RESUMO
The world's largest extant carnivorous marsupial, the Tasmanian devil, is challenged by Devil Facial Tumor Disease (DFTD), a fatal, clonally transmitted cancer. In two decades, DFTD has spread across 95% of the species distributional range. A previous study has shown that factors such as season, geographic location, and infection with DFTD can impact the expression of immune genes in Tasmanian devils. To date, no study has investigated within-individual immune gene expression changes prior to and throughout the course of DFTD infection. To explore possible changes in immune response, we investigated four locations across Tasmania that differed in DFTD exposure history, ranging between 2 and >30 years. Our study demonstrated considerable complexity in the immune responses to DFTD. The same factors (sex, age, season, location and DFTD infection) affected immune gene expression both across and within devils, although seasonal and location specific variations were diminished in DFTD affected devils. We also found that expression of both adaptive and innate immune genes starts to alter early in DFTD infection and continues to change as DFTD progresses. A novel finding was that the lower expression of immune genes MHC-II, NKG2D and CD8 may predict susceptibility to earlier DFTD infection. A case study of a single devil with regressed tumor showed opposite/contrasting immune gene expression patterns compared to the general trends observed across devils with DFTD infection. Our study highlights the complexity of DFTD's interactions with the host immune system and the need for long-term studies to fully understand how DFTD alters the evolutionary trajectory of devil immunity.
Assuntos
Daunorrubicina/análogos & derivados , Neoplasias Faciais , Marsupiais , Animais , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Sistema Imunitário/patologia , Expressão Gênica , Marsupiais/genéticaRESUMO
Coevolution is common and frequently governs host-pathogen interaction outcomes. Phenotypes underlying these interactions often manifest as the combined products of the genomes of interacting species, yet traditional quantitative trait mapping approaches ignore these intergenomic interactions. Devil facial tumor disease (DFTD), an infectious cancer afflicting Tasmanian devils (Sarcophilus harrisii), has decimated devil populations due to universal host susceptibility and a fatality rate approaching 100%. Here, we used a recently developed joint genome-wide association study (i.e., co-GWAS) approach, 15 y of mark-recapture data, and 960 genomes to identify intergenomic signatures of coevolution between devils and DFTD. Using a traditional GWA approach, we found that both devil and DFTD genomes explained a substantial proportion of variance in how quickly susceptible devils became infected, although genomic architectures differed across devils and DFTD; the devil genome had fewer loci of large effect whereas the DFTD genome had a more polygenic architecture. Using a co-GWA approach, devil-DFTD intergenomic interactions explained ~3× more variation in how quickly susceptible devils became infected than either genome alone, and the top genotype-by-genotype interactions were significantly enriched for cancer genes and signatures of selection. A devil regulatory mutation was associated with differential expression of a candidate cancer gene and showed putative allele matching effects with two DFTD coding sequence variants. Our results highlight the need to account for intergenomic interactions when investigating host-pathogen (co)evolution and emphasize the importance of such interactions when considering devil management strategies.
Assuntos
Doenças Transmissíveis , Daunorrubicina/análogos & derivados , Neoplasias Faciais , Marsupiais , Animais , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Estudo de Associação Genômica Ampla , Marsupiais/genéticaRESUMO
Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and devil facial tumor 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analyzing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982 to 1989) and DFT2 in 2011 (2009 to 2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation of MGA, but none are common to both cancers. This study reveals the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.
Assuntos
Evolução Molecular , Neoplasias Faciais , Marsupiais , Seleção Genética , Animais , Neoplasias Faciais/classificação , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Genoma , Marsupiais/genética , FilogeniaRESUMO
The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100â%. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2 and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as a vaccine platform for devils and potentially other marsupials.
Assuntos
Infecções por Adenoviridae , Adenovírus Humanos , Neoplasias Faciais , Marsupiais , Animais , Humanos , Adenovírus Humanos/genética , Interferon gama , Adenoviridae/genética , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Antígenos de Histocompatibilidade Classe I/genéticaRESUMO
MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4+ T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.
