Genetic and maternal contributions to offspring viability under different environmental conditions in various salmonids

Summary : Due to anthropogenic impacts and natural fluctuations, fish usually have to cope with constantly changing and often hostile environments. Whereas adult fish have various possibilities to counteract unfavourable environmental conditions, embryos have much fewer options. Besides by their developing immune system, they are protected by the egg envelopes and several immune substances provided by their mothers. In addition to this, they may also adjust their hatching timing in reaction to various risks. However, individuals may vary in their defensive potential. This variation may be either based on their genetics and/or on differential maternal investments and may be dependent on the experienced stress. Nevertheless, in fish, the impact of such parental contributions on embryo and/or juvenile viability is still poorly investigated. The main objective of this thesis was to investigate the importance of paternal (i.e. genetic) and maternal (i.e. genetic + egg investment) contributions to offspring viability under different environmental conditions and at different life stages. In order to investigate this, we used gametes of various salmonids for in vitro fertilisation experiments based on full-factorial breeding designs. The individual studies are summarised in the following chapters: In the first chapter, we tested the effectiveness of the embryonic immune system in Lake whitefish (Coregonus palaea). Namely, we investigated paternal and maternal contributions to the embryos' tolerance to different kinds of pathogen exposure. Additionally, we tested whether an early sub-léthal exposure has a positive or a negative effect on an embryo's susceptibility to later pathogen exposures with the same pathogen. We found that pre-challenged embryos were more susceptible to future challenges. Moreover, pathogen susceptibility was dependent on maternal investments and/or the embryos' own genetics, depending on the challenge level. Chapter 2 summarises a similar study with brown trout (Salmo trutta). In addition to the previously described investigations, we analysed if genetic effects on offspring viability are mediated either by parental MHC genotypes or relatedness based on neutral microsatellite markers, and we tested if males signal their genetic quality either by their body size or their melanin-based skin colouration. We found that embryo survival was lower at higher stress levels and dependent on the embryos' genetics. Addirionally, parents with similar and/or, very common MHC genotypes had higher offspring viabilities. Finally, darker males produced more viable offspring. In the first two chapters we investigated the embryos' defensive potential based on their immune system, i.e. their pathogen tolerance. In chapter 3 we investigate whether hatching timing of Lake whitefìsh (C. palaea) is dependent on parental contributions and/or on pathogen pressure, and whether there are parental-environmental interactions. We found that whitefish embryos hatch earlier under increasing pathogen pressure. Moreover, hatching timing was affected by embryo genetics and/or maternally provided resources, but the magnitude of the effect was dependent on the pathogen. pressure. We also found a significant paternal-environmental interaction, indicating that the hatching efficiency of a certain sib group is dependent on the pathogen environment. Chapter 4 describes an analogous study with brown trout (S. trutta), with similar findings. In the former chapters, we only looked at offspring performance during the embryonic period, and only under semi-natural conditions. In chapter 5 we now test the performance and viability of embryonic and juvenile brown trout (S. trutta) under natural conditions. To measure embryo viability, we put them in brood boxes, buried them in the gravel of a natural river, and analysed survival after several months. To investigate juvenile survival and performance, wé reared embryos under different stress levels in the laboratory and subsequently released the resulting hatchlings in to a closed river section. Juvenile size and survival was then determined one year later. Additionally, we investigated if sires differ in their genetic quality, determined by embryo and juvenile survival as well as juvenile size, and if they signal their quality by either body size or melanin-based body darkness. We found hat juvenile size was dependent on genetic effects and on maternal investment, whereas this was neither the case for embryo nor for juvenile survival. Additionally, we found that offspring of darker males grew larger, and larger juveniles had also an increased survival. Finally, we found acarry-over effect of the early non-lethal challenge: exposing embryos to higher stress levels resulted in smaller juveniles. To evaluate the long-term performance of differently treated groups, mark-recapture studies are inevitable. For this purpose, effective mass-marking techniques are essential. In chapter 6 we tested the suitability of the fluorescent pigment spray marking method for the mass marking of European graylings (Thymallus thymallus), with very promising results. Our in vitro fertilisation studies on whitefish may reveal new insights on potential genetic benefits of mate choice, but the mating system of whitefish under natural conditions is still poorly investigated. In order to study this, we installed underwater cameras at the spawning place of a Coregonus suidteri population, recorded the whole mating period and subsequently analysed the recordings. Confirmations of previous findings as well as exciting new observations are listed and discussed in chapter 7. Dus aux impacts anthropogéniques et aux fluctuations naturelles, les poissons doivent faire face à des environnements en perpétuel changement. Ces changements font que les poissons doivent s'adapter à de nouvelles situations, souvent hostiles pour eux. Les adultes ont différentes