Intratumoral hypoxia as the genesis of genetic instability and clinical prognosis in prostate cancer

Intratumoral hypoxia is prevalent in many solid tumors and is a marker of poor clinical prognosis in prostate cancer. The presence of hypoxia is associated with increased chromosomal instability, gene amplification, downregulation of DNA damage repair pathways, and altered sensitivity to agents that damage DNA. These genomic changes could also lead to oncogene activation or tumor suppressor gene inactivation during prostate cancer progression. We review here the concept of repair-deficient hypoxic tumor cells that can adapt to low oxygen levels and acquire an aggressive "unstable mutator" phenotype. We speculate that hypoxia-induced genomic instability may also be a consequence of aberrant mitotic function in hypoxic cells, which leads to increased chromosomal instability and aneuploidy. Because both hypoxia and aneuploidy are prognostic factors in prostate cancer, a greater understanding of these biological states in prostate cancer may lead to novel prognostic and predictive tests and drive new therapeutic strategies in the context of personalized cancer medicine.

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

The domestication of the horse revolutionized warfare, trade, and the exchange of people and ideas. This at least 5,500-y-long process, which ultimately transformed wild horses into the hundreds of breeds living today, is difficult to reconstruct from archeological data and modern genetics alone. We therefore sequenced two complete horse genomes, predating domestication by thousands of years, to characterize the genetic footprint of domestication. These ancient genomes reveal predomestic population structure and a significant fraction of genetic variation shared with the domestic breeds but absent from Przewalski’s horses. We find positive selection on genes involved in various aspects of locomotion, physiology, and cognition. Finally, we show that modern horse genomes contain an excess of deleterious mutations, likely representing the genetic cost of domestication.

Genetic composition, genetic diversity, and small-scale environmental variation matter for the experimental reintroduction of a rare plant

Aims Reintroduction has become an important tool for the management of endangered plant species. We tested the little-explored effects of small-scale environmental variation, genotypic composition (i.e. identity of genotypes), and genotypic diversity on the population survival of the regionally rare clonal plant Ranunculus reptans. For this species of periodically inundated lakeshores genetic differentiation had been reported between populations and between short-flooded and long-flooded microsites within populations.Methods We established 306 experimental test populations at a previously unoccupied lake shore, comprising either monocultures of 32 genotypes, mixtures of genotypes within populations or mixtures of genotypes between populations. In 2000, three years after planting out at the experimental site, a long-lasting flood caused the death of half of the experimental populations. In 2003, an extreme drought resulted in the lowest summer water levels ever measured.Important findings Despite these climatic extremes, 27 of the established populations survived until the end of the experiment in December 2003. The success of experimental populations largely differed between microsites. Moreover, the success of genotype monocultures depended on genotype and source population. Genetic differentiation between microsites played a minor role for the success of reintroduction. After the flood, populations planted with genotypes from different source populations increased in abundance, whereas populations with genotypes from single source populations and genotype monocultures decreased. We conclude that sources for reintroductions need to be selected carefully. Moreover, mixtures of plants from different populations appear to be the best choice for successful reintroduction, at least in unpredictably varying environments.

Genetic diversity and differentiation follow secondary succession in a multi-species study on woody plants from subtropical China

Aims: Species diversity and genetic diversity may be affected in parallel by similar environmental drivers. However, genetic diversity may also be affected independently by habitat characteristics. We aim at disentangling relationships between genetic diversity, species diversity and habitat characteristics of woody species in subtropical forest. Methods: We studied 11 dominant tree and shrub species in 27 plots in Gutianshan, China, and assessed their genetic diversity (Ar) and population differentiation (F’ST) with microsatellite markers. We tested if Ar and population specific F’ST were correlated to local species diversity and plot characteristics. Multi-model inference and model averaging were used to determine the relative importance of each predictor. Additionally we tested for isolation-by-distance and isolation-by-elevation by regressing pairwise F’ST against pairwise spatial and elevational distances. Important findings: Genetic diversity was not related to species diversity for any of the study species. Thus, our results do not support joint effects of habitat characteristics on these two levels of biodiversity. Instead, genetic diversity in two understory shrubs, Rhododendron simsii and Vaccinium carlesii, was affected by plot age with decreasing genetic diversity in successionally older plots. Population differentiation increased with plot age in Rhododendron simsii and Lithocarpus glaber. This shows that succession can reduce genetic diversity within, and increase genetic diversity between populations. Furthermore, we found four cases of isolation-by-distance and two cases of isolation-by-elevation. The former indicates inefficient pollen and seed dispersal by animals whereas the latter might be due to phenological asynchronies. These patterns indicate that succession can affect genetic diversity without parallel effects on species diversity and that gene flow in a continuous subtropical forest can be restricted even at a local scale.

