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The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid [Formula: see text] that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain's interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had [Formula: see text] higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs.

We estimated additive genetic variation and heritability of survival after Gyrodactylus salaris infection from survival records in a pedigreed family material of wild Atlantic salmon (Salmo salar) in a controlled challenge test. We used a statistical model that distinguishes between survival time for the fish that died and the ability to survive the entire test as two separate traits. Eleven of the 49 full-sib families suffered 100% mortality, 15 families had between 10% and 25% survival, and the four least affected families had survival rates between 36% and 48%. Estimated heritability of survival on the liability scale was 0.32 ± 0.10. Time until death for fish that died during the test and the ability to survive the entire test were not expressions of the same genetic trait. Simply selecting survivors as parents for the next generation is expected to more than double the overall survival rate in only one generation, given similar exposure to the parasite. Improving the genetic capacity to survive the infection will probably not eradicate the parasite, but when used as a disease control measure, such improvement may contain the infection at a level where the parasite ceases to be a major problem. Resume: Nous estimons la variation genetique additive et l'heritabilite de la survie apres une infection a Gyrodactylus salaris a partir des donnees de survie dans un echantillon provenant d'une famille d'ascendance connue de saumons atlantiques (Salmo salar) sauvages dans un test controle d'exposition au parasite. Nous utilisons un modele statistique qui discrimine entre la duree de survie des poissons qui sont morts et la capacite de survivre a l'ensemble du test comme deux caracteristiques differentes. Onze des 49 familles de meme fratrie ont connu 100% de mortalite, 15 familles entre 10% et 25% de survie et les quatre familles les moins affectees ont eu des taux de survie variant de 36% a 48 %. L'heritabilite estimee de la survie sur une echelle de predisposition est de 0,32 ± 0,10. La duree de la survie jusqu'a la mort chez les poissons qui sont morts durant le test et la capacite de survivre a l'ensemble du test ne sont pas les expressions du meme trait genetique. Une simple selection des survivants comme parents de la generation suivante devrait vraisemblablement plus que doubler le taux global de survie dans une seule generation, lors d'expositions semblables au parasite. L'amelioration de la capacite genetique de survie a l'infection n'eradiquera probablement pas le parasite, mais une telle amelioration, utilisee comme mesure de controle de la maladie, peut maintenir l'infection a un niveau ou le parasite cesse d'etre un probleme serieux. [Traduit par la Redaction], Introduction Wild Atlantic salmon (Salmo salar) populations remain at historical low levels throughout the North Atlantic despite all of the measures that have been taken to arrest their continuous decline. [...]

The Pacific chinook salmon occurs as both white- and red-fleshed populations, with the flesh color type (red or white) seemingly under strong genetic influence. Previously published data on crosses between red- and white-fleshed individuals cannot be reconciled with a simple Mendelian two-locus, two-allele model, pointing to either a more complex inheritance pattern or the existence of gene interactions. Here we show that a standard single-locus, three-allele model can fully explain these data. Moreover, by implementing the single-locus model at the parameter level of a previously developed mathematical model describing carotenoid dynamics in salmon, we show that variation at a single gene involved in the muscle uptake of carotenoids is able to explain the available data. This illustrates how such a combined approach can generate biological understanding that would not be possible in a classical population genetic explanatory structure. An additional asset of this approach is that by allowing parameters to become phenotypes obeying a given genetic model, biological interpretations of mechanisms involved at a resolution level far beyond what is built into the original dynamic model are made possible. These insights can in turn be exploited in experimental studies as well as in construction of more detailed models.

Abstract: Pigmented flesh, a trait uniquely present in four of the 10 genera of salmonid fishes, is caused by the ubiquitous capacity of these genera for accumulating dietary carotenoids in [...]

Functional dependencies between genes are a defining characteristic of gene networks underlying quantitative traits. However, recent studies show that the proportion of the genetic variation that can be attributed to statistical epistasis varies from almost zero to very high. It is thus of fundamental as well as instrumental importance to better understand whether different functional dependency patterns among polymorphic genes give rise to distinct statistical interaction patterns or not. Here we address this issue by combining a quantitative genetic model approach with genotype-phenotype models capable of translating allelic variation and regulatory principles into phenotypic variation at the level of gene expression. We show that gene regulatory networks with and without feedback motifs can exhibit a wide range of possible statistical genetic architectures with regard to both type of effect explaining phenotypic variance and number of apparent loci underlying the observed phenotypic effect. Although all motifs are capable of harboring significant interactions, positive feedback gives rise to higher amounts and more types of statistical epistasis. The results also suggest that the inclusion of statistical interaction terms in genetic models will increase the chance to detect additional QTL as well as functional dependencies between genetic loci over a broad range of regulatory regimes. This article illustrates how statistical genetic methods can fruitfully be combined with nonlinear systems dynamics to elucidate biological issues beyond reach of each methodology in isolation.