Assuntos
Neoplasias Faciais , Marsupiais , Animais , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Neoplasias Faciais/patologia , Antígenos de Histocompatibilidade Classe II , Peptídeos e Proteínas de Sinalização Intracelular , Marsupiais/genéticaRESUMO
A plethora of intrinsic and environmental factors have been shown to influence the length of telomeres, the protector of chromosome ends. Despite the growing interest in infection-telomere interactions, there is very limited knowledge on how transmissible cancers influence telomere maintenance. An emblematic example of transmissible cancer occurs in the Tasmanian devil (Sarcophilus harrisii), whose populations have been dramatically reduced by infectious cancer cells. To investigate associations between telomere dynamics and the transmissible cancer, we used longitudinal data from a Tasmanian devil population that has been exposed to the disease for over 15 years. We detected substantial temporal variation in individual telomere length (TL), and a positive significant association between TL and age, as well as a marginally significant trend for devils with devil facial tumour disease (DFTD) having longer telomeres. A proportional hazard analysis yielded no significant effect of TL on the development of DFTD. Like previous studies, we show the complexity that TL dynamics may exhibit across the lifetime of organisms. Our work highlights the importance of long-term longitudinal sampling for understanding the effects of wildlife diseases on TL.
Assuntos
Neoplasias Faciais , Marsupiais , Animais , Animais Selvagens/genética , Neoplasias Faciais/epidemiologia , Neoplasias Faciais/genética , Neoplasias Faciais/patologia , Marsupiais/genética , Telômero/genéticaRESUMO
BackgroundTuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.MethodsA multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).ResultsMHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical "micro-FAFs") in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.ConclusionTSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.FundingThis work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).
Assuntos
Neoplasias Faciais , Esclerose Tuberosa , Neoplasias Faciais/genética , Humanos , Mutação , Nucleotídeos , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Understanding the effects of wildlife diseases on populations requires insight into local environmental conditions, host defence mechanisms, host life-history trade-offs, pathogen population dynamics, and their interactions. The survival of Tasmanian devils (Sarcophilus harrisii) is challenged by a novel, fitness limiting pathogen, Tasmanian devil facial tumour disease (DFTD), a clonally transmissible, contagious cancer. In order to understand the devils' capacity to respond to DFTD, it is crucial to gain information on factors influencing the devils' immune system. By using RT-qPCR, we investigated how DFTD infection in association with intrinsic (sex and age) and environmental (season) factors influences the expression of 10 immune genes in Tasmanian devil blood. Our study showed that the expression of immune genes (both innate and adaptive) differed across seasons, a pattern that was altered when infected with DFTD. The expression of immunogbulins IgE and IgM:IgG showed downregulation in colder months in DFTD infected animals. We also observed strong positive association between the expression of an innate immune gene, CD16, and DFTD infection. Our results demonstrate that sampling across seasons, age groups and environmental conditions are beneficial when deciphering the complex ecoevolutionary interactions of not only conventional host-parasite systems, but also of host and diseases with high mortality rates, such as transmissible cancers.
Assuntos
Neoplasias Faciais , Marsupiais , Animais , Animais Selvagens/genética , Neoplasias Faciais/epidemiologia , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Expressão Gênica , Marsupiais/genética , Estações do AnoRESUMO
OBJECTIVE: Uncontrolled proliferation and aberrations in cell-cycle progression are fundamental issues in cancer. In this study we aimed to determine and compare deoxyribonucleic acid (DNA) replication licensing factors at the mRNA and protein levels among squamous cell carcinomas (SCCs) of the lip, facial-skin and oral cavity. MATERIALS AND METHODS: A total of 103 lip, oral and face SCCs were immunohistochemically stained with MCM2 (mini-chromosome maintenance 2), geminin, and ki67, and their labeling-indices were calculated. Also, 57 SCCs from the same regions along with their adjacent normal tissues underwent quantitative reverse transcription-polymerase chain reaction analysis. RESULTS: All three proteins were overexpressed in the studied SCCs, but only geminin (P = 0.004) showed significant difference among the three regions, with higher levels in oral SCCs compared to lip (P = 0.005) and skin (P = 0.024) tumors. Geminin expression did not differ between skin- and lip-SCCs (P = 0.822). MCM2/ki67 ratio was higher in oral- compared to skin-neoplasms (P = 0.039), but no difference was found in geminin/ki67 among the SCC-subsites. There were significant differences in MCM2 and geminin mRNA between carcinomatous- and normal-tissues in all tumors, but not among the three locations. CONCLUSION: MCM2 and geminin are involved in the tumorigenesis of lip, face and oral SCC at both mRNA- and protein-levels. Geminin may have a role in the site-specific biologic behavior of SCC. Skin SCCs had the highest proportion of licensed non-proliferating cells, while actively proliferating cells were more prominent in oral tumors. Regarding DNA replication, lip SCCs seem to be closer to skin tumors compared to their oral counterparts.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Faciais , Neoplasias Labiais , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Replicação do DNA , Geminina/genética , Geminina/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , RNA Mensageiro/genética , Neoplasias Faciais/genética , Neoplasias Faciais/metabolismo , Neoplasias Labiais/genética , Neoplasias Labiais/metabolismoRESUMO
BACKGROUND: Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown. RESULTS: We sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation. CONCLUSIONS: Expression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival.
