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Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics. Author summary: The prevalence of KSHV infection, one of eight viruses associated with human cancer, differs geographically as does the incidence of Kaposi sarcoma and other KSHV-associated diseases. Distribution of KSHV subtypes, defined solely by the sequence of the K1 gene, also differs by region. One hundred and two near full-length KSHV genomes from people with associated diseases from a wide variety of countries were sequenced, substantially increasing the number and diversity of KSHV genomes publicly available, thereby allowing the analysis of variance across geographical regions, potential contributions of viral genetics to the risk of disease, and viral evolution. Our data demonstrate that viral recombination is common, as previously published, and that infections with multiple KSHV genomes may also be frequent, which has not been widely reported. We did not find evidence of an association between viral subtypes and disease nor indications that different sampling sites from the same individual, including tumor specimens, harbored substantially different KSHV genomes. Our data significantly inform the current efforts to study epidemiology and the prevention of KSHV infection, including vaccine development, as well as the pathogenesis of associated diseases. [ABSTRACT FROM AUTHOR]