possibilités d'échapper à un environnement peu favorable, ce n'est par contre pas le cas des embryons. Les embryons sont protégés d'une part par leur système immunitaire en développement, d'autre part, par la coquille de l'eeuf et différentes substances immunitaires fournies par leur mère. De plus, ils sont capables d'influencer leur propre date d'éclosion en réponse à différents facteurs de stress. Malgré tout, les individus varient dans leur capacité à se défendre. Cette variation peut être basé sur des facteurs génétiques et/ou sur des facteurs maternels, et est dépendante du stress subi. Néanmoins, chez les poissons, l'impact de telles contributions parentales sur la survie d'embryons et/ou juvéniles est peu étudié. L'objectif principal de cette thèse a été d'approfondir les connaissances sur l'importance de la contribution paternelle (c.a.d. génétique) et maternelle (c.a.d. génétique + investissement dans l'oeuf) sur la survie des jeunes dans différentes conditions expérimentales et stades de vie. Pour faire ces analyses, nous avons utilisé des gamètes de divers salmonidés issus de croisements 'full-factorial'. Les différentes expériences sont résumées dans les chapitres suivants: Dans le premier chapitre, nous avons testé l'efficacité du système immunitaire des embryons chez les corégones (Coregonus palea). Plus précisément nous avons étudié la contribution paternelle et maternelle à la tolérance des embryons à différents niveaux de stress pathogène. Nous avons aussi testé, si une première exposition non létale à un pathogène avait un effet positif ou négatif sur la susceptibilité d'un embryon a une deuxième exposition au même pathogène. Nous avons trouvé que des embryons qui avaient été exposés une première fois étaient plus sensibles au pathogène par la suite. Mais aussi que la sensibilité au pathogène était dépendante de l'investissement de la mère et/ou des gènes de l'embryon, dépendamment du niveau de stress. Le deuxième chapitre résume une étude similaire avec des truites (Salmo truffa). Nous avons examiné, si la survie des jeunes variait sous différentes intensités de stress, et si la variance observée était due aux gènes des parents. Nous avons aussi analysé si les effets génétiques sur la survie des juvéniles étaient dus au MHC (Major Histocompatibility Complex) ou au degré de parenté des parents. De plus, nous avons analysé si les mâles signalaient leur qualité génétique par la taille du corps ou par leur coloration noire, due à la mélanine. On a trouvé que la survie des embryons était plus basse quand le niveau de stress était plus haut mais que la variation restait dépendante de la génétique des embryons. De plus, les parents avec des MHC similaires et/ou communs avaient des embryons avec une meilleure survie. Par contre, des parents avec un degré de parenté plus haut produisent des embryons avec une survie plus mauvaise. Finalement nous avons montré que les mâles plus foncés ont des embryons qui survivent mieux, mais que la taille des mâles n'a pas d'influence sur la survie de ces mêmes embryons. Dans les deux premiers chapitres, nous avons étudié le potentiel de défense des embryons basé sur leur système immunitaire, c.a.d. leur tolérance aux pathogènes. Dans le troisième chapitre, nous nous intéressons à la date d'éclosion des corégones (C. palea), pour voir si elle est influencée par les parents ou par la pression des pathogènes, et si il y a une interaction entre ces deux facteurs. Nous avons trouvé que les jeunes naissent plus rapidement lorsque la pression en pathogènes augmente. La date d'éclosion est influencée par la génétique des embryons et/ou l'investissement des parents, mais c'est la magnitude des effets qui est dépendante de la pression du pathogène. Nous avons aussi trouvé une interaction entre l'effet paternel et l'environnement, ce qui indique que la rapidité d'éclosion de certains croisements est dépendante des pathogènes dans l'environnement. Le chapitre 4 décrit une étude analogue avec de truites (S. truffa), avec des résultats sitzimilaires. Dans les précédents chapitres nous nous sommes uniquement concentrés sur les performances des jeunes durant leur stade embryonnaire, et seulement dans des conditions semi naturelles. Dans le chapitre 5 nous testons la performance et la viabilité des embryons et de juvéniles de truites (S. truffa) dans des conditions naturelles. Nous avons trouvé que la taille des juvéniles était dépendante d'effets génétiques et de l'investissement maternel, mais ceci n'était ni les cas pour les survie des embryons et des juvéniles. De plus, nous avons trouvé que les jeunes des mâles plus foncés devenaient plus grands et que les grands ont un meilleur taux de survie. Finalement nous avons trouvé un 'carry-over effect' d'une première exposition non létale à un pathogène: exposer des embryons à des plus hauts niveaux de stress donnait des juvéniles plus petits. Pour évaluer la performance à long terme de groupes traités dé manières différentes, une méthode de marquage-recapture est inévitable. Pour cette raison, des techniques de marquage en masse sont nécessaires. Dans le chapitre 6, nous avons testé l'efficacité de la technique `fluorescent pigment spray marking' pour le marquage en masse de l'Ombre commun (Thymallus thymallus), avec des résultats très prometteurs. Les études de fertilisations in vitro avec les corégones nous donnent une idée du potentiel bénéfice génétique que représente la sélection d'un bon partenaire, même si le système d'accouplement des corégones en milieu naturel reste peu connu. Pour combler cette lacune, nous avons installé des caméras sous-marines autour de la frayère d'une population de corégones (C. suidteri), nous avons enregistré toute la période de reproduction et nous avons analysé les données par la suite. Ainsi, nous avons été capables de confirmer bien des résultats trouvés précédemment, mais aussi de faire de nouvelles observations. Ces résultats sont reportés dans le septième chapitre, où elles sont comparées avec des observations antérieures.

