Identification of common predisposing loci to hematopoietic cancers in four dog breeds

Histiocytic sarcoma (HS) is a rare but aggressive cancer in both humans and dogs. The spontaneous canine model, which has clinical, epidemiological, and histological similarities with human HS and specific breed predispositions, provides a unique opportunity to unravel the genetic basis of this cancer. In this study, we aimed to identify germline risk factors associated with the development of HS in canine-predisposed breeds. We used a methodology that combined several genome-wide association studies in a multi-breed and multi-cancer approach as well as targeted next-generation sequencing, and imputation We combined several dog breeds (Bernese mountain dogs, Rottweilers, flat-coated retrievers, and golden retrievers), and three hematopoietic cancers (HS, lymphoma, and mast cell tumor). Results showed that we not only refined the previously identified HS risk CDKN2A locus, but also identified new loci on canine chromosomes 2, 5, 14, and 20. Capture and targeted sequencing of specific loci suggested the existence of regulatory variants in non-coding regions and methylation mechanisms linked to risk haplotypes, which lead to strong cancer predisposition in specific dog breeds. We also showed that these canine cancer predisposing loci appeared to be due to the additive effect of several risk haplotypes involved in other hematopoietic cancers such as lymphoma or mast cell tumors as well. This illustrates the pleiotropic nature of these canine cancer loci as observed in human oncology, thereby reinforcing the interest of predisposed dog breeds to study cancer initiation and progression.     

Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.     

Dynamic interactions among badgers: implications for sociality and disease transmission

1. Direct interactions between individuals play an important part in the sociality of group-living animals, their mating system and disease transmission. Here, we devise a methodology to quantify relative rates of proximity interaction from radio-tracking data and highlight potential asymmetries within the contact network of a moderate-density badger population in the north-east of England. 2. We analysed radio-tracking data from four contiguous social groups, collected over a 3-year period. Dynamic interaction analysis of badger dyads was used to assess the movement of individuals in relation to the movement of others, both within and between social groups. Dyads were assessed with regard to season, sex, age and sett use pattern of the badgers involved. 3. Intragroup separation distances were significantly shorter than intergroup separation distances, and interactions between groups were rare. Within groups, individuals interacted with each other more often than expected, and interaction patterns varied significantly with season and sett use pattern. Non-mover dyads (using the main sett for day-resting on > 50% of occasions) interacted more frequently than mover dyads (using an outlier sett for day-resting on > 50% of occasions) or mover-non-mover dyads. Interactions between group members occurred most frequently in winter. 4. Of close intragroup interactions (< 50 m separation distance), 88.6% were associated with a main sett and only 4.4% with outlier setts. Non-mover dyads and non-mover-mover dyads interacted significantly more often at the main sett than mover-only dyads. These results highlight the importance of the main sett to badger sociality and support the suggestion that badger social groups are comprised of different subgroups, in our case based on differential sett use patterns. 5. Asymmetries in contact structure within a population will affect the way in which diseases are transmitted through a social network. Assessment of these networks is essential for understanding the persistence and spread of disease within populations which do not mix freely or which exhibit heterogeneities in their spatial or social behaviour.     

Differential attraction in mosquito–human interactions and implications for disease control

Mosquito-borne diseases are a major burden on human health worldwide and their eradication through vector control methods remains challenging. In particular, the success of vector control interventions for targeting diseases such as malaria is under threat, in part due to the evolution of insecticide resistance, while for other diseases effective control solutions are still lacking. The rate at which mosquitoes encounter and bite humans is a key determinant of their capacity for disease transmission. Future progress is strongly reliant on improving our understanding of the mechanisms leading to a mosquito bite. Here, we review the biological factors known to influence the attractiveness of mosquitoes to humans, such as body odour, the skin microbiome, genetics and infection by parasites. We identify the knowledge gaps around the relative contribution of each factor, and the potential links between them, as well as the role of natural selection in shaping vector–host–parasite interactions. Finally, we argue that addressing these questions will contribute to improving current tools and the development of novel interventions for the future.This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases''.     

