Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B

Background

Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.

Results

Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.

Conclusions

Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.     

Genomic divergence of zebu and taurine cattle identified through high-density SNP genotyping

Background

Natural selection has molded evolution across all taxa. At an arguable date of around 330,000 years ago there were already at least two different types of cattle that became ancestors of nearly all modern cattle, the Bos taurus taurus more adapted to temperate climates and the tropically adapted Bos taurus indicus. After domestication, human selection exponentially intensified these differences. To better understand the genetic differences between these subspecies and detect genomic regions potentially under divergent selection, animals from the International Bovine HapMap Experiment were genotyped for over 770,000 SNP across the genome and compared using smoothed F_ST. The taurine sample was represented by ten breeds and the contrasting zebu cohort by three breeds.

Results

Each cattle group evidenced similar numbers of polymorphic markers well distributed across the genome. Principal components analyses and unsupervised clustering confirmed the well-characterized main division of domestic cattle. The top 1% smoothed F_ST, potentially associated to positive selection, contained 48 genomic regions across 17 chromosomes. Nearly half of the top F_ST signals (n = 22) were previously detected using a lower density SNP assay. Amongst the strongest signals were the BTA7:~50 Mb and BTA14:~25 Mb; both regions harboring candidate genes and different patterns of linkage disequilibrium that potentially represent intrinsic differences between cattle types. The bottom 1% of the smoothed F_ST values, potentially associated to balancing selection, included 24 regions across 13 chromosomes. These regions often overlap with copy number variants, including the highly variable region at BTA23:~24 Mb that harbors a large number of MHC genes. Under these regions, 318 unique Ensembl genes are annotated with a significant overrepresentation of immune related pathways.

Conclusions

Genomic regions that are potentially linked to purifying or balancing selection processes in domestic cattle were identified. These regions are of particular interest to understand the natural and human selective pressures to which these subspecies were exposed to and how the genetic background of these populations evolved in response to environmental challenges and human manipulation.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-14-876) contains supplementary material, which is available to authorized users.     

Design,synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.     

Contrasting responses of large carnivores to land use management across an Asian montane landscape in Iran

Land-use change has led to substantial range contractions for many species. Such contractions are particularly acute for wide-ranging large carnivores in Asia’s high altitude areas, which are marked by high spatiotemporal variability in resources. Current conservation planning for human-dominated landscapes often takes one of two main approaches: a “coexistence” (land sharing) approach or a “separation” (land sparing) approach. In this study, we evaluated the effects of land-use management on a guild of large carnivores in a montane ecosystem located in northeastern Iran. We used interview surveys to collect data on Persian leopard Panthera pardus saxicolor and grey wolf Canis lupus and modeled the areas occupied by these species in a Bayesian framework. After accounting for imperfect detection, we found that wolves had a higher probability of occupying the study area than leopards (82%; 95% CI 73–90% vs. 63%; 95% CI 53–73%). Importantly, each predator showed contrasting response to land-use management. National Parks (i.e. human-free areas) had a positive association with leopard occupancy (α_{National Park}?=?2.56, 95% CI 0.22–5.77), in contrast to wolves, which displayed a negative association with National Parks (α_{National Park} = ? 1.62, 95% CI ? 2.29 to 0.31). An opposite pattern was observed for human-dominated areas (i.e. Protected Areas and Communal Lands), where occupancy was higher for wolves but lower for leopards. Our study suggests that to protect these large carnivores, a combination of land sharing and land sparing approaches is desirable within Iran montane landscapes. Any recovery program for big cats in Iranian mountains, and likely similar mountainous landscapes in west Asia, should take into account other sympatric carnivores and how they can affect adjacent human communities. For example, conflict mitigation and compensation efforts are required to include the guild of large carnivores, instead of solely targeting the charismatic big cats.

