Beyond microbial core genomic epidemiology: towards pan genomic epidemiology

Abstract

Whole-genome sequencing has essentially changed molecular epidemiology forever. Whole-genome sequencing has ultrafine genotyping resolution so that we can track the dissemination of microbial pathogens at unprecedented micro-spatiotemporal scales.1Baker KS Microbe hunting in the modern era: reflecting on a decade of microbial genomic epidemiology.Curr Biol. 2020; 30: R1124-R1130Google Scholar, 2Hill V Ruis C Bajaj S Pybus OG Kraemer MUG Progress and challenges in virus genomic epidemiology.Trends Parasitol. 2021; 37: 1038-1049Google Scholar There is no doubt that genomic epidemiology, including genomic surveillance, has been one of the most successful stories of whole-genome sequencing applied to public health. SARS-CoV-2 has shown the potential of genomic epidemiology; a deluge of studies over the past 2 years has been essential to establish the transmission of this virus at very different spatial scales. In the case of bacteria, especially concerning very relevant human pathogens such as Staphylococcus aureus or Acinetobacter baumannii, genomic epidemiology has been of paramount importance not only to identify outbreaks but also to help infection control teams to better manage and curtail the multidrug-resistant pathogens causing them.3Tang P Gardy JL Stopping outbreaks with real-time genomic epidemiology.Genome Med. 2014; 6: 104Google Scholar The standard procedure for bacterial genomic epidemiology is to focus on the genetic variation, usually single nucleotide polymorphisms (known as SNPs), present in the core genome which are regions of the genome present in all the isolates considered. This strategy has been very useful to appraise the dissemination of bacterial pathogens over different scales, from global to national and even in local settings.4Frisch MB Castillo-Ramírez S Petit 3rd, RA et al.Invasive methicillin-resistant Staphylococcus aureus USA500 strains from the US Emerging Infections Program constitute three geographically distinct lineages.MSphere. 2018; 3: e00571Google Scholar, 5Graña-Miraglia L Evans BA López-Jácome LE et al.Origin of OXA-23 variant OXA-239 from a recently emerged lineage of Acinetobacter baumannii international clone V.MSphere. 2020; 5: e00801-e00819Google Scholar, 6Mateo-Estrada V Fernández-Vázquez JL Moreno-Manjón J et al.Accessory genomic epidemiology of cocirculating Acinetobacter baumannii clones.mSystems. 2021; 6e0062621Google Scholar However, core genomic epidemiology neglects an important amount of the phylogenetic information contained in the accessory genome, which are regions of the genome present in some but not all of the isolates considered. In bacterial genomic epidemiology the accessory genome is commonly discarded as it does not follow vertical transmission; however, we now have a much better understanding of this part of the genome and a better framework to integrate it with the phylogenetic signals residing the in the core genome. Notably, for some bacterial species it is difficult to distinguish bacterial isolates at very short periods of time, as they might not accrue enough core genome variation; this can be the case for very clonal bacteria. Under these circumstances, variation in the accessory genome might be the only option to establish the transmission dynamics of the isolates under consideration. In a 2021 study, which analysed the dissemination of A baumannii within a hospital, the potential for using the accessory genome to conduct genomic epidemiology was shown.6Mateo-Estrada V Fernández-Vázquez JL Moreno-Manjón J et al.Accessory genomic epidemiology of cocirculating Acinetobacter baumannii clones.mSystems. 2021; 6e0062621Google Scholar To fully understand the transmission of several co-circulating lineages of A baumannii, Mateo-Estrada and colleagues6Mateo-Estrada V Fernández-Vázquez JL Moreno-Manjón J et al.Accessory genomic epidemiology of cocirculating Acinetobacter baumannii clones.mSystems. 2021; 6e0062621Google Scholar made use of gene content variation within the accessory genome in addition to using classical core genomic epidemiology. Notably, the variation in the accessory genome was of paramount importance to establish the high rate of transmission across the different wards in the hospital. The core genome did not have as much genotyping resolution as the accessory genome over very short time periods. Moreover, the study also shows how the phylogenetic signals present in the accessory genome can complement those residing in the core genome, which can be extremely useful when conducting genomic epidemiology at very short temporal scales. Clearly, using both core and accessory genome phylogenetic signals provides an unparalleled resolution that surpasses the use of only the core genome. By integrating and contrasting core and accessory genomic epidemiology (termed pan genomic epidemiology) we can gain unprecedented insights into the transmission dynamics of bacterial populations.6Mateo-Estrada V Fernández-Vázquez JL Moreno-Manjón J et al.Accessory genomic epidemiology of cocirculating Acinetobacter baumannii clones.mSystems. 2021; 6e0062621Google Scholar, 7Abudahab K Prada JM Yang Z et al.PANINI: pangenome neighbour identification for bacterial populaçtions.Microb Genom. 2019; 5e000220Google Scholar, 8McNally A Oren Y Kelly D et al.Combined analysis of variation in core, accessory and regulatory genome regions provides a super-resolution view into the evolution of bacterial populations.PLoS Genet. 2016; 12e1006280Google Scholar However, whether to use core or accessory genomic epidemiology or even pan genomic epidemiology will depend on the genetics of the bacterial species in question; accessory genomic epidemiology is more suitable for species with dynamic genomes.9Graña-Miraglia L Lozano LF Velázquez C et al.Rapid gene turnover as a significant source of genetic variation in a recently seeded population of a healthcare-associated pathogen.Front Microbiol. 2017; 81817Google Scholar Another important factor to consider is the spatiotemporal scale: core genomic epidemiology should be sufficient for global, intercontinental, and even national investigations but might not be suitable for analysing transmission dynamics over very short periods of time. Conversely, both accessory and pan genomic epidemiology should be extremely useful at very short temporal scales to establish routes and sources of infections; they are both very relevant to epidemiological investigations dealing with outbreaks within clinical and non-clinical settings. We foresee that in the coming years we will witness a substantial increase in the number of studies going beyond core genomic epidemiology. These future studies undoubtedly will include the phylogenetic signals contained in the accessory genome and integrate them to those signals present in core genome. This pan genomic epidemiology is bound to become a central component for outbreak management. I declare no competing interests.

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