Genetic variants predisposing to cardiovascular disease

PURPOSE OF REVIEW: The goal of this review is to provide an update on the most recent and relevant findings in the area of genotype-phenotype associations as well as the relationships between genetic factors and cardiovascular disease risk markers and events. In addition, emphasis will be placed on the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases. RECENT FINDINGS: Genes associated with cardiovascular disease predisposition have been examined, including traditional cardiovascular disease candidate genes, such as ACE, AGT, eNOS, PON and MTHFR, new loci that have recently been added to the growing list of cardiovascular disease candidate genes (i.e. MEF2A, ALOX5, LTA, APOM, PDE4D), and genes that have been shown to be at the intersection of several age-related disorders through interaction with one another or with environmental factors (i.e. APOA5, APOE, PPARgamma, LPL and LIPC). SUMMARY: During the last year, tremendous effort has been made in elucidating new genes associated with cardiovascular disease predisposition. For the most part, however, major breakthroughs have not been made, primarily due to the poor replication of results among studies, as a consequence of poor experimental design. Nevertheless, we have increased our understanding of the complexity of cardiovascular disease and the relevance of gene-environment interactions as the ultimate drivers of the individual predisposition to the disease. It is essential, therefore, that present and future genetic studies in this area take into consideration the inclusion of high-quality environmental data in the analytical process to test the clinical usefulness of a genetic marker as a risk predictor.     

The generalized multiplicative model for viability selection at multiple loci

Selection due to differential viability is studied in an n-locus two-allele model using a set indexation that allows the simplicity of the one-locus two-allele model to be carried to multi-locus models. The existence condition is analyzed for polymorphic equilibria with linkage equilibrium: Robbins' equilibria. The local stability condition is given for the Robbins' equilibria on the boundaries in the generalized non-epistatic selection regimes of Karlin and Liberman (1979). These generalized non-epistatic regimes include the additive selection model, the multiplicative selection model and the multiplicative interaction model, and their symmetric versions cover all the symmetric viability models.Research supported by grant no. 11-7805 from the Danish Natural Science Research Council, by NIH grant GM 28016, by a fellowship from the Research Foundation of Aarhus University, and by a visiting fellowship from the University of New England, N.S.W.     

Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice

To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies.     

An integrated epigenetic and genetic approach to common human disease

Epigenetic information is heritable during cell division but is not contained within the DNA sequence itself. Despite increasing evidence for and interest in the role of epigenetics in human disease, particularly in cancer, virtually no epigenetic information is routinely or systematically measured at the genome level. The current population-based approach to common disease relates common DNA sequence variants to either disease status or incremental quantitative traits contributing to disease. Although this purely genetic approach is powerful and general, there is currently no conceptual framework to integrate epigenetic information. In this article, we propose an approach to common human disease that incorporates epigenetic variation into genetic studies. Epigenetic variation might also help to explain the late onset and progressive nature of most common diseases, the quantitative nature of complex traits and the role of environment in disease development, which a purely sequence-based approach might not.     

Evidence for simultaneous protein interactions between human Rad51 paralogs

In yeast, the Rad51-related proteins include Rad55 and Rad57, which form a heterodimer that interacts with Rad51. Five human Rad51 paralogs have been identified (XRCC2, XRCC3, Rad51B/Rad51L1, Rad51C/Rad51L2, and Rad51D/Rad51L3), and each interacts with one or more of the others. Previously we reported that HsRad51 interacts with XRCC3, and Rad51C interacts with XRCC3, Rad51B, and HsRad51. Here we report that in the yeast two-hybrid system, Rad51D interacts with XRCC2 and Rad51C. No other interactions, including self-interactions, were found, indicating that the observed interactions are specific. The yeast Rad51 interacts with human Rad51 and XRCC3, suggesting Rad51 conservation since the human yeast divergence. Data from yeast three-hybrid experiments indicate that a number of the pairs of interactions between human Rad51 paralogs can occur simultaneously. For example, Rad51B expression enhances the binding of Rad51C to XRCC3 and to HsRad51D, and Rad51C expression allows the indirect interaction of Rad51B with Rad51D. Experiments using 6xHis-tagged proteins in the baculovirus system confirm several of our yeast results, including Rad51B interaction with Rad51D only when Rad51C is simultaneously expressed and Rad51C interaction with XRCC2 only when Rad51D is present. These results suggest that these proteins may participate in one complex or multiple smaller ones.     