     

Habitat use of the endangered golden‐rumped sengi Rhynchocyon chrysopygus

The endangered golden‐rumped sengi are found only in Arabuko‐Sokoke Forest with 395.4 km² of forest habitat, and perhaps in a few isolated forest and thicket fragments of total area less than 30 km² all within central coastal Kenya. Understanding its habitat use is an important requirement to develop better conservation measures for the species and its remaining forest habitat. A more reliable method for monitoring its status is also needed. We used the Bayesian occupancy modelling with camera trap data and habitat mapping to characterise the species habitat use in the Arabuko‐Sokoke Forest. The species uses 328 km² (95% CI: 289–364 km²) of Arabuko‐Sokoke Forest habitat, and its site use increases with distance from forest edge, with the highest site use in the Cynometra thicket (0.93; 95% CI: 0.82–1). Its use of the mixed forest habitat has been significantly reduced following years of logging of Afzelia quanzensis. We recommend the use of modelled occupancy, interpreted as the proportion of area used by the species, to monitor the species status. Occupancy models account for detection probability, and heterogeneity in site use and detection can be incorporated. Estimated territory sizes can be combined to obtain abundance estimates.     

Effects of Winter Ticks and Internal Parasites on Moose Survival in Vermont,USA

Moose (Alces alces) have experienced considerable declines along the periphery of their range in the northeastern United States. In Vermont, the population declined 45% from 2010 to 2017 despite minimal hunter harvest and adequate habitat. Similarly, nearby populations recently experienced epizootics characterized by >50% mortality. Declines have largely been associated with the effects of winter ticks (Dermacentor albipictus), but uncertainty exists about the effects of environmental and other parasite-related conditions on moose survival. We examined patterns of moose survival among a radio-collared population (n = 127) in Vermont from 2017 to 2019. Our objectives were to estimate causes of mortality and model survival probability as a function of individual and landscape variables for calves (<1 yr) and adults (≥1 yr). Observed adult survival was 90% in 2017, 84% in 2018, and 86% in 2019, and winter calf survival was 60% in 2017, 50% in 2018, and 37% in 2019. Winter tick infestation was the primary cause of mortality (91% of calves, 25% of adults), and 32% of all mortalities had evidence of meningeal worm (Parelaphostrongylus tenuis). Other sources of mortality such as vehicles, harvest, predation, deep snow, and other parasitic infections were negligible. The best supported calf model included sex differences and negative effects of tick engorgement (%/week) and parasite level (roundworm and lungworm). The best supported adult model included the effect of cumulative tick engorgement (cumulative %/week), which negatively affected survival. Our results indicate that winter tick engorgement strongly affects survival, and is probably compounded by the presence of meningeal worm and other parasites. Reduced tick effects may be achieved by decreasing moose density through harvest and managing late winter habitat to minimize tick density. Management of white-tailed deer (Odocoileus virginianus) density may also affect the transmission of meningeal worm. © 2021 The Authors. The Journal of Wildlife Management published by Wiley Periodicals LLC on behalf of The Wildlife Society.     

Using the T-Coffee package to build multiple sequence alignments of protein, RNA, DNA sequences and 3D structures

T-Coffee (Tree-based consistency objective function for alignment evaluation) is a versatile multiple sequence alignment (MSA) method suitable for aligning most types of biological sequences. The main strength of T-Coffee is its ability to combine third party aligners and to integrate structural (or homology) information when building MSAs. The series of protocols presented here show how the package can be used to multiply align proteins, RNA and DNA sequences. The protein section shows how users can select the most suitable T-Coffee mode for their data set. Detailed protocols include T-Coffee, the default mode, M-Coffee, a meta version able to combine several third party aligners into one, PSI (position-specific iterated)-Coffee, the homology extended mode suitable for remote homologs and Expresso, the structure-based multiple aligner. We then also show how the T-RMSD (tree based on root mean square deviation) option can be used to produce a functionally informative structure-based clustering. RNA alignment procedures are described for using R-Coffee, a mode able to use predicted RNA secondary structures when aligning RNA sequences. DNA alignments are illustrated with Pro-Coffee, a multiple aligner specific of promoter regions. We also present some of the many reformatting utilities bundled with T-Coffee. The package is an open-source freeware available from http://www.tcoffee.org/.