The multiple facets of homology and their use in comparative genomics to study the evolution of genes, genomes, and species.

The incredible development of comparative genomics during the last decade has required a correct use of the concept of homology that was previously utilized only by evolutionary biologists. Unhappily, this concept has been often misunderstood and thus misused when exploited outside its evolutionary context. This review brings back to the correct definition of homology and explains how this definition has been progressively refined in order to adapt it to the various new kinds of analysis of gene properties and of their products that appear with the progress of comparative genomics. Then, we illustrate the power and the proficiency of such a concept when using the available genomics data in order to study the evolution of individual genes, of entire genomes and of species, respectively. After explaining how we detect homologues by an exhaustive comparison of a hundred of complete proteomes, we describe three main lines of research we have developed in the recent years. The first one exploits synteny and gene context data to better understand the mechanisms of genome evolution in prokaryotes. The second one is based on phylogenomics approaches to reconstruct the tree of life. The last one is devoted to reminding that protein homology is often limited to structural segments (SOH=segment of homology or module). Detecting and numbering modules allows tracing back protein history by identifying the events of gene duplication and gene fusion. We insist that one of the main present difficulties in such studies is a lack of a reliable method to identify genuine orthologues. Finally, we show how these homology studies are helpful to annotate genes and genomes and to study the complexity of the relationships between sequence and function of a gene.

Correct assignment of homology is crucial when genomics meets molecular evolution.

Pertinent evolutionary studies are based on a correct use of homology terms such as paralogues, metalogues and orthologues. Such crucial concepts have been applied to intragenomic and intergenomic analyses. A further requisite is a proper definition of what is a structural segment of homology. Such segments are called modules to reflect that they play a role in the mechanism of combinational construction of a gene from ready-made basic components. Since identifying a module is operationally equivalent to determining the ancestor to this gene segment, it becomes possible to track back protein history and genome evolution. Such studies underline the importance of two fundamental processes, gene duplication and gene fusion. Moreover, grouping the closest orthologues in families is a pertinent way to reconstruct a genomic tree for all available prokaryotes.

Single and double mutations in gyrA but not in gyrB are associated with low- and high-level fluoroquinolone resistance in Helicobacter pylori.

In one French hospital the rate of resistance to ciprofloxacin in Helicobacter pylori was 3.3% (2 of 60 strains) in 1999. The six resistant clinical strains (four from 1996 and two from 1999) and three ciprofloxacin-selected single-step mutants studied carried one gyrA mutation but none in gyrB. Clinafloxacin and garenoxacin were the most active fluoroquinolones against these mutants. Occurrence of a second gyrA mutation was associated with high MICs of all fluoroquinolones tested.