other known genes.

By comparing the transcriptional profiles of M. pneumoniae cells grown under a range of conditions, the researchers found that genes within the same operon were expressed differently depending on these growth conditions.

And, the researchers noted, numerous protein-coding genes detected were coded on the complementary DNA strand — a pattern resembling the double-stranded gene expression regulation found in eukaryotic genomes.

Together, the papers "report features of transcriptional control and protein organization that are much more subtle and intricate than were previously considered possible in bacteria," University of Arizona at Tucson ecology and evolutionary biology researcher Howard Ochman and post-doctoral researcher Rahul Raghavan wrote in a perspectives article in the same issue of Science.

"The reduced genome of M. pneumoniae belies an underlying eukaryote-like cellular organization replete with intricate regulatory networks and innovative pathways, revealing that there is no such thing as a 'simple' bacterium," Ochman and Raghavan concluded. "[T]he extraordinary information now available for M. pneumoniae sets a new standard for understanding systems-level questions about bacterial physiology and evolution."

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