, 2003). Additionally, many subtelomeres are enriched with retrotransposons and other mobile genetic elements, which can lead to local insertions, deletions, duplications and inversions (Volff, 2006). Virulence-associated genes are often located in pathogen subtelomeres, and include those directing antigenic variation in Plasmodium Etoposide manufacturer falciparum and Trypanosoma brucei, surface glycoproteins of Candida glabrata (De Las et al., 2003), secondary metabolites, catabolism and transport in A. fumigatus (Fedorova et al., 2008) and secondary metabolites in U. maydis (Bolker et al., 2008). While targeted sequencing of M. grisea chromosomes demonstrated no virulence-associated

gene enrichment at subtelomeres (Farman, 2007), gene expression analysis of A. fumigatus germlings during host invasion found that genes induced during infection displayed subtelomeric and lineage-specific

bias, supporting the diversity of these regions being more important than HGT in Venetoclax order the evolution of pathogenicity for this species (McDonagh et al., 2008). Both the HGT and DDL hypotheses suggest that an increase in the virulence-associated gene content at restricted genomic locations leads to an increase in the pathogenicity spectrum within a population, enabling differential survival in the host niche. A different hypothesis suggests that clustering may facilitate the epigenetic regulation of functionally related genes during niche adaptation. This model stresses

that genes grouped in close proximity may be regulated by gross modifications to the chromosome environment, such as the boundaries between euchromatin and heterochromatin. This model is contingent with the discovery of an Aspergillus methyl transferase, LaeA, which was found to be required for the production of many secondary metabolite toxins and essential for virulence in a murine model of infection (Bok et al., 2005). The movement of genes into or out of these clusters leads to gain or loss of LaeA regulation, respectively, suggesting that this global regulator of secondary metabolite ID-8 biosynthesis regulates gene expression at the level of chromatin remodelling (Bok et al., 2006b). In vitro gene expression analysis shows that LaeA regulates the expression of key genes at multiple secondary metabolite loci, including gliotoxin and the cytotoxic quinine pseurotin (Perrin et al., 2007). These data collectively support the hypothesis that clusters facilitate epigenetic control of functionally related genes that are required for virulence. Of great interest will be the global expression analysis of the ΔlaeA strain during infection, to determine the epigenetic regulation of virulence-associated clusters in vivo (Cairns et al., unpublished data). Other pathogens display remarkable coordination of cluster-related gene expression during infection. For example, 12 U.