Project description:Genetic diversity in global populations of the Critically Endangered addax (Addax nasomaculatus) and its implications for conservation
Project description:Since the 19th century, the addax (Addax nasomaculatus) has lost approximately 99% of its former range. Along with its close relatives, the blue antelope (Hippotragus leucophaeus) and the scimitar-horned oryx (Oryx dammah), the addax may be the third large African mammal species to go extinct in the wild in recent times. Despite this, the evolutionary history of this critically endangered species remains virtually unknown. To gain insight into the population history of the addax, we used hybridization capture to generate ten complete mitochondrial genomes from historical samples and assembled a nuclear genome. We found that both mitochondrial and nuclear diversity are low compared to other African bovids. Analysis of mitochondrial genomes revealed a most recent common ancestor ~32 kya (95% CI 11-58 kya) and weak phylogeographic structure, indicating that the addax likely existed as a highly mobile, panmictic population across its Sahelo-Saharan range in the past. PSMC analysis revealed a continuous decline in effective population size since ~2 Ma, with short intermediate increases at ~500 and ~44 kya. Our results suggest that the addax went through a major bottleneck in the Late Pleistocene, remaining at low population size prior to the human disturbances of the last few centuries.
Project description:Threatened species are frequently patchily distributed across small wild populations, ex situ populations managed with varying levels of intensity and reintroduced populations. Best practice advocates for integrated management across in situ and ex situ populations. Wild addax (Addax nasomaculatus) now number fewer than 100 individuals, yet 1000 of addax remain in ex situ populations, which can provide addax for reintroductions, as has been the case in Tunisia since the mid-1980s. However, integrated management requires genetic data to ascertain the relationships between wild and ex situ populations that have incomplete knowledge of founder origins, management histories, and pedigrees. We undertook a global assessment of genetic diversity across wild, ex situ and reintroduced populations in Tunisia to assist conservation planning for this Critically Endangered species. We show that the remnant wild populations retain more mitochondrial haplotypes that are more diverse than the entirety of the ex situ populations across Europe, North America and the United Arab Emirates, and the reintroduced Tunisian population. Additionally, 1704 SNPs revealed that whilst population structure within the ex situ population is minimal, each population carries unique diversity. Finally, we show that careful selection of founders and subsequent genetic management is vital to ensure genetic diversity is provided to, and minimize drift and inbreeding within reintroductions. Our results highlight a vital need to conserve the last remaining wild addax population, and we provide a genetic foundation for determining integrated conservation strategies to prevent extinction and optimize future reintroductions.
Project description:Primary objectives: The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Primary endpoints: circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Project description:Ruminants are critical as prey in transferring solar energy fixed by plants into carnivorous species, yet the genetic signature of the driving forces leading to the evolutionary success of the huge number of ruminant species remains largely unknown. Here we report a complete DNA map of the major histocompatibility complex (MHC) of the addax (Addax nasomaculatus) genome by sequencing a total of 47 overlapping BAC clones previously mapped to cover the MHC region. The addax MHC is composed of 3,224,151 nucleotides, harboring a total of 150 coding genes, 50 tRNA genes, and 14 non-coding RNA genes. The organization of addax MHC was found to be highly conserved to those of sheep and cattle, highlighted by a large piece of chromosome inversion that divided the MHC class II into IIa and IIb subregions. It is now highly possible that all of the ruminant species in the family of Bovidae carry the same chromosome inversion in the MHC region, inherited from a common ancestor of ruminants. Phylogenetic analysis indicated that DY, a ruminant-specific gene located at the boundary of the inversion and highly expressed in dendritic cells, was possibly evolved from DQ, with an estimated divergence time ~140 million years ago. Homology modeling showed that the overall predicted structure of addax DY was similar to that of HLA-DQ2. However, the pocket properties of P1, P4, P6, and P9, which were critical for antigen binding in the addax DY, showed certain distinctive features. Structural analysis suggested that the populations of peptide antigens presented by addax DY and HLA-DQ2 were quite diverse, which in theory could serve to promote microbial regulation in the rumen by ruminant species, contributing to enhanced grass utilization ability. In summary, the results of our study helped to enhance our understanding of the MHC evolution and provided additional supportive evidence to our previous hypothesis that an ancient chromosome inversion in the MHC region of the last common ancestor of ruminants may have contributed to the evolutionary success of current ruminants on our planet.
Project description:BackgroundThe mammalian major histocompatibility complex (MHC) harbours clusters of genes associated with the immunological defence of animals against infectious pathogens. At present, no complete MHC physical map is available for any of the wild ruminant species in the world.ResultsThe high-density physical map is composed of two contigs of 47 overlapping bacterial artificial chromosome (BAC) clones, with an average of 115 Kb for each BAC, covering the entire addax MHC genome. The first contig has 40 overlapping BAC clones covering an approximately 2.9 Mb region of MHC class I, class III, and class IIa, and the second contig has 7 BAC clones covering an approximately 500 Kb genomic region that harbours MHC class IIb. The relative position of each BAC corresponding to the MHC sequence was determined by comparative mapping using PCR screening of the BAC library of 192,000 clones, and the order of BACs was determined by DNA fingerprinting. The overlaps of neighboring BACs were cross-verified by both BAC-end sequencing and co-amplification of identical PCR fragments within the overlapped region, with their identities further confirmed by DNA sequencing.ConclusionsWe report here the successful construction of a high-quality physical map for the addax MHC region using BACs and comparative mapping. The addax MHC physical map we constructed showed one gap of approximately 18 Mb formed by an ancient autosomal inversion that divided the MHC class II into IIa and IIb. The autosomal inversion provides compelling evidence that the MHC organizations in all of the ruminant species are relatively conserved.
Project description:The study is intended to collect specimens to support the application of genome analysis technologies, including large-scale genome sequencing. This study will ultimately provide cancer researchers with specimens that they can use to develop comprehensive catalogs of genomic information on at least 50 types of human cancer. The study will create a resource available to the worldwide research community that could be used to identify and accelerate the development of new diagnostic and prognostic markers, new targets for pharmaceutical interventions, and new cancer prevention and treatment strategies. This study will be a competitive enrollment study conducted at multiple institutions.