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Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

ABSTRACT: The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

SUBMITTER: Murchison EP

PROVIDER: S-EPMC3281993 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

Murchison Elizabeth P EP Schulz-Trieglaff Ole B OB Ning Zemin Z Alexandrov Ludmil B LB Bauer Markus J MJ Fu Beiyuan B Hims Matthew M Ding Zhihao Z Ivakhno Sergii S Stewart Caitlin C Ng Bee Ling BL Wong Wendy W Aken Bronwen B White Simon S Alsop Amber A Becq Jennifer J Bignell Graham R GR Cheetham R Keira RK Cheng William W Connor Thomas R TR Cox Anthony J AJ Feng Zhi-Ping ZP Gu Yong Y Grocock Russell J RJ Harris Simon R SR Khrebtukova Irina I Kingsbury Zoya Z Kowarsky Mark M Kreiss Alexandre A Luo Shujun S Marshall John J McBride David J DJ Murray Lisa L Pearse Anne-Maree AM Raine Keiran K Rasolonjatovo Isabelle I Shaw Richard R Tedder Philip P Tregidgo Carolyn C Vilella Albert J AJ Wedge David C DC Woods Gregory M GM Gormley Niall N Humphray Sean S Schroth Gary G Smith Geoffrey G Hall Kevin K Searle Stephen M J SM Carter Nigel P NP Papenfuss Anthony T AT Futreal P Andrew PA Campbell Peter J PJ Yang Fengtang F Bentley David R DR Evers Dirk J DJ Stratton Michael R MR

Cell 20120201 4

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically dive ...[more]

PMID: 22341448

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Project description:Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.

Dataset Information

Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

Publications

Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

Similar Datasets

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