Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.

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Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

10.1101/2020.06.04.133199 ◽

2020 ◽

Author(s):

László Bányai ◽

Mária Trexler ◽

Krisztina Kerekes ◽

Orsolya Csuka ◽

László Patthy

Keyword(s):

Negative Selection ◽

Cancer Genomics ◽

Tumor Evolution ◽

Cancer Genes ◽

Cancer Evolution ◽

Human Genes ◽

Strong Negative Selection ◽

Selection For ◽

Inactivating Mutations

AbstractA major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. In the present work we have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

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Multiple mutations acquired into canine RecQ-like helicases encoded by the aneuploid genome of transmissible sarcoma

10.1101/508101 ◽

2018 ◽

Author(s):

Wadim J. Kapulkin

Keyword(s):

Genomic Structure ◽

Single Gene ◽

Domestic Dog ◽

Dna Helicases ◽

Structural Aberrations ◽

Canine Transmissible Venereal Tumour ◽

Multiple Hit ◽

Genetic Events ◽

Transmissible Venereal Tumour

ABSTRACTSticker sarcoma – a highly aneuploid, contagious neoplasm circulating in a domestic dog population - is broadly referred as a canine transmissible venereal tumour (CTVT). The karyotype of transmissible Sticker sarcoma appears as a collage of numerical and structural aberrations; the CTVT genome represents the generalized but stable neoplastic aneuploidy of monoclonal origins. Presented is an analysis of genetic events and variants underlying the aneuploid genomic structure of Sticker sarcoma described previously by Murchison et al. (2014) and Decker et al. (2015). Here we explored the above CTVT genomic compendia and mined the existing data - specifically looking for cases of convergence of multiple non-synonymous variants onto a single gene - the mutational patterns indicative for Knudsonian ‘two-hit’ kinetics. A Table I is given, providing theoretical estimates of retaining the intact wild-type copy, expected as a function of a cumulative mutational convergence observed in unphased sequence consensus. We demonstrate that the two canine RecQ-like helicases: Bloom syndrome helicase and RECQL4, encoded by the aneuploid transmissible tumour, have accumulated a multitude of different mutations. Among the sets of most intensely mutated transmissible sarcoma genes, we also identified a canine FANCD2 – yet another previously unnoticed multiple-hit candidate factor. We discuss a possible role of mutated RecQ-like helicases and other cooperating factors, perceivably involved in the maintenance of the neoplastic aneuploidy. We suggest the proposed cooperative actions of CTVT RecQ-like DNA helicases could be relevant interpreting whether variants contributing to RecQ-dependent karyotypic traits, respond to selective pressures that preserve the aneuploid genomic structure of transmissible Sticker sarcoma.

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Role of exfoliative cytology in the diagnosis of canine transmissible venereal tumour

Journal of Small Animal Practice ◽

10.1111/j.1748-5827.1993.tb02732.x ◽

1993 ◽

Vol 34 (8) ◽

pp. 399-401 ◽

Cited By ~ 2

Author(s):

E. K. Batamuzi ◽

B. M. Kessy

Keyword(s):

Exfoliative Cytology ◽

Canine Transmissible Venereal Tumour ◽

Transmissible Venereal Tumour

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Urinary tract infection: The role of canine transmissible venereal tumour

Journal of Small Animal Practice ◽

10.1111/j.1748-5827.1996.tb02378.x ◽

1996 ◽

Vol 37 (6) ◽

pp. 276-279 ◽

Cited By ~ 6

Author(s):

E. K. Batatnuzi ◽

F. Kristensen

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Canine Transmissible Venereal Tumour ◽

Transmissible Venereal Tumour

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Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

eLife ◽

10.7554/elife.59629 ◽

2021 ◽

Vol 10 ◽

Author(s):

László Bányai ◽

Maria Trexler ◽

Krisztina Kerekes ◽

Orsolya Csuka ◽

László Patthy

Keyword(s):

Negative Selection ◽

Cancer Genomics ◽

Tumor Evolution ◽

Cancer Genes ◽

Cancer Evolution ◽

Human Genes ◽

Strong Negative Selection ◽

Selection For ◽

Inactivating Mutations

A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations, oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