Le peuple élu et les autres. L'Ancien Testament entre exclusion et ouverture

La conviction d'être le peuple élu s'enracine au coeur de la foi d'Israël. Mais elle justifia aussi par réaction tous les antisémitismes. La Bible, pourtant, ne nous fait pas entendre qu'un seul discours sur l'élection. A trop vite tirer à soi tel passage, on en vient à travestir dangereusement son message. En réalité la critique des dérives intégristes auxquelles peut donner et a donné lieu le thème de l'élection d'Israël est le fait de l'Ancien Testament lui-même. Il est vrai que dans les temps d'oppresion et de déportation la conscience d'être le peuple de Dieu a permis à Israël de fortifier son espérance et d'assurer son identité. Et ce fut là, notamment, le grand dessein auquel se consacrèrent les auteurs successsifs du Deutéronome, à l'époque de la domination assyrienne, puis de l'exil babylonien. Mais il est tout aussi vrai qu'à chaque fois aussi se sont levés des hommes avertis, dans la foulée des propnètes de jadis, pour mettre en garde contre la tentation du nombrilisme voire de l'exclusivisme ravageur. L'histoire d'Abraham réécrite au retour de l'exil, en est l'exemple le plus impressionnant, qui souligne combien Dieu n'a cessé d'élargir à tous les pepes son électon et sa bénédiction.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Chromosomal rearrangement and genetic structure in the shrews of the Sorex araneus group

