Abstract
Metagenomic sequencing is a powerful tool for examining the diversity and complexity of microbial communities. Most widely used tools for taxonomic profiling of metagenomic sequence data allow for a species-level overview of the composition. However, individual strains within a species can differ greatly in key genotypic and phenotypic characteristics, such as drug resistance, virulence and growth rate. Therefore, the ability to resolve microbial communities down to the level of individual strains within a species is critical to interpreting metagenomic data for clinical and environmental applications, where identifying a particular strain, or tracking a particular strain across a set of samples, can help aid in clinical diagnosis and treatment, or in characterizing yet unstudied strains across novel environmental locations. Recently published approaches have begun to tackle the problem of resolving strains within a particular species in metagenomic samples. In this review, we present an overview of these new algorithms and their uses, including methods based on assembly reconstruction and methods operating with or without a reference database. While existing metagenomic analysis methods show reasonable performance at the species and higher taxonomic levels, identifying closely related strains within a species presents a bigger challenge, due to the diversity of databases, genetic relatedness, and goals when conducting these analyses. Selection of which metagenomic tool to employ for a specific application should be performed on a case-by case basis as these tools have strengths and weaknesses that affect their performance on specific tasks. A comprehensive benchmark across different use case scenarios is vital to validate performance of these tools on microbial samples. Because strain-level metagenomic analysis is still in its infancy, development of more fine-grained, high-resolution algorithms will continue to be in demand for the future.
Highlights
Within a species, bacteria can be highly diverse in terms of their virulence, resistance to antibiotics, geographical transmission patterns, and other phenotypic characteristics (Fournier et al, 2014; Maxson and Mitchell, 2016)
The ability to identify specific strains in a noisy background of other organisms present in a metagenomic sample could allow for improved tracking of strains involved in an outbreak across a population
Mixed infections, defined as infections caused by multiple strains of a single pathogen species (Marshall, 2002; Cohen et al, 2012), represent an underappreciated challenge to understanding infections and have been described for at least 22 bacterial species (Balmer and Tanner, 2011), including M. tuberculosis (Cohen et al, 2012; Plazzotta et al, 2015), C. difficile (Eyre et al, 2013, 2012), and Streptococcus pneumoniae (Esposito et al, 2002; Minagawa et al, 2008)
Summary
Bacteria can be highly diverse in terms of their virulence, resistance to antibiotics, geographical transmission patterns, and other phenotypic characteristics (Fournier et al, 2014; Maxson and Mitchell, 2016). Identifying specific pathogenic strains would aid in patient diagnosis, allowing for personalized treatment regimens, improved treatment outcomes, and a reduction in the spread of antibiotic resistance. Mixed infections put patients at a higher risk of treatment failure (Balmer and Tanner, 2011; Cohen et al, 2012; Plazzotta et al, 2015), as strains with different drug susceptibility and antibiotic resistance profiles (Falagas et al, 2008; El-Halfawy and Valvano, 2015) can complicate diagnosis and identification of the optimal treatment regimen (Balmer and Tanner, 2011). Accurate classification of individual strains is critical for identifying mixed infections and will help determine proper treatment options for patients with complex infections, track transmission of pathogenic strains in a population, and differentiate between reinfection and intra-host pathogen evolution
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