Abstract Background Red flesh colour is a unique trait found in some salmonid genera. Carotenoid pigments are not synthesized de novo in the fish, but are provided by dietary uptake. A better understanding of the molecular mechanisms underlying the cellular uptake and deposition of carotenoids could potentially be used to improve the low muscle deposition rate that is typically found in farmed Atlantic salmon. In addition, from an evolutionary point of view, the establishment and maintenance of this trait is still poorly understood. It has been demonstrated in several species that scavenger receptor class B, member 1 (SCARB1) is involved in intestinal absorption of carotenoids, which makes this gene a possible source of genetic variation in salmonid flesh pigmentation. Results In this study, a novel paralog of SCARB1 (SCARB1-2) was detected through screening for genetic variation in Atlantic salmon SCARB1. Full length SCARB1-2 encodes a protein with 89% identity to Atlantic salmon SCARB1, except for the C-terminal cytoplasmic tail that shows only 12% identity. The most prominent site of SCARB1 mRNA expression was in the mid gut, while a five-fold lower level was detected in Atlantic salmon skeletal muscle and liver. The SCARB1-2 mRNA was equally expressed in liver, muscle and mid gut, and at a lower level than SCARB1 mRNA. A total of seven different SCARB1-2 alleles comprising repetitive enhancer of zeste motifs (EZH2) were identified in the founding parents of a resource Atlantic salmon population. We mapped the SCARB1-2 paralog to a region on Atlantic salmon chromosome 1, containing a putative QTL for flesh colour. Addition of the SCARB1-2 marker increased the significance of this QTL, however the large confidence interval surrounding the QTL precludes confirmation of SCARB1-2 as a causative gene underlying variation in this trait. Conclusion We have characterised a novel paralog of SCARB1 (SCARB1-2), have mapped it to Atlantic salmon chromosome 1 and have described its expression in various tissues. Mapping with SCARB1-2 alleles added further evidence for a QTL affecting flesh colour on this chromosome, however further studies are needed to confirm a functional role for this gene in flesh colour pigmentation.

Abstract Background The Atlantic salmon is a species of commercial and ecological significance. Like other salmonids, the species displays residual tetrasomy and a large difference in recombination rate between sexes. Linkage maps with full genome coverage, containing both type I and type II markers, are needed for progress in genomics. Furthermore, it is important to estimate levels of linkage disequilibrium (LD) in the species. In this study, we developed several hundred single nucleotide polymorphism (SNP) markers for the Atlantic salmon, and constructed male and female linkage maps containing SNP and microsatellite markers. We also investigated further the distribution of male and female recombination events across the genome, and estimated levels of LD between pairs of markers. Results The male map had 29 linkage groups and was 390 cM long. The female map had 30 linkage groups as was 1983 cM long. In total, the maps contained 138 microsatellite markers and 304 SNPs located within genes, most of which were successfully annotated. The ratio of male to female recombination events was either close to zero or very large, indicating that there is little overlap between regions in which male and female crossovers occur. The female map is likely to have close to full genome coverage, while the majority of male linkage groups probably lack markers in telomeric regions where male recombination events occur. Levels of r2 increased with decreasing inter-marker distance in a bimodal fashion; increasing slowly from ~60 cM, and more rapidly more from ~12 cM. Long-ranging LD may be consequence of recent admixture in the population, the population being a 'synthetic' breeding population with contributions from several distinct rivers. Levels of r2 dropped to half its maximum value (above baseline) within 15 cM, and were higher than 0.2 above baseline for unlinked markers ('useful LD') at inter-marker distances less than 5 cM. Conclusion The linkage map presented here is an important resource for genetic, comparative, and physical mapping of the Atlantic salmon. The female map is likely to have a map coverage that is not far from complete, whereas the male map length is likely to be significantly shorter than the true map, due to suboptimal marker coverage in the apparently small physical regions where male crossovers occur. 'Useful LD' was found at inter-marker distances less than 5 cM.

Abstract Background Carotenoids are pigment molecules produced mainly in plants and heavily exploited by a wide range of organisms higher up in the food-chain. The fundamental processes regulating how carotenoids are absorbed and metabolized in vertebrates are still not fully understood. We try to further this understanding here by presenting a dynamic ODE (ordinary differential equation) model to describe and analyse the uptake, deposition, and utilization of a carotenoid at the whole-organism level. The model focuses on the pigment astaxanthin in Atlantic salmon because of the commercial importance of understanding carotenoid dynamics in this species, and because deposition of carotenoids in the flesh is likely to play an important life history role in anadromous salmonids. Results The model is capable of mimicking feed experiments analyzing astaxanthin uptake and retention over short and long time periods (hours, days and years) under various conditions. A sensitivity analysis of the model provides information on where to look for possible genetic determinants underlying the observed phenotypic variation in muscle carotenoid retention. Finally, the model framework is used to predict that a specific regulatory system controlling the release of astaxanthin from the muscle is not likely to exist, and that the release of the pigment into the blood is instead caused by the androgen-initiated autolytic degradation of the muscle in the sexually mature salmon. Conclusion The results show that a dynamic model describing a complex trait can be instrumental in the early stages of a project trying to uncover underlying determinants. The model provides a heuristic basis for an experimental research programme, as well as defining a scaffold for modelling carotenoid dynamics in mammalian systems.

Abstract Background The ability to manipulate the genetic networks underlying the physiological and behavioural repertoires of the adult honeybee worker (Apis mellifera) is likely to deepen our understanding of issues such as learning and memory generation, ageing, and the regulatory anatomy of social systems in proximate as well as evolutionary terms. Here we assess two methods for probing gene function by RNA interference (RNAi) in adult honeybees. Results The vitellogenin gene was chosen as target because its expression is unlikely to have a phenotypic effect until the adult stage in bees. This allowed us to introduce dsRNA in preblastoderm eggs without affecting gene function during development. Of workers reared from eggs injected with dsRNA derived from a 504 bp stretch of the vitellogenin coding sequence, 15% had strongly reduced levels of vitellogenin mRNA. When dsRNA was introduced by intra-abdominal injection in newly emerged bees, almost all individuals (96 %) showed the mutant phenotype. An RNA-fragment with an apparent size similar to the template dsRNA was still present in this group after 15 days. Conclusion Injection of dsRNA in eggs at the preblastoderm stage seems to allow disruption of gene function in all developmental stages. To dissect gene function in the adult stage, the intra-abdominal injection technique seems superior to egg injection as it gives a much higher penetrance, it is much simpler, and it makes it possible to address genes that are also expressed in the embryonic, larval or pupal stages.