FLICKR, MASAHIKO OHKUBO
Genomic sequencing of samples from multiple patients during a bacterial epidemic has revealed gene mutations that give the bugs a selective advantage. The large-scale sequencing approach, which is reported today (November 13) in Nature Genetics, should help researchers find chinks in the armor of a wide range of human pathogens.
“This is a really superb study,” said Richard Lenski of Michigan State University, who was not involved in the study, “[It] shows how the tools and approaches of genomics, epidemiology, and evolutionary biology can be combined to give new insights into disease.”
Roy Kishony of Harvard Medical School, who led the research, said in an email that the aim of the study was “to ask, what does a pathogen experience while infecting the human body, what are the main challenges it encounters… what genes are evolving under selection during infection?”
Thanks to the good record keeping of a Boston hospital during a small epidemic of a lung-infecting bacterium called Burkholderia dolosa that spread among cystic fibrosis patients in the 1990s, Kishony and his colleagues were able to answer these questions. The researchers tracked the epidemic by comparing the bacterial genomes isolated from new infectees against the strain isolated from the first infected individual—patient zero.
In total, the team sequenced 112 bacterial samples, collected from 14 cystic fibrosis patients, who are particularly vulnerable to chronic, long-lasting lung infections, over a period of 16 years.
“It is the first such study at this scale… that goes into this much depth with so many isolates being sequenced and fully analyzed,” said Arjan de Visser of Wageningen University in The Netherlands, who was not involved in the study. “It reveals all kinds of interesting new genes that could be involved in pathogenesis.”
Indeed, the sequence analysis identified 17 genes that had independently acquired nonsynonymous mutations—mutations causing functional change—in multiple individuals. This pattern of mutations suggests that the genes were under selection during the epidemic. “These genes include some of the hallmarks for pathogenesis, such as resistance to antibiotics, adhesion, and secretion,” said Kishony. “But [they] also include some less expected genes, such as genes involved in oxygen sensing and regulation, as well as some genes whose function was not linked to pathogenesis before,” including a metabolic enzyme and a transcription factor.
Investigating the function of these genes and the selective advantage they give the bacteria should help in the development of strategies for tackling Burkholderia dolosa infections in cystic fibrosis patients, said Kishony. But it might also help researchers tackle other bugs in other hosts.
For example, it is possible that related genes in other bacterial species are under similar selective pressures during infections. Failing that, other genes could be identified by the same sequencing approach. “This same methodology can be used in other cases where we can track multiple infections of the same pathogen in different hosts,” said Kishony. “It might even be possible to extend the approach to diagnostics in a single person, utilizing the idea that even in a single host, the pathogen may evolve independently in multiple niches and body compartments.”
T.D. Lieberman et al., “Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes,” Nature, doi:10.1038/ng.997, 2011.