broadinstitute.org, http://www.genome.wustl.edu). G186A has four chromosomes whereas G217B has only three (Steele et al., 1989). However, the total genome size of G217B is roughly 30% larger than G186A (41 megabases vs. 30.4 megabases, respectively) primarily due to repetitive DNA, which includes mobile DNA insertions, retrotransposons and multiple copies of a crypton (Goodwin et al., 2003). This suggests that the non-repetitive

‘core’ Histoplasma genome is roughly 26–28 megabases. Bioinformatics analyses of the sequence predicts that the Histoplasma genome encodes between 9000 and 10 000 genes (http://www.broadinstitute.org). Large regions of synteny exist between G186A and IDO inhibitor G217B and

much of the ‘extra’ DNA is located intergenically as clusters of repetitive sequence. Nucleotide sequence identity for homologous genes is roughly 97 ± 2% between G186A and G217B (J.A. Edwards and C.A. Rappleye, unpublished data) suggesting C59 wnt in vivo differential gene regulation, rather than amino acid change, is an important contributor to phenotypic differences between strains. Histoplasma capsulatum is a haploid organism and has a heterothallic mating system (Kwon-Chung, 1973). A mating type locus (MAT locus) is present in the genome and two MAT alleles are correlated with opposite mating types in clinical strains; G217B has the MAT1-1 allele whereas G186A has the MAT1-2 allele (Bubnick & Smulian, 2007). Some correlation exists between mating type and virulence. Considerable variation exists in the proportions of mating types (designated as + or −) in environmental sources of Histoplasma (Kwon-Chung et al., 1974; Gaur & Lichtwardt, 1980), however, in clinical samples – mating types predominate (Kwon-Chung et al., 1974, 1984). The significance of this correlation

is from presently unknown. Attempts to manipulate G186A and G217B in the lab have indicated differences in the efficiency of homologous recombination between the two strains. Whereas several gene deletion strains have been created through allelic replacement in the Panamanian background (G186A or G184A strains) (Woods et al., 1998; Sebghati et al., 2000; Tian & Shearer, 2002; Rappleye et al., 2004; Marion et al., 2006; Hwang et al., 2008; Hilty et al., 2011), only a limited number of gene knockout alleles exist in the NAm2 isolate G217B (Marion et al., 2006; Cooper & Woods, 2009). As a consequence, RNA interference (RNAi) has been adopted as a more practical means to deplete gene functions in Histoplasma (Rappleye et al., 2004) when efforts to delete genes through homologous recombination fail.