Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences hamper annotation, experimental design and interpretation. We have generated a new C. parvum IOWA genome assembly supported by PacBio and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species C. parvum, Cryptosporidium hominis and Cryptosporidium tyzzeri. We made 1,926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum, C. hominis and C. tyzzeri revealed that most "missing" orthologs are found suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation and single nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.

SMARCB1 is a critical component of the BAF complex that is responsible for global chromatin remodeling. Loss of SMARCB1 has been implicated in the initiation of cancers such as malignant rhabdoid tumor (MRT), atypical teratoid rhabdoid tumor (ATRT), and, more recently, renal medullary carcinoma (RMC). These SMARCB1-deficient tumors have remarkably stable genomes, offering unique insights into the epigenetic mechanisms in cancer biology. Given the lack of druggable targets and the high mortality associated with SMARCB1-deficient tumors, a significant research effort has been directed toward understanding the mechanisms of tumor transformation and proliferation. Accumulating evidence suggests that tumorigenicity arises from aberrant enhancer and promoter regulation followed by dysfunctional transcriptional control. In this review, we outline key mechanisms by which loss of SMARCB1 may lead to tumor formation and cover how these mechanisms have been used for the design of targeted therapy.