Genetic variability and limited clonality of Mycoplasma hyorhinis in pig herds

Mycoplasma hyorhinis is a common inhabitant of the upper respiratory tract and tonsils of pigs. Its role as a possible pathogen remains controversial. In order to gain more insight into the epidemiology and population structure of M. hyorhinis we genetically characterized 60 isolates by multi locus sequence typing (MLST). The M. hyorhinis strains originated from Swiss and German pig herds with knowledge on the clinical background. The MLST scheme of Tocqueville et al. (J. Clin. Microbiol. 2014) was optimized, primers for the six MLST gene fragments were newly designed to allow amplification and sequencing with a single protocol. A total of 27 ST were observed with the 60 strains, 26 of those were previously unknown types. Generally identical genotypes were observed within a farm but they differed between farms. The identical genotype was also observed in three different Swiss farms. On the other Hand different genotypes within a farm were found with three German farms. The Swiss isolates formed a distinct cluster but otherwise there was no geographical nor a clinical association with specific Clusters observed. Data shows a high variability of M. hyorhinis comparable to what is observed for Mycoplasma hyopneumoniae. Similar to this pathogen the population structure of M. hyorhinis also shows some limited clonality with predominant genotypes within an animal and a single farm but different ones between farms. The comparable population structure of M. hyopneumoniae and M. hyorhinis could indicate a similar evolution of the two species in the common pig host.

Contribution of Genetic Background and Clinical Risk Factors to Low-Trauma Fractures in Human Immunodeficiency Virus (HIV)-Positive Persons: The Swiss HIV Cohort Study.

Background.  The impact of human genetic background on low-trauma fracture (LTF) risk has not been evaluated in the context of human immunodeficiency virus (HIV) and clinical LTF risk factors. Methods.  In the general population, 6 common single-nucleotide polymorphisms (SNPs) associate with LTF through genome-wide association study. Using genome-wide SNP arrays and imputation, we genotyped these SNPs in HIV-positive, white Swiss HIV Cohort Study participants. We included 103 individuals with a first, physician-validated LTF and 206 controls matched on gender, whose duration of observation and whose antiretroviral therapy start dates were similar using incidence density sampling. Analyses of nongenetic LTF risk factors were based on 158 cases and 788 controls. Results.  A genetic risk score built from the 6 LTF-associated SNPs did not associate with LTF risk, in both models including and not including parental hip fracture history. The contribution of clinical LTF risk factors was limited in our dataset. Conclusions.  Genetic LTF markers with a modest effect size in the general population do not improve fracture prediction in persons with HIV, in whom clinical LTF risk factors are prevalent in both cases and controls.

The genetic basis of craniofacial and dental abnormalities

The embryonic head development, including the formation of dental structures, is a complex and delicate process guided by specific genetic programs. Genetic changes and environmental factors can disturb the execution of these programs and result in abnormalities in orofacial and dental structures. Orofacial clefts and hypodontia/ oligodontia are examples of such abnormalities frequently seen in dental clinics. An insight into the mechanisms and genes involved in the formation of orofacial and dental structures has been gradually gained by genetic analysis of families and by the use of experimental vertebrate models such as the mouse and chick models. The development of novel clinical therapies for orofacial and dental pathological conditions depends very much on a detailed knowledge of the molecular and cellular processes that are involved in head formation.

Is hatchery stocking a help or harm? Evidence, limitations and future directions in ecological and genetic surveys

Hatchery fish stocking for stock enhancement has been operated at a massive and global scale. However, the use of hatchery fish as a means of stock enhancement is highly controversial, and little is known about its effects on wild stock and consequences for stock enhancement. Here we review the scientific literature on this subject in order to address a fundamental - question is hatchery stocking a help or harm for wild stock and stock enhancement? We summarized 266 peer-reviewed papers that were published in the last 50 years, which describe empirical case studies on ecology and genetics of hatchery stocks and their effects on stock enhancement. Specifically, we asked whether hatchery stock and wild stock differed in fitness and the level of genetic variation, and whether stocking affected population abundance. Seventy studies contained comparisons between hatchery and wild stocks, out of which 23 studies showed significantly negative effects of hatchery rearing on the fitness of stocked fish, and 28 studies showed reduced genetic variation in hatchery populations. None of these studies suggested a positive genetic effect on the fitness of hatchery-reared individuals after release. These results suggest that negative effects of hatchery rearing are not just a concern but undeniably present in many aquaculture species. In a few cases, however, no obvious effect of hatchery rearing was observed, and a positive contribution of hatchery stock to the abundance of fish populations was indicated. These examples suggest that there is a chance to improve hatchery practices and mitigate the negative effects on wild stocks, although scientific data supporting the positive effect on stock enhancement are largely missing at this moment. Technically, microsatellite-based parentage assignments have been proven as a useful tool for the evaluation of reproductive fitness in natural settings, which is a key for stock enhancement by hatchery-based stocking. We discuss implications of these results, as well as their limitations and future directions. (C) 2010 Elsevier B.V. All rights reserved.

Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-Κb activation

Epstein-Barr virus (EBV) is associated with several types of cancers including Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane protein 1 (LMP1), a multifunctional oncoprotein, is a powerful activator of the transcription factor NF-κB, a property that is essential for EBV-transformed lymphoblastoid cell survival. Previous studies reported LMP1 sequence variations and induction of higher NF-κB activation levels compared to the prototype B95-8 LMP1 by some variants. Here we used biopsies of EBV-associated cancers and blood of individuals included in the Swiss HIV Cohort Study (SHCS) to analyze LMP1 genetic diversity and impact of sequence variations on LMP1-mediated NF-κB activation potential. We found that a number of variants mediate higher NF-κB activation levels when compared to B95-8 LMP1 and mapped three single polymorphisms responsible for this phenotype: F106Y, I124V and F144I. F106Y was present in all LMP1 isolated in this study and its effect was variant dependent, suggesting that it was modulated by other polymorphisms. The two polymorphisms I124V and F144I were present in distinct phylogenetic groups and were linked with other specific polymorphisms nearby, I152L and D150A/L151I, respectively. The two sets of polymorphisms, I124V/I152L and F144I/D150A/L151I, which were markers of increased NF-κB activation in vitro, were not associated with EBV-associated HL in the SHCS. Taken together these results highlighted the importance of single polymorphisms for the modulation of LMP1 signaling activity and demonstrated that several groups of LMP1 variants, through distinct mutational paths, mediated enhanced NF-κB activation levels compared to B95-8 LMP1.

Genetic variations in IL28B and allergic disease in children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences.

The quantitative genetic basis of offspring solicitation and parental response in a passerine bird with biparental care

The coevolution of parental investment and offspring solicitation is driven by partly different evolutionary interests of genes expressed in parents and their offspring. In species with biparental care, the outcome of this conflict ma!: be influenced by the sexual conflict over parental investment, Models for the resolution of such family conflicts have made so far untested assumptions about genetic variation and covariation in the parental resource provisioning response and the level of offspring solicitation. Using a combination of cross-fostering and begging playback experiments, we show that, in the great tit (Parus major), (i) the begging call intensity of nestlings depends on their common origin, suggesting genetic variation for this begging display, (ii) only mothers respond to begging calls by increased food provisioning, and (iii! the size of the parental response is positively related to the begging call intensity of nestlings in the maternal but not paternal line. This study indicates that genetic covariation, its differential expression in the maternal and paternal lines and/or early environmental and parental effects need to be taken into account when predicting the phenotypic outcome of the conflict over investment between genes expressed in each parent and the offspring. [References: 36]

Effects of genetic and environmental factors on chronic lower airway disease in horses

BACKGROUND: Environment and genetics influence the manifestation of recurrent airway obstruction (RAO), but the associations of specific factors with mild, moderate, and severe clinical signs are unknown. HYPOTHESIS: We hypothesized that sire, feed, bedding, time outdoors, sex, and age are associated with clinical manifestations of mild, moderate, and severe lower airway disease. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (F1S1, n = 172; F1S2, n = 135); maternal half-siblings of F1S1 (mHSS1, n = 66); and an age-matched, randomly chosen control group (CG, n = 33). METHODS: A standardized questionnaire was used to assess potential risk factors and to establish a horse owner assessed respiratory signs index (HOARSI 1-4, from healthy to severe) according to clinical signs of lower airway disease. RESULTS: More F1S1 and F1S2 horses showed moderate to severe clinical signs (HOARSI 3 and HOARSI 4 combined, 29.6 and 27.3%, respectively) compared with CG and mHSS1 horses (9.1 and 6.2%, respectively; contingency table overall test, P < .001). Sire, hay feeding, and age (in decreasing order of strength) were associated with more severe clinical signs (higher HOARSI), more frequent coughing, and nasal discharge. CONCLUSIONS AND CLINICAL RELEVANCE: There is a genetic predisposition and lesser but also marked effects of hay feeding and age on the manifestation of moderate to severe clinical signs, most markedly on coughing frequency. In contrast, mild clinical signs were not associated with sire or hay feeding in our populations.

Distribution and genetic variability among Campylobacter spp. isolates from different animal species and humans in Switzerland

In Switzerland, a national database with 1028 Campylobacter isolates from poultry, pigs, cats, dogs, cattle, humans, zoo animals and water has been created. The database contains the genetic fingerprint and background information of each Campylobacter isolate. Dominant species could be identified in the different sources with a majority of Campylobacter jejuni in poultry (73%), humans (79%), cattle (95%), zoo animals (40%) and water (100%), of Campylobacter coli in pigs (72%), and of Campylobacter upsaliensis/helveticus in cats and dogs (55%). The comparison of three genotyping methods, amplified fragment length polymorphism (AFLP), pulsed field gel electrophoresis and restriction fragment length polymorphism, revealed that AFLP allows discrimination between the different Campylobacter species and is the most appropriate method to distinguish specific strains within the same species. Genotyping analysis demonstrated that the Campylobacter population is heterogeneous among the different sources and that no dominant clone is spread in the country. Genotyping and the resulting database are useful tools to trace back future Campylobacter infections.