Detection of fused genes in eukaryotic genomes using gene deFuser: analysis of the Tetrahymena thermophila genome.

BACKGROUND: Fused genes are important sources of data for studies of evolution and protein function. To date no service has been made available online to aid in the large-scale identification of fused genes in sequenced genomes. We have developed a program, Gene deFuser, that analyzes uploaded protein sequence files for characteristics of gene fusion events and presents the results in a convenient web interface. RESULTS: To test the ability of this software to detect fusions on a genome-wide scale, we analyzed the 24,725 gene models predicted for the ciliated protozoan Tetrahymena thermophila. Gene deFuser detected members of eight of the nine families of gene fusions known or predicted in this species and identified nineteen new families of fused genes, each containing between one and twelve members. In addition to these genuine fusions, Gene deFuser also detected a particular type of gene misannotation, in which two independent genes were predicted as a single transcript by gene annotation tools. Twenty-nine of the artifacts detected by Gene deFuser in the initial annotation have been corrected in subsequent versions, with a total of 25 annotation artifacts (about 1/3 of the total fusions identified) remaining in the most recent annotation. CONCLUSIONS: The newly identified Tetrahymena fusions belong to classes of genes involved in processes such as phospholipid synthesis, nuclear export, and surface antigen generation. These results highlight the potential of Gene deFuser to reveal a large number of novel fused genes in evolutionarily isolated organisms. Gene deFuser may also prove useful as an ancillary tool for detecting fusion artifacts during gene model annotation.

Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways.

CONTEXT: Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence. OBJECTIVE: Identify driver mutations of sporadic PC and potential actionable pathways. METHODS: Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded (FFPE) PC tumor tissue were included and their clinical data analyzed to assess extent of disease. Patients with parathyroid tumors of uncertain malignancy or atypical parathyroid neoplasms were excluded. Thirty-one patients meeting diagnostic criteria had available tissue for analysis. FFPE PC tumors were subjected to DNA extraction and next-generation whole-exome sequencing. All variant calls are single-algorithm only. Twenty-nine samples passed quality assurance after DNA extraction. MAIN OUTCOME MEASURES: Somatic or private germline mutations present in sporadic PC and identification of pathways involved in tumorigenesis. RESULTS: We identified 35 genes with considerable mutational load; only eight genes were previously identified in other PC cohorts. These genes mediate critical processes, including chromosome organization, DNA repair, and cell cycle regulations. Gene mutations involved in MAPK signaling and immune response are also heavily implicated. These findings are limited by inherent molecular artifacts in FFPE tissue analysis and the absence of matched germline DNA. Additionally, variant calls are only single algorithm and may include false-positive/negative calls. CONCLUSION: We identified 33 candidate driver genes of sporadic PC, in addition to previously known driver genes CDC73 and MEN1.

Fusion of the subunits α and ß of succinyl-CoA synthetase as a phylogenetic marker for Pezizomycotina fungi.

Gene fusions, yielding the formation of multidomain proteins, are evolutionary events that can be utilized as phylogenetic markers. Here we describe a fusion gene comprising the α and ß subunits of succinyl-coA synthetase, an enzyme of the TCA cycle, in Pezizomycotina fungi. This fusion is present in all Pezizomycotina with complete genome sequences and absent from all other organisms. Phylogenetic analysis of the α and ß subunits of succinyl-CoA synthetase suggests that both subunits were duplicated and retained in Pezizomycotina while one copy was lost from other fungi. One of the duplicated copies was then fused in Pezizomycotina. Our results suggest that the fusion of the α and ß subunits of succinyl-CoA synthetase can be used as a molecular marker for membership in the Pezizomycotina subphylum. If a species has the fusion it can be reliably classified as Pezizomycotina, while the absence of the fusion is suggestive that the species is not a member of this subphylum.

Fusion of the subunits α and β of succinyl-CoA synthetase as a phylogenetic marker for Pezizomycotina fungi

Gene fusions, yielding the formation of multidomain proteins, are evolutionary events that can be utilized as phylogenetic markers. Here we describe a fusion gene comprising the α and β subunits of succinyl-coA synthetase, an enzyme of the TCA cycle, in Pezizomycotina fungi. This fusion is present in all Pezizomycotina with complete genome sequences and absent from all other organisms. Phylogenetic analysis of the α and β subunits of succinyl-CoA synthetase suggests that both subunits were duplicated and retained in Pezizomycotina while one copy was lost from other fungi. One of the duplicated copies was then fused in Pezizomycotina. Our results suggest that the fusion of the α and β subunits of succinyl-CoA synthetase can be used as a molecular marker for membership in the Pezizomycotina subphylum. If a species has the fusion it can be reliably classified as Pezizomycotina, while the absence of the fusion is suggestive that the species is not a member of this subphylum.