A key enzyme, most commonly an NRPS or polyketide synthase, produces a precursor molecule, which is subsequently modified by other enzymes encoded by the cluster. These genes usually produce a single product of small molecular weight, for example polyketides (lovastatin and aflatoxin B1), nonribosomal peptides (penicillin G and gliotoxin),

terpenes (gibbererellin) and indole alkaloids (fumitromorgin C), which are dispensable for cellular growth and have a restricted taxanomic distribution (Keller et al., 2005). The well-documented cytotoxic and phytotoxic properties of many of these compounds have long identified them as putative virulence factors. Gene expression profiling and candidate gene analysis of multiple SGI-1776 price secondary metabolite-producing species present us with the first opportunity to assess their role as a common molecular feature used by fungi to overcome universal challenges encountered in the host niche. Other secondary metabolites have impacts on virulence that are unique to

both the host environment and the stage of infection. The immunotoxic dipeptide gliotoxin, produced by a cluster of 19 genes in A. fumigatus (Cramer et al., 2006), is induced 14-h postinfection relative to laboratory culture (McDonagh et al., 2008) and is a virulence factor in a hydrocortisone acetate-treated, but not neutropenic, murine infection model. The action of gliotoxin as a virulence factor Metabolism inhibitor in vivo is most likely due to action against neutrophils, which is supported by ex vivo cellular assays (Bok et al., 2006a), and has recently been substantiated as acting at the level of proapoptotic gene family members in a physiologically relevant context using hydrocortisone acetate-treated BAK knockout mice (Pardo et al., 2006). A unifying model to NADPH-cytochrome-c2 reductase explain the existence of fungal clusters is currently unavailable, but it seems clear that multiple evolutionary mechanisms may explain their origin. Currently, three main hypotheses have been proposed, and gene expression analysis

represents a useful tool for determining the relative contribution of these hypotheses to fungal gene clustering. Horizontal gene transfer (HGT) suggests that clusters may both originate and be maintained from selective pressure following HGT events. Gene clusters that encode an entire metabolic pathway or virulence factor are more likely to result in a phenotypic advantage to the recipient genome (Walton, 2000). The gene duplication, diversification and differential gene loss (DDL) hypothesis emphasizes the fundamental features of specific genomic regions as being the driving force behind clustering. Areas of microbial eukaryotes that are most subject to high genetic and genomic variability are the subtelomeres, located between the telomeric end of linear chromosomes and chromosome-specific sequences (Farman, 2007).