Genetics of common disease: implications for therapy,screening and redefinition of disease.

Susceptibility to most common human diseases is, at least in part, determined by genetic factors. Rapid progress is being made in defining these genetic determinants for a range of diseases including breast cancer, colon cancer, diabetes, arthritis and dementia. The ability to define susceptibility in genetic terms has already led to a reclassification of some of these diseases on genetic and mechanistic grounds. This information is likely to have a profound effect on our approach to human diseases as it will allow a better definition of these disorders, permitting more effective therapeutic intervention, and will lead to both a more precise understanding of the natural history of these diseases and the possibility of identifying populations at risk. An understanding of the mechanisms underlying disease susceptibilty will also improve our ability to develop rational therapeutic interventions for many of these diseases. The role of genetic screening in these common diseases will be discussed, particularly in regard to the application of health care in populations.     

Eotaxin and eosinophil recruitment: implications for human disease

Eosinophils have been implicated in a broad range of diseases, notably allergic conditions (for example, asthma, rhinitis and atopic dermatitis) and other inflammatory disorders (for example, inflammatory bowel disease, eosinophilic gastroenteritis and pneumonia). These disease states are characterized by an accumulation of eosinophils in tissues. Severe tissue damage ensues as eosinophils release their highly cytotoxic granular proteins. Defining the mechanisms that control recruitment of eosinophils to tissues is fundamental to understanding these disease processes and provides targets for novel drug therapy. An important discovery in this context was the identification of an eosinophil-specific chemoattractant, eotaxin. Over the past six years there has been intensive investigation into the biological effects of eotaxin and its role in specific disease processes and this is the subject of this review.     

Evidence for significant overlap between common risk variants for Crohn's disease and ankylosing spondylitis

Background

A multicenter genome-wide association scan for Crohn''s Disease (CD) has recently reported 40 CD susceptibility loci, including 29 novel ones (19 significant and 10 putative). To gain insight into the genetic overlap between CD and ankylosing spondylitis (AS), these markers were tested for association in AS patients.

Principal Findings

Two previously established associations, namely with the MHC and IL23R loci, were confirmed. In addition, rs2872507, which maps to a locus associated with asthma and influences the expression of the ORMDL3 gene in lymphoblastoid cells, showed a significant association with AS (p = 0.03). In gut biopsies of AS and CD patients, ORMDL3 expression was not significantly different from controls and no correlation was found with the rs2872507 genotype (Spearman''s rho: −0.067). The distribution of p-values for the remaining 36 SNPs was significantly skewed towards low p-values unless the top 5 ranked SNPs (ORMDL3, NKX2–3, PTPN2, ICOSLG and MST1) were excluded from the analysis.

Conclusions

Association analysis using risk variants for CD led to the identification of a new risk variant associated with AS (ORMDL3), underscoring a role for ER stress in AS. In addition, two known and five potentially relevant associations were detected, contributing to common susceptibility of CD and AS.     

Protein-protein interactions in human disease

Many human diseases are the result of abnormal protein-protein interactions involving endogenous proteins, proteins from pathogens or both. The inhibition of these aberrant associations is of obvious clinical significance. Because of the diverse nature of protein-protein interactions, however, the successful design of therapeutics requires detailed knowledge of each system at a molecular and atomic level. Several recent studies have identified and/or characterised specific interactions from various disease systems, including cervical cancer, bacterial infection, leukaemia and neurodegenerative disease. A range of approaches are being developed to generate inhibitors of protein-protein interactions that may form useful therapeutics for human disease.     