Assuntos
Neoplasias Faciais , Marsupiais , Animais , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Imunidade , Marsupiais/genética , TranscriptomaRESUMO
Tasmanian devils (Sarcophilus harrisii) are evolving in response to a unique transmissible cancer, devil facial tumour disease (DFTD), first described in 1996. Persistence of wild populations and the recent emergence of a second independently evolved transmissible cancer suggest that transmissible cancers may be a recurrent feature in devils. Here, we compared signatures of selection across temporal scales to determine whether genes or gene pathways under contemporary selection (six to eight generations) have also been subject to historical selection (65-85 Myr). First, we used targeted sequencing, RAD-capture, in approximately 2500 devils in six populations to identify genomic regions subject to rapid evolution. We documented genome-wide contemporary evolution, including 186 candidate genes related to cell cycling and immune response. Then we used a molecular evolution approach to identify historical positive selection in devils compared to other marsupials and found evidence of selection in 1773 genes. However, we found limited overlap across time scales, with only 16 shared candidate genes, and no overlap in enriched functional gene sets. Our results are consistent with a novel, multi-locus evolutionary response of devils to DFTD. Our results can inform conservation by identifying high priority targets for genetic monitoring and guiding maintenance of adaptive potential in managed populations.
Assuntos
Neoplasias Faciais , Marsupiais , Neoplasias , Animais , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Genômica , Marsupiais/genética , Neoplasias/genética , Neoplasias/veterináriaRESUMO
PURPOSE: Downregulation of MHC class I (MHC-I) is a common immune evasion strategy of many cancers. Similarly, two allogeneic clonal transmissible cancers have killed thousands of wild Tasmanian devils (Sarcophilus harrisii) and also modulate MHC-I expression to evade anti-cancer and allograft responses. IFNG treatment restores MHC-I expression on devil facial tumor (DFT) cells but is insufficient to control tumor growth. Transcriptional co-activator NLRC5 is a master regulator of MHC-I in humans and mice but its role in transmissible cancers remains unknown. In this study, we explored the regulation and role of MHC-I in these unique genetically mis-matched tumors. METHODS: We used transcriptome and flow cytometric analyses to determine how MHC-I shapes allogeneic and anti-tumor responses. Cell lines that overexpress NLRC5 to drive antigen presentation, and B2M-knockout cell lines incapable of presenting antigen on MHC-I were used to probe the role of MHC-I in rare cases of tumor regressions. RESULTS: Transcriptomic results suggest that NLRC5 plays a major role in MHC-I regulation in devils. NLRC5 was shown to drive the expression of many components of the antigen presentation pathway but did not upregulate PDL1. Serum from devils with tumor regressions showed strong binding to IFNG-treated and NLRC5 cell lines; antibody binding to IFNG-treated and NRLC5 transgenic tumor cells was diminished or absent following B2M knockout. CONCLUSION: MHC-I could be identified as a target for anti-tumor and allogeneic immunity. Consequently, NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
Assuntos
Apresentação de Antígeno/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Faciais/imunologia , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias Faciais/genética , Neoplasias Faciais/metabolismo , Neoplasias Faciais/patologia , Antígenos de Histocompatibilidade Classe I/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Marsupiais , Transcriptoma , Células Tumorais CultivadasRESUMO
Round cell sarcomas with EWSR1-PATZ1 fusion are rare polyphenotypic sarcomas that typically show both neural and myogenic differentiation on immunohistochemistry. The histology features lobular admixture of cellular fascicles of relatively monotonous spindle cells and small blue round cells separated by fibrotic stroma. The clinical behavior of EWSR1-PATZ1 sarcoma is uncertain currently with mixed outcomes reported even in cases with metastases. We herein report an additional case of EWSR1-PATZ1 fusion-related round cell sarcoma in the face of a 5-year-old boy with unusual histologic features of pale zones, rosette/gland-like structures and expression of epithelial markers. Fluorescent in-situ hybridization study (FISH) using EWSR1 breakapart probes was negative and molecular study with RNA sequencing was required to confirm the diagnosis. These findings highlight the diagnostic challenge and potential pitfall of FISH study in EWSR1-PATZ1 sarcoma. Further studies are required to increase the understanding of their behavior, morphologic spectrum and molecular features that will help devise new treatment strategies to these rare tumours.