ABSTRACT The role of chromosomal rearrangements in the speciation process is much debated and many theoretical models have been developed. The shrews of the Sorex araneus group offer extraordinary opportunities to study the relationship between chromosomal variation and speciation. Indeed, this group of morphologically very similar species received a great deal of attention due to its karyotypic variability, which is mainly attributed to Robertsonian fusions. To explore the impact of karyotypic changes on genetic differentiation, we first studied the relationship between genetic and karyotypic structure among Alpine species and among chromosome races of the S. araneus group using Bayesian admixture analyses. The results of these analyses confirmed the taxonomic status of the studied species even though introgression can still be detected between species. Moreover, the strong spatial sub-structure highlighted the role of historical factors (e.g. geographical isolation) on genetic structure. Next, we studied gene flow at the chromosome level to address the question of the impact of chromosomal rearrangements on genetic differentiation. We used flow sorted chromosomes from three different karyotypic taxa of the S. araneus group to map microsatellite markers at the chromosóme arm level. We have been able to map 24 markers and to show that the karyotypic organisation of these taxa is well conserved, which suggests that these markers can be used for further inter-taxa studies. A general prediction of chromosomal speciation models is that genetic differentiation between two taxa should be larger across rearranged chromosomes than across chromosomes common to both taxa. We combined two approaches using mapped microsatellites to test this prediction. First, we studied the genetic differentiation among five shrew taxa placed at different evolutionary levels (i.e. within and among species). In this large scale study, we detected an overall significant difference in genetic structure between rearranged vs. common chromosomes. Moreover, this effect varied among pairwise comparisons, which allowed us to differentiate the role of the karyotypic complexity of hybrids and of the evolutionary divergence between taxa. Secondly, we compared the levels of gene flow measured across common vs. rearranged chromosomes in two karyotypically different hybrid zones (strong vs. low complexity of hybrids), which show similar levels of genetic structure. We detected a significantly stronger genetic structure across rearranged chromosomes in the hybrid zone showing the highest level of hybrid complexity. The large variance observed among loci suggested that other factors, such as the position of markers within the chromosome, also certainly affects genetic structure. In conclusion, our results strongly support the role of chromosomal rearrangements in the reproductive barrier and suggest their importance in speciation process of the S. araneus group. RESUME Le rôle des réarrangements chromosomiques dans les processus de spéciation est fortement débattu et de nombreux modèles théoriques ont été développés sur le sujet. Les musaraignes du groupe Sorex araneus présentent de nombreuses opportunités pour étudier les relations entre les variations chromosomiques et la spéciation. En effet, ce groupe d'espèces morphologiquement très proches a attiré l'attention des chercheurs en raison de sa variabilité caryotypique principalement attribuée à des fusions Robertsoniennes. Pour explorer l'impact des changements caryotypiques sur la différenciation génétique, nous avons tout d'abord étudié les relations entre la structure génétique et caryotypique de races chromosomiques et d'espèces alpine du groupe S. araneus en utilisant des analyses Bayesiennes d' « admixture ». Les résultats de ces analyses ont confirmé le statut taxonomique des espèces étudiées bien que nous ayons détecté de l'introgression entre espèces. L'observation d'une sous structure spatiale relativement forte souligne l'importance des facteurs historiques (telle que l'isolation géographique) sur la structure génétique de ce groupe. Ensuite, nous avons étudié le flux de gène au niveau des chromosomes pour aborder de manière directe la question de l'impact des réarrangements chromosomiques sur la différenciation génétique. En conséquence, nous avons utilisé des tris de chromosomes de trois taxons du groupe S. araneus pour localiser des marqueurs microsatellites au niveau du bras chromosomique. Au cours de cette étude, nous avons pu localiser 24 marqueurs et montrer une forte conservation dans l'organisation du caryotype de ces taxa. Ce résultat suggère que leur utilisation est appropriée pour des études entre taxa. Une prédiction générale à tous les modèles de spéciation chromosomique correspond à la plus grande différenciation génétique des chromosomes réarrangés que des chromosomes communs. Nous avons combiné deux approches utilisant des microsatellites localisés au niveau du bras chromosomique pour tester cette prédiction. Premièrement, nous avons étudié la différenciation génétique entre cinq taxa du groupe S. araneus se trouvant à des niveaux évolutifs différents (i.e. à l'intérieur et entre espèce). Au cours de cette étude, nous avons détecté une différenciation globale significativement plus élevée sur les chromosomes réarrangés. Cet effet varie entre les comparaisons, ce qui nous a permis de souligner le rôle de la complexité caryotypique des hybrides et du niveau de divergence évolutive entre taxa. Deuxièmement, nous avons comparé le flux de gènes des chromosomes communs et réarrangés dans deux zones d'hybridation caryotypiquement différentes (forte vs. Faible complexité des hybrides) mais présentant un niveau de différenciation génétique similaire. Ceci nous a permis de détecter une structure génétique significativement plus élevée sur les chromosomes réarrangés au centre de la zone d'hybridation présentant la plus grande complexité caryotypic. La forte variance observée entre loci souligne en outre le fait que d'autres facteurs, tel que la position du marqueur sur le chromosome, affectent probablement aussi la structure génétique mesurée. En conclusion, nos résultats supportent fortement le rôle des réarrangements chromosomiques dans la barrière reproductive entre espèces ainsi que leur importance dans les processus de spéciation des musaraignes du groupe S. araneus.

