No abstract

The bacterium Neisseria meningitidis is commonly found harmlessly colonising the mucosal surfaces of the human nasopharynx. Occasionally strains can invade host tissues causing septicaemia and meningitis, making the bacterium a major cause of morbidity and mortality in both the developed and developing world. The species is known to be diverse in many ways, as a product of its natural transformability and of a range of recombination and mutation-based systems. Previous work on pathogenic Neisseria has identified several mechanisms for the generation of diversity of surface structures, including phase variation based on slippage-like mechanisms and sequence conversion of expressed genes using information from silent loci. Comparison of the genome sequences of two N. meningitidis strains, serogroup B MC58 and serogroup A Z2491, suggested further mechanisms of variation, including C-terminal exchange in specific genes and enhanced localised recombination and variation related to repeat arrays. We have sequenced the genome of N. meningitidis strain FAM18, a representative of the ST-11/ET-37 complex, providing the first genome sequence for the disease-causing serogroup C meningococci; it has 1,976 predicted genes, of which 60 do not have orthologues in the previously sequenced serogroup A or B strains. Through genome comparison with Z2491 and MC58 we have further characterised specific mechanisms of genetic variation in N. meningitidis, describing specialised loci for generation of cell surface protein variants and measuring the association between noncoding repeat arrays and sequence variation in flanking genes. Here we provide a detailed view of novel genetic diversification mechanisms in N. meningitidis. Our analysis provides evidence for the hypothesis that the noncoding repeat arrays in neisserial genomes (neisserial intergenic mosaic elements) provide a crucial mechanism for the generation of surface antigen variants. Such variation will have an impact on the interaction with the host tissues, and understanding these mechanisms is important to aid our understanding of the intimate and complex relationship between the human nasopharynx and the meningococcus.

Neisseria meningitidis causes globally 1.2 million invasive disease cases and 135 000 deaths per year, mostly in infants and adolescents. A century of traditional vaccinology had failed the fight against the serogroup B meningococcus (MenB), mostly prevalent in developed countries. Eighteen years after the publication of the first complete genome sequence from a living organism, thanks to an innovative genome-based approach named 'reverse vaccinology', the first broadly effective MenB vaccine was licensed for use by the European Medical Agency and other authorities, and is being implemented worldwide. Here we review this long and passionate journey, from the disease epidemiology to novel antigen discovery, from vaccine clinical development to public health impact: two decades of scientific and technological innovation to defeat one of the most sudden and devastating invasive diseases.

Background: Killer Immunoglobulin-like Receptors (KIR) are essential immuno-surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving. Since few KIR remain orthologous between species, with only one of them, KIR2DL4, shown to be common to human, apes and monkeys, the evolution of the KIR gene family in primates remains unclear.

With the advance of sequencing technologies, the landscape of genomic analysis has been transformed, by moving from single strain to species (or even higher taxa)-wide genomic resolution, toward the direction of capturing the “totality” of life diversity; from this scientific advance and curiosity, the concept of “pangenome” was born. Herein we will review, from practical and technical implementation, existing projects of pangenome analysis, with the aim of providing the reader with a snapshot of useful tools should they need to embark on such a pangenomic journey.