Assuntos
Neoplasias Faciais/diagnóstico , Neoplasias Faciais/genética , Fatores de Transcrição Kruppel-Like/genética , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Sarcoma/diagnóstico , Sarcoma/genética , Pré-Escolar , Diagnóstico Diferencial , Neoplasias Faciais/patologia , Neoplasias Faciais/cirurgia , Humanos , Masculino , Sarcoma/patologia , Sarcoma/cirurgiaRESUMO
Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin arising from the dermis. Its location is most commonly presented on the trunk of middle-aged adults and rarely on the face. The characteristic genetic aberration in the form of a reciprocal translocation t(17;22)(q21;q13) or a ring fusing the COL1A1 and PDGFB genes is found in 90% of DFSP. We present a case of a 42-year-old man who presented with a DFSP on the left cheek with foci of myxoid-fibrosarcomatous transformation. A conventional chromosomal analysis revealed a complex karyotype without a supernumerary ring chromosome or a linear translocation t(17;22). Comparative genome hybridization and fluorescence in-situ hybridization revealed the fusion of COL1A1 and PDGFB probes inserted in chromosome 15. This is a unique case of DFSP characterized by a rare body location, unique histopathological features, and novel chromosome COL1A1-PDGFB insertion, and may help guide future diagnostic and patient care modalities.
Assuntos
Cromossomos Humanos Par 15 , Neoplasias Faciais , Fibrossarcoma , Mutagênese Insercional , Proteínas de Fusão Oncogênica , Neoplasias Cutâneas , Adulto , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/metabolismo , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 22/metabolismo , Neoplasias Faciais/genética , Neoplasias Faciais/metabolismo , Neoplasias Faciais/patologia , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Translocação GenéticaRESUMO
Emerging infectious diseases pose one of the greatest threats to human health and biodiversity. Phylodynamics is often used to infer epidemiological parameters essential for guiding intervention strategies for human viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Here, we applied phylodynamics to elucidate the epidemiological dynamics of Tasmanian devil facial tumor disease (DFTD), a fatal, transmissible cancer with a genome thousands of times larger than that of any virus. Despite prior predictions of devil extinction, transmission rates have declined precipitously from ~3.5 secondary infections per infected individual to ~1 at present. Thus, DFTD appears to be transitioning from emergence to endemism, lending hope for the continued survival of the endangered Tasmanian devil. More generally, our study demonstrates a new phylodynamic analytical framework that can be applied to virtually any pathogen.
Assuntos
Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/veterinária , Doenças Endêmicas/veterinária , Neoplasias Faciais/epidemiologia , Neoplasias Faciais/veterinária , Marsupiais , Animais , Doenças Transmissíveis Emergentes/genética , Extinção Biológica , Neoplasias Faciais/genética , Filogenia , Tasmânia/epidemiologiaRESUMO
Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.
Assuntos
Neoplasias Faciais/veterinária , Marsupiais/genética , Doenças dos Animais/epidemiologia , Doenças dos Animais/genética , Doenças dos Animais/transmissão , Animais , Variações do Número de Cópias de DNA , Evolução Molecular , Neoplasias Faciais/epidemiologia , Neoplasias Faciais/genética , Feminino , Instabilidade Genômica , Masculino , Filogenia , Tasmânia/epidemiologia , Encurtamento do Telômero/genética , Células Tumorais CultivadasRESUMO
Telomeres protect chromosomes from degradation during cellular replication. In humans, it is well-documented that excessive telomere degradation is one mechanism by which cells can become cancerous. Increasing evidence from wildlife studies suggests that telomere length is positively correlated with survival and health and negatively correlated with disease infection intensity. The recently emerged devil facial tumor disease (DFTD) has led to dramatic and rapid population declines of the Tasmanian devil throughout its geographic range. Here, we tested the hypothesis that susceptibility to DFTD is negatively correlated with telomere length in devils across three populations with different infection histories. Our findings suggest telomere length is correlated with DFTD resistance in three ways. First, devils from a population with the slowest recorded increase in DFTD prevalence (West Pencil Pine) have significantly longer telomeres than those from two populations with rapid and exponential increases in prevalence (Freycinet and Narawantapu). Second, using extensive mark-recapture data obtained from a long-term demographic study, we found that individuals with relatively long telomeres tend to be infected at a significantly later age than those with shorter telomeres. Third, a hazard model showed devils with longer telomeres tended to become infected at a lower rate than those with shorter telomeres. This research provides a rare study of telomere length variation and its association with disease in a wildlife population. Our results suggest that telomere length may be a reliable marker of susceptibility to DFTD and assist with future management of this endangered species.