Are invasive marsh frogs (Pelophylax ridibundus) replacing the native P. lessonae /P. esculentus hybridogenetic complex in Western Europe? Genetic evidence from a field study.

The water-frog L-E system, widespread in Western Europe, comprises the pool frog Pelophylax lessonae and the hybridogenetic edible frog P. esculentus, which originated from hybridization between pool frogs and marsh frogs (P. ridibundus). In P. esculentus, the lessonae (L) genome is eliminated during meiosis and has to be gained anew each generation from a P. lessonae partner, while the ridibundus (R') genome is transmitted clonally. It therefore accumulates deleterious mutations, so that R'R' offspring from P. esculentus x P. esculentus crosses are normally unviable. This system is now threatened by invasive P. ridibundus (RR) imported from Eastern Europe and the Balkans. We investigated the genetic interactions between invasive marsh frogs and native water frogs in a Swiss wetland area, and used genetic data collected in the field to validate several components of a recently postulated mechanism of species replacement. We identified neo-ridibundus individuals derived from crosses between invasive ridibundus and native esculentus, as well as newly arisen hybridogenetic esculentus lineages stemming from crosses between invasive ridibundus (RR) and native lessonae (LL). As their ridibundus genomes are likely to carry less deleterious mutations, such lineages are expected to produce viable ridibundus offspring, contributing to species replacement. However, such crosses with invasive ridibundus only occurred at a limited scale; moreover, RR x LL crosses did not induce any introgression from the ridibundus to the lessonae genome. We did not find any ridibundus stemming from crosses between ancient esculentus lineages. Despite several decades of presence on the site, introduced ridibundus individuals only represent 15% of sampled frogs, and their spatial distribution seems shaped by specific ecological requirements rather than history of colonization. We therefore expect the three taxa to coexist stably in this area.

Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo.

Secretory immunoglobulin (Ig) A (SIgA) is essential in protecting mucosal surfaces. It is composed of at least two monomeric IgA molecules, covalently linked through the J chain, and secretory component (SC). We show here that a dimeric/polymeric IgA (IgA(d/p)) is more efficient when bound to SC in protecting mice against bacterial infection of the respiratory tract. We demonstrate that SC ensures, through its carbohydrate residues, the appropriate tissue localization of SIgA by anchoring the antibody to mucus lining the epithelial surface. This in turn impacts the localization and the subsequent clearance of bacteria. Thus, SC is directly involved in the SIgA function in vivo. Therefore, binding of IgA(d/p) to SC during the course of SIgA-mediated mucosal response constitutes a crucial step in achieving efficient protection of the epithelial barrier by immune exclusion.

Early onset collagen VI myopathies: Genetic and clinical correlations.

OBJECTIVE: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. METHODS: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. RESULTS: ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). INTERPRETATION: This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.

Estimates of genetic parameters of trotting performance traits for repeated annual records

Selostus: Ravihevosten jalostettavia ominaisuuksia kuvaavien kilpailumittojen perinnölliset tunnusluvut

Genetic parameters for growth traits in pigs estimated using third degree polynomial functions

Selostus: Sian kasvuominaisuuksien perinnölliset tunnusluvut arvioituna kolmannen asteen polynomifunktion avulla

The genetic basis of sleep disorders.

The contribution of genes, environment and gene-environment interactions to sleep disorders is increasingly recognized. Well-documented familial and twin sleep disorder studies suggest an important influence of genetic factors. However, only few sleep disorders have an established genetic basis including four rare diseases that may result from a single gene mutation: fatal familial insomnia, familial advanced sleep-phase syndrome, chronic primary insomnia, and narcolepsy with cataplexy. However, most sleep disorders are complex in terms of their genetic susceptibility together with the variable expressivity of the phenotype even within a same family. Recent linkage, genome-wide and candidate gene association studies resulted in the identification of gene mutations, gene localizations, or evidence for susceptibility genes and/or loci in several sleep disorders. Molecular techniques including mainly genome-wide linkage and association studies are further required to identify the contribution of new genes. These identified susceptibility genetic determinants will provide clues to better understand pathogenesis of sleep disorders, to assess the risk for diseases and also to find new drug targets to treat and to prevent the underlying conditions. We reviewed here the role of genetic basis in most of key sleep disorders.

