Predicting the pathogenicity of bacterial genomes using widely spread protein families.

BACKGROUND: The human body is inhabited by a diverse community of commensal non-pathogenic bacteria, many of which are essential for our health. By contrast, pathogenic bacteria have the ability to invade their hosts and cause a disease. Characterizing the differences between pathogenic and commensal non-pathogenic bacteria is important for the detection of emerging pathogens and for the development of new treatments. Previous methods for classification of bacteria as pathogenic or non-pathogenic used either raw genomic reads or protein families as features. Using protein families instead of reads provided a better interpretability of the resulting model. However, the accuracy of protein-families-based classifiers can still be improved. RESULTS: We developed a wide scope pathogenicity classifier (WSPC), a new protein-content-based machine-learning classification model. We trained WSPC on a newly curated dataset of 641 bacterial genomes, where each genome belongs to a different species. A comparative analysis we conducted shows that WSPC outperforms existing models on two benchmark test sets. We observed that the most discriminative protein-family features in WSPC are widely spread among bacterial species. These features correspond to proteins that are involved in the ability of bacteria to survive and replicate during an infection, rather than proteins that are directly involved in damaging or invading the host.

Approximate search for known gene clusters in new genomes using PQ-trees.

Gene clusters are groups of genes that are co-locally conserved across various genomes, not necessarily in the same order. Their discovery and analysis is valuable in tasks such as gene annotation and prediction of gene interactions, and in the study of genome organization and evolution. The discovery of conserved gene clusters in a given set of genomes is a well studied problem, but with the rapid sequencing of prokaryotic genomes a new problem is inspired. Namely, given an already known gene cluster that was discovered and studied in one genomic dataset, to identify all the instances of the gene cluster in a given new genomic sequence. Thus, we define a new problem in comparative genomics, denoted PQ-TREE SEARCH that takes as input a PQ-tree T representing the known gene orders of a gene cluster of interest, a gene-to-gene substitution scoring function h, integer arguments [Formula: see text] and [Formula: see text], and a new sequence of genes S. The objective is to identify in S approximate new instances of the gene cluster; These instances could vary from the known gene orders by genome rearrangements that are constrained by T, by gene substitutions that are governed by h, and by gene deletions and insertions that are bounded from above by [Formula: see text] and [Formula: see text], respectively. We prove that PQ-TREE SEARCH is NP-hard and propose a parameterized algorithm that solves the optimization variant of PQ-TREE SEARCH in [Formula: see text] time, where [Formula: see text] is the maximum degree of a node in T and [Formula: see text] is used to hide factors polynomial in the input size. The algorithm is implemented as a search tool, denoted PQFinder, and applied to search for instances of chromosomal gene clusters in plasmids, within a dataset of 1,487 prokaryotic genomes. We report on 29 chromosomal gene clusters that are rearranged in plasmids, where the rearrangements are guided by the corresponding PQ-trees. One of these results, coding for a heavy metal efflux pump, is further analysed to exemplify how PQFinder can be harnessed to reveal interesting new structural variants of known gene clusters.

Discovery of multi-operon colinear syntenic blocks in microbial genomes.

MOTIVATION: An important task in comparative genomics is to detect functional units by analyzing gene-context patterns. Colinear syntenic blocks (CSBs) are groups of genes that are consistently encoded in the same neighborhood and in the same order across a wide range of taxa. Such CSBs are likely essential for the regulation of gene expression in prokaryotes. Recent results indicate that colinearity can be conserved across multiple operons, thus motivating the discovery of multi-operon CSBs. This computational task raises scalability challenges in large datasets. RESULTS: We propose an efficient algorithm for the discovery of cross-strand multi-operon CSBs in large genomic datasets. The proposed algorithm uses match-point arithmetic, which is scalable for large datasets of microbial genomes in terms of running time and space requirements. The algorithm is implemented and incorporated into a tool with a graphical user interface, called CSBFinder-S. We applied CSBFinder-S to data mine 1485 prokaryotic genomes and analyzed the identified cross-strand CSBs. Our results indicate that most of the syntenic blocks are exclusively colinear. Additional results indicate that transcriptional regulation by overlapping transcriptional genes is abundant in bacteria. We demonstrate the utility of CSBFinder-S to identify common function of the gene-pair PulEF in multiple contexts, including Type 2 Secretion System, Type 4 Pilus System and DNA uptake machinery. AVAILABILITY AND IMPLEMENTATION: CSBFinder-S software and code are publicly available at https://github.com/dinasv/CSBFinder. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

CSBFinder: discovery of colinear syntenic blocks across thousands of prokaryotic genomes.

MOTIVATION: Identification of conserved syntenic blocks across microbial genomes is important for several problems in comparative genomics such as gene annotation, study of genome organization and evolution and prediction of gene interactions. Current tools for syntenic block discovery do not scale up to the large quantity of prokaryotic genomes available today. RESULTS: We present a novel methodology for the discovery, ranking and taxonomic distribution analysis of colinear syntenic blocks (CSBs)-groups of genes that are consistently located close to each other, in the same order, across a wide range of taxa. We present an efficient algorithm that identifies CSBs in large genomic datasets. The algorithm is implemented and incorporated in a novel tool with a graphical user interface, denoted CSBFinder, that ranks the discovered CSBs according to a probabilistic score and clusters them to families according to their gene content similarity. We apply CSBFinder to data mine 1487 prokaryotic genomes including chromosomes and plasmids. For post-processing analysis, we generate heatmaps for visualizing the distribution of CSB family members across various taxa. We exemplify the utility of CSBFinder in operon prediction, in deciphering unknown gene function and in taxonomic analysis of colinear syntenic blocks. AVAILABILITY AND IMPLEMENTATION: CSBFinder software and code are publicly available at https://github.com/dinasv/CSBFinder. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.