Assuntos
Biomarcadores , Neoplasias Faciais/genética , Marsupiais , Telômero/fisiologia , Animais , DNA/análise , Neoplasias Faciais/epidemiologia , TasmâniaRESUMO
Genetic structure in host species is often used to predict disease spread. However, host and pathogen genetic variation may be incongruent. Understanding landscape factors that have either concordant or divergent influence on host and pathogen genetic structure is crucial for wildlife disease management. Devil facial tumour disease (DFTD) was first observed in 1996 and has spread throughout almost the entire Tasmanian devil geographic range, causing dramatic population declines. Whereas DFTD is predominantly spread via biting among adults, devils typically disperse as juveniles, which experience low DFTD prevalence. Thus, we predicted little association between devil and tumour population structure and that environmental factors influencing gene flow differ between devils and tumours. We employed a comparative landscape genetics framework to test the influence of environmental factors on patterns of isolation by resistance (IBR) and isolation by environment (IBE) in devils and DFTD. Although we found evidence for broad-scale costructuring between devils and tumours, we found no relationship between host and tumour individual genetic distances. Further, the factors driving the spatial distribution of genetic variation differed for each. Devils exhibited a strong IBR pattern driven by major roads, with no evidence of IBE. By contrast, tumours showed little evidence for IBR and a weak IBE pattern with respect to elevation in one of two tumour clusters we identify herein. Our results warrant caution when inferring pathogen spread using host population genetic structure and suggest that reliance on environmental barriers to host connectivity may be ineffective for managing the spread of wildlife diseases. Our findings demonstrate the utility of comparative landscape genetics for identifying differential factors driving host dispersal and pathogen transmission.
Assuntos
Neoplasias Faciais , Marsupiais , Animais , Animais Selvagens , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Estruturas Genéticas , Marsupiais/genéticaRESUMO
The emergence of a second transmissible tumour in the Tasmanian devil population, devil facial tumour 2 (DFT2), has prompted questions on the origin and evolution of these transmissible tumours. We used a combination of cytogenetic mapping and telomere length measurements to predict the evolutionary trajectory of chromosome rearrangements in DFT2. Gene mapping by fluorescence in situ hybridization (FISH) provided insight into the chromosome rearrangements in DFT2 and identified the evolution of two distinct DFT2 lineages. A comparison of devil facial tumour 1 (DFT1) and DFT2 chromosome rearrangements indicated that both started with the fusion of a chromosome, with potentially critically short telomeres, to chromosome 1 to form dicentric chromosomes. In DFT1, the dicentric chromosome resulted in breakage-fusion-bridge cycles leading to highly rearranged chromosomes. In contrast, the silencing of a centromere on the dicentric chromosome in DFT2 stabilized the chromosome, resulting in a less rearranged karyotype than DFT1. DFT2 retains a bimodal distribution of telomere length dimorphism observed on Tasmanian devil chromosomes, a feature lost in DFT1. Using long term cell culture, we observed homogenization of telomere length over time. We predict a similar homogenization of telomere lengths occurred in DFT1, and that DFT2 is unlikely to undergo further substantial rearrangements due to maintained telomere length.
Assuntos
Neoplasias Faciais/genética , Marsupiais/genética , Homeostase do Telômero/genética , Telômero/genética , Animais , Neoplasias Faciais/patologia , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , CariotipagemRESUMO
Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We used Illumina Methylation EPIC BeadChip to study DNA methylation differences between orbitofacial NFs (N = 20) and NFs at other sites (N = 4). Global methylation differences were detected between the two groups and the top differentially methylated genes were part of the HOX (Homebox) family of transcription factors (HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4), which were hypomethylated in orbitofacial NFs compared to the non-orbital NFs. Conversely, LTF (lactoferrin) was relatively hypermethylated in orbitofacial NF compared to non-orbitofacial NF. HOXC8 protein levels were higher in orbitofacial plexiform NFs (p = 0.04). We found no significant differences in the expression of HOXC4, HOXA6, or HOXD4 between the two groups. HOXC8 mRNA levels were also higher in orbitofacial NFs and HOXC8 overexpression in a non-neoplastic human Schwann cell line resulted in increased growth. In summary, we identified gene methylation and expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that the HOX family of genes play an important role during development, are dysregulated in a variety of cancers, and may provide novel insights into therapeutic approaches.