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Microsatellite variation reveals low genetic subdivision in a chromosome race of Sorex araneus (Mammalia, Insectivora)

Two hundred and forty-five individuals of the common shrew (Sorex araneus, Insectivora, Mammalia) from 24 sampling localities situated in four different valleys of the western European Alps were genotyped for six microsatellite loci. Allelic variability ranged from 3 to 32 different alleles at a single locus and the average gene diversity over all loci was 0.69. An analysis for F and R statistics revealed weak genetic population subdivision (Fst = 0.032; Rst = 0.016). This suggests considerable gene flow and little phylogeographic structure within and between valleys. We tested whether a stepwise mutation model (SMM) better explained variation at the microsatellite loci than an infinite allele model (IAM). No trend in favor of either model was detected.

Consequences of genetic erosion on fitness and phenotypic plasticity in European tree frog populations (Hyla arborea).

The detrimental effects of genetic erosion on small isolated populations are widely recognized contrary to their interactions with environmental changes. The ability of genotypes to plastically respond to variability is probably essential for the persistence of these populations. Genetic erosion impact may be exacerbated if inbreeding affects plastic responses or if their maintenance were at higher phenotypic costs. To understand the interplay 'genetic erosion-fitness-phenotypic plasticity', we experimentally compared, in different environments, the larval performances and plastic responses to predation of European tree frogs (Hyla arborea) from isolated and connected populations. Tadpoles from isolated populations were less performant, but the traits affected were environmental dependant. Heterosis observed in crosses between isolated populations allowed attributing their low fitness to inbreeding. Phenotypic plasticity can be maintained in the face of genetic erosion as inducible defences in response to predator were identical in all populations. However, the higher survival and developmental costs for isolated populations in harsh conditions may lead to an additional fitness loss for isolated populations.

Genetic Variants of Serum Uric Acid and Gout: An Analysis of > 170,000 Individuals

Background/Purpose: Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricemia. In addition to various lifestyle risk factors, a substantial genetic predisposition to gout has long been recognized. The Global Urate Genetics Consortium (GUGC) has aimed to comprehensively investigate the genetics of serum uric acid and gout using data from _ 140,000 individuals of European-ancestry, 8,340 individuals of Indian ancestry, 5,820 African-Americans, and 15,286 Japanese. Methods: We performed discovery GWAS meta-analyses of serum urate levels (n_110,347 individuals) followed by replication analyses (n_32,813 different individuals). Our gout analysis involved 3,151 cases and 68,350 controls, including 1,036 incident gout cases that met the American College of Rheumatology Criteria. We also examined the association of gout with fractional excretion of uric acid (n_6,799). A weighted genetic urate score was constructed based on the number of risk alleles across urate-associated loci, and their association with the risk of gout was evaluated. Furthermore, we examined implicated transcript expression in cis (expression quantitative trait loci databases) for potential insights into the gene underlying the association signal. Finally, in order to further identify urate-associated genomic regions, we performed functional network analyses that incorporated prior knowledge on molecular interactions in which the gene products of implicated genes operate. Results: We identified and replicated 28 genome-wide significant loci in association with serum urate (P 5_10_8), including all previously-reported loci as well as 18 novel genetic loci. Unlike the majority of previouslyidentified loci, none of the novel loci appeared to be obvious candidates for urate transport. Rather, they were mapped to genes that encode for purine production, transcription, or growth factors with broad downstream responses. Besides SLC2A9 and ABCG2, no additional regions contained SNPs that differed significantly (P _ 5_10_8) between sexes. Urateincreasing alleles were associated with an increased risk of gout for all loci. The urate genetic risk score (ranging from 10 to 45) was significantly associated with an increased odds of prevalent gout (OR per unit increase, 1.11; 95% CI, 1.09-1.14) and incident gout (OR, 1.10; 95% CI, 1.08-1.13). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. Detailed characterization of the loci revealed associations with transcript expression and the fractional excretion of urate. Network analyses implicated the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. Conclusion: The novel genetic candidates identified in this urate/gout consortium study, the largest to date, highlight the importance of metabolic control of urate production and urate excretion. The modulation by signaling processes that influence metabolic pathways such as glycolysis and the pentose phosphate pathway appear to be central mechanisms underpinned by the novel GWAS candidates. These findings may have implications for further research into urate-lowering drugs to treat and prevent gout.