WGS in the micro lab

Nucleic acid technologies are making steady inroads into the clinical microbiology lab as they get faster, better and cheaper. The logical endpoint of this development is the use of microbial genome sequencing as a diagnostic method. Given the pace of improvement in sequencing technology, the feasibility of routine sequencing of clinical isolates is inevitable. The question is whether this technology will add any value.

Writing in the Journal of Antimicrobial Chemotherapy, Torok and Peacock say the answer is yes: "...we believe that rapid whole bacterial genome sequencing has the potential to transform diagnostic clinical and public health microbiology in the not too distant future."

I am more skeptical and think the value of whole genome sequencing will be limited:

ID/Speciation: Genome sequencing is overkill. All the DNA information needed to speciate an isolate is contained in its ribosomal RNA genes. PCR and oligonucleotide hybridization methods return gold standard speciation results now. Additional sequence information will just be noise.

Epidemiology: Probably the best use of WGS information, as the additional sequence data allow the spread and evolution of strains to be tracked. This has already happened in the case of the KPC outbreak at NIH, and will become more common.

Resistance and susceptibility testing: A seductive but terrible idea. The response of bacteria to antibiotics is a complex phenotype, involving many genes. Reliably predicting this response would require a thorough understanding of the actions of all these genes. Even more difficult, it would require us to be able to predict the effect of various mutations in these genes on their activity. For example, a point mutation that changes the amino acid sequence of a metallo beta lactamase could make it more active, less active, or have no effect at all. There are billions of possible mutations in hundreds of genes that would have to be accounted for in order to reliably predict antibiotic response. This is not going to happen soon, or probably ever. More to the point, what actionable information would WGS provide that phenotypic susceptibility testing does not?

Don't get me wrong, I love this technology. I wish it had been around when I was in grad school - synthesizing oligos manually and then sequencing them by the Maxam-Gilbert method was some of the most tedious lab work I've ever done. But the application of WGS to clinical microbiology is likely to be much more hype than substance. Even the epidemiological applications could potentially be done just as well by much more old-fashioned methods such as phage typing (if anyone still knew how to do this). Just because it's new doesn't mean it's better.

 

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