The "domino theory" of gene death: gradual and mass gene extinction events in three lineages of obligate symbiotic bacterial pathogens.

During the adaptation of an organism to a parasitic lifestyle, various gene functions may be rendered superfluous due to the fact that the host may supply these needs. As a consequence, obligate symbiotic bacterial pathogens tend to undergo reductive genomic evolution through gene death (nonfunctionalization or pseudogenization) and deletion. Here, we examine the evolutionary sequence of gene-death events during the process of genome miniaturization in three bacterial species that have experienced extensive genome reduction: Mycobacterium leprae, Shigella flexneri, and Salmonella typhi. We infer that in all three lineages, the distribution of functional categories is similar in pseudogenes and genes but different from that of absent genes. Based on an analysis of evolutionary distances, we propose a two-step "domino effect" model for reductive genome evolution. The process starts with a gradual gene-by-gene-death sequence of events. Eventually, a crucial gene within a complex pathway or network is rendered nonfunctional triggering a "mass gene extinction" of the dependent genes. In contrast to published reports according to which genes belonging to certain functional categories are prone to nonfunctionalization more frequently and earlier than genes belonging to other functional categories, we could discern no characteristic regularity in the temporal order of function loss.

Inferring the pattern of spontaneous mutation from the pattern of substitution in unitary pseudogenes of Mycobacterium leprae and a comparison of mutation patterns among distantly related organisms.

The pattern of spontaneous mutation can be inferred from the pattern of substitution in pseudogenes, which are known to be under very weak or no selective constraint. We modified an existing method (Gojobori T, et al., J Mol Evol 18:360, 1982) to infer the pattern of mutation in bacteria by using 569 pseudogenes from Mycobacterium leprae. In Gojobori et al.'s method, the pattern is inferred by using comparisons involving a pseudogene, a conspecific functional paralog, and an outgroup functional ortholog. Because pseudogenes in M. leprae are unitary, we replaced the missing paralogs by functional orthologs from M. tuberculosis. Functional orthologs from Streptomyces coelicolor served as outgroups. We compiled a database consisting of 69,378 inferred mutations. Transitional mutations were found to constitute more than 56% of all mutations. The transitional bias was mainly due to C-->T and G-->A, which were also the most frequent mutations on the leading strand and the only ones that were significantly more frequent than the random expectation. The least frequent mutations on the leading strand were A-->T and T-->A, each with a relative frequency of less than 3%. The mutation pattern was found to differ between the leading and the lagging strands. This asymmetry is thought to be the cause for the typical chirochoric structure of bacterial genomes. The physical distance of the pseudogene from the origin of replication (ori) was found to have almost no effect on the pattern of mutation. A surprising similarity was found between the mutation pattern in M. leprae and previously inferred patterns for such distant taxa as human and Drosophila. The mutation pattern on the leading strand of M. leprae was also found to share some common features with the pattern inferred for the heavy strand of the human mitochondrial genome. These findings indicate that taxon-specific factors may only play secondary roles in determining patterns of mutation.