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Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽

10.1007/s12268-021-1589-1 ◽

2021 ◽

Vol 27 (4) ◽

pp. 390-393

Author(s):

F.-Nora Vögtle

Keyword(s):

Stress Response ◽

Cellular Stress ◽

Critical Role ◽

Mitochondrial Protein ◽

Nuclear Genome ◽

Cellular Stress Response ◽

Mitochondrial Proteins ◽

Protein Biogenesis ◽

Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

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The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

Journal of Clinical Medicine ◽

10.3390/jcm10051081 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1081

Author(s):

Mikkel Parsberg Werge ◽

Adrian McCann ◽

Elisabeth Douglas Galsgaard ◽

Dorte Holst ◽

Anne Bugge ◽

...

Keyword(s):

Liver Disease ◽

Animal Models ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Precise Control ◽

Transsulfuration Pathway ◽

Global Population ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

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Kidney organoid systems for studies of immune-mediated kidney diseases: challenges and opportunities

Cell and Tissue Research ◽

10.1007/s00441-021-03499-4 ◽

2021 ◽

Author(s):

Melissa C. Stein ◽

Fabian Braun ◽

Christian F. Krebs ◽

Madeleine J. Bunders

Keyword(s):

Kidney Diseases ◽

Three Dimensional ◽

Renal Tissue ◽

Chronic Kidney Diseases ◽

Immune Mediated ◽

Primary Epithelial Cell ◽

Challenges And Opportunities ◽

Underlying Mechanisms ◽

Global Population

AbstractAcute and chronic kidney diseases are major contributors to morbidity and mortality in the global population. Many nephropathies are considered to be immune-mediated with dysregulated immune responses playing an important role in the pathogenesis. At present, targeted approaches for many kidney diseases are still lacking, as the underlying mechanisms remain insufficiently understood. With the recent development of organoids—a three-dimensional, multicellular culture system, which recapitulates important aspects of human tissues—new opportunities to investigate interactions between renal cells and immune cells in the pathogenesis of kidney diseases arise. To date, kidney organoid systems, which reflect the structure and closer resemble critical aspects of the organ, have been established. Here, we highlight the recent advances in the development of kidney organoid models, including pluripotent stem cell-derived kidney organoids and primary epithelial cell-based tubuloids. The employment and further required advances of current organoid models are discussed to investigate the role of the immune system in renal tissue development, regeneration, and inflammation to identify targets for the development of novel therapeutic approaches of immune-mediated kidney diseases.

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A Role for Fas in Negative Selection of Thymocytes In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.187.9.1427 ◽

1998 ◽

Vol 187 (9) ◽

pp. 1427-1438 ◽

Cited By ~ 112

Author(s):

Hidehiro Kishimoto ◽

Charles D. Surh ◽

Jonathan Sprent

Keyword(s):

Negative Selection ◽

Cell Receptor ◽

Staphylococcal Enterotoxin B ◽

Thymic Medulla ◽

Enterotoxin B ◽

High Doses ◽

Specific Peptide ◽

Selection Of

To seek information on the role of Fas in negative selection, we examined subsets of thymocytes from normal neonatal mice versus Fas-deficient lpr/lpr mice injected with graded doses of antigen. In normal mice, injection of 1–100 μg of staphylococcal enterotoxin B (SEB) induced clonal elimination of SEB-reactive Vβ8+ cells at the level of the semi-mature population of HSAhi CD4+ 8− cells found in the thymic medulla; deletion of CD4+ 8+ cells was minimal. SEB injection also caused marked elimination of Vβ8+ HSAhi CD4+ 8− thymocytes in lpr/lpr mice. Paradoxically, however, elimination of these cells in lpr/lpr mice was induced by low-to-moderate doses of SEB (≤1 μg) but not by high doses (100 μg). Similar findings applied when T cell receptor transgenic mice were injected with specific peptide. These findings suggest that clonal elimination of semi-mature medullary T cells is Fas independent at low doses of antigen but Fas dependent at high doses. Previous reports documenting that negative selection is not obviously impaired in lpr/lpr mice could thus reflect that the antigens studied were expressed at only a low level.

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