Until recently, the apicomplexan parasites, Cryptosporidium hominis and C. parvum, were considered the same species. However, the two parasites, now considered distinct species, exhibit significant differences in host range, infectivity, and pathogenicity, and their sequenced genomes exhibit only 95–97% identity. The availability of the complete genome sequences of these organisms provides the potential to identify the genetic variations that are responsible for the phenotypic differences between the two parasites. We compared the genome organization and structure, gene composition, the metabolic and other pathways, and the local sequence identity between the genes of these two Cryptosporidium species. Our observations show that the phenotypic differences between C. hominis and C. parvum are not due to gross genome rearrangements, structural alterations, gene deletions or insertions, metabolic capabilities, or other obvious genomic alterations. Rather, the results indicate that these genomes exhibit a remarkable structural and compositional conservation and suggest that the phenotypic differences observed are due to subtle variations in the sequences of proteins that act at the interface between the parasite and its host. 1. Introduction Organisms of the genus Cryptosporidium are protozoa of the phylum Apicomplexa. These obligatory intracellular organisms parasitize animals of all vertebrate classes [1]. Although mostly ignored as a pathogen until relatively late in the 20th century, diarrhea caused by Cryptosporidium species is debilitating for adults and children and can be life threatening for immunocompromised individuals such as those with AIDS. Cryptosporidiosis is also a significant factor in animal husbandry practices and represents a significant challenge to agriculture, for example, the beef industry [2]. Development of molecular tools now permits efficient differentiation of morphologically indistinguishable isolates of these parasites, and this new capability has led to important new insights into their epidemiology and pathogenicity. Although several Cryptosporidium species can cause human disease, two species, C. hominis and C. parvum, are responsible for the majority of the human impact. C. parvum infects ruminants as primary hosts and humans as incidental hosts. C. hominis, in contrast, is highly infectious to humans but generally does not infect other species [3]. Until very recently, these two species were considered genotypes of C. parvum [4]: genotype 1 (or type H) found nearly exclusively in humans; and genotype 2 (or type C) found
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