Complex interactions among mammalian carnivores in Australia, and their implications for wildlife management

Mammalian carnivore populations are often intensively managed, either because the carnivore in question is endangered, or because it is viewed as a pest and is subjected to control measures, or both. Most management programmes treat carnivore species in isolation. However, there is a large and emerging body of evidence to demonstrate that populations of different carnivores interact with each other in a variety of complex ways. Thus, the removal or introduction of predators to or from a system can often affect other species in ways that are difficult to predict. Wildlife managers must consider such interactions when planning predator control programmes. Integrated predator control will require a greater understanding of the complex relationships between species. In many parts of the world, sympatric species of carnivores have coexisted over an evolutionary time scale so that niche differentiation has occurred, and competition is difficult to observe. Australia has experienced numerous introductions during the past 200 years, including those of the red fox (Vulpes vulpes) and the feral cat (Felis catus). These species now exist in sympatry with native mammalian predators, providing ecologists with the opportunity to study their interactions without the confounding effects of coevolution. Despite an increasing body of observational evidence for complex interactions among native and introduced predators in Australia, few studies have attempted to clarify these relationships experimentally, and the interactions remain largely unacknowledged. A greater understanding of these interactions would provide ecologists and wildlife managers world-wide with the ability to construct robust predictive models of carnivore communities, and to identify their broader effects on ecosystem functioning. We suggest that future research should focus on controlled and replicated predator removal or addition experiments. The dingo (Canis lupus dingo), as a likely keystone species, should be a particular focus of attention.     

Diversity of Ukrainian winter common wheat varieties with respect to storage protein loci and molecular markers for disease resistance genes

Diversity of Ukrainian winter common wheat varieties was studied with respect to the storage protein loci Gli-A1, Gli-B1, Gli-D1, Glu-A1, Glu-B1, Glu-D1, Gli-A3, Gli-B5, and Gli-A6 (362 varieties) and markers for the Lr34/Yr18/Pm38/Sr57/Bdv1 gene conferring moderate resistance to a number of biotrophic pathogens, the Tsn1 gene for sensitivity to the toxins A of the necrotrophic fungi Pyrenophora tritici-repentis and Stagonospora nodorum, the Tsc2 gene for sensitivity to the toxin B of P. tritici-repentis, and the TDF_076_2D gene for moderate resistance to Fusarium head blight (181 varieties). Significant differences in frequencies of alleles at these marker loci between groups of varieties developed in different soil and climatic zones were revealed. The retention of a set of predominant alleles in groups of varieties of a certain zone in different periods of breeding was confirmed. At the same time, the appearance of new allele associations in the groups of varieties of the Steppe (in particular Gli-A1g and Glu-B1al) and the Central Forest-Steppe (1AL/1RS and Glu-B1d) in the last two decades has been noted. Nonrandom associations between alleles of disease resistance genes as well as alleles of disease resistance genes and storage protein alleles were revealed.     

Heterogeneity of microsatellite mutations within and between loci,and implications for human demographic histories.

Microsatellites have been widely used to reconstruct human evolution. However, the efficient use of these markers relies on information regarding the process producing the observed variation. Here, we present a novel approach to the locus-by-locus characterization of this process. By analyzing somatic mutations in cancer patients, we estimated the distributions of mutation size for each of 20 loci. The same loci were then typed in three ethnically diverse population samples. The generalized stepwise mutation model was used to test the predicted relationship between population and mutation parameters under two demographic scenarios: constant population size and rapid expansion. The agreement between the observed and expected relationship between population and mutation parameters, even when the latter are estimated in cancer patients, confirms that somatic mutations may be useful for investigating the process underlying population variation. Estimated distributions of mutation size differ substantially amongst loci, and mutations of more than one repeat unit are common. A new statistic, the normalized population variance, is introduced for multilocus estimation of demographic parameters, and for testing demographic scenarios. The observed population variation is not consistent with a constant population size. Time estimates of the putative population expansion are in agreement with those obtained by other methods.