The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p

Quantitative Metabolomics Reveals an Epigenetic Blueprint for Iron Acquisition in Uropathogenic Escherichia coli

Bacterial pathogens are frequently distinguished by the presence of acquired genes associated with iron acquisition. The presence of specific siderophore receptor genes, however, does not reliably predict activity of the complex protein assemblies involved in synthesis and transport of these secondary metabolites. Here, we have developed a novel quantitative metabolomic approach based on stable isotope dilution to compare the complement of siderophores produced by Escherichia coli strains associated with intestinal colonization or urinary tract disease. Because uropathogenic E. coli are believed to reside in the gut microbiome prior to infection, we compared siderophore production between urinary and rectal isolates within individual patients with recurrent UTI. While all strains produced enterobactin, strong preferential expression of the siderophores yersiniabactin and salmochelin was observed among urinary strains. Conventional PCR genotyping of siderophore receptors was often insensitive to these differences. A linearized enterobactin siderophore was also identified as a product of strains with an active salmochelin gene cluster. These findings argue that qualitative and quantitative epi-genetic optimization occurs in the E. coli secondary metabolome among human uropathogens. Because the virulence-associated biosynthetic pathways are distinct from those associated with rectal colonization, these results suggest strategies for virulence-targeted therapies

EST Analysis of Ostreococcus lucimarinus, the Most Compact Eukaryotic Genome, Shows an Excess of Introns in Highly Expressed Genes

Background: The genome of the pico-eukaryotic (bacterial-sized) prasinophyte green alga Ostreococcus lucimarinus has one of the highest gene densities known in eukaryotes, yet it contains many introns. Phylogenetic studies suggest this unusually compact genome (13.2 Mb) is an evolutionarily derived state among prasinophytes. The presence of introns in the highly reduced O. lucimarinus genome appears to be in opposition to simple explanations of genome evolution based on unidirectional tendencies, either neutral or selective. Therefore, patterns of intron retention in this species can potentially provide insights into the forces governing intron evolution. Methodology/Principal Findings: Here we studied intron features and levels of expression in O. lucimarinus using expressed sequence tags (ESTs) to annotate the current genome assembly. ESTs were assembled into unigene clusters that were mapped back to the O. lucimarinus Build 2.0 assembly using BLAST and the level of gene expression was inferred from the number of ESTs in each cluster. We find a positive correlation between expression levels and both intron number (R = +0.0893, p =,0.0005) and intron density (number of introns/kb of CDS; R = +0.0753, p =,0.005). Conclusions/Significance: In a species with a genome that has been recently subjected to a great reduction of non-coding DNA, these results imply the existence of selective/functional roles for introns that are principally detectable in highly expressed genes. In these cases, introns are likely maintained by balancing the selective forces favoring their maintenanc

Cranial Growth and Variation in Edmontosaurs (Dinosauria: Hadrosauridae): Implications for Latest Cretaceous Megaherbivore Diversity in North America

The well-sampled Late Cretaceous fossil record of North America remains the only high-resolution dataset for evaluating patterns of dinosaur diversity leading up to the terminal Cretaceous extinction event. Hadrosaurine hadrosaurids (Dinosauria: Ornithopoda) closely related to Edmontosaurus are among the most common megaherbivores in latest Campanian and Maastrichtian deposits of western North America. However, interpretations of edmontosaur species richness and biostratigraphy have been in constant flux for almost three decades, although the clade is generally thought to have undergone a radiation in the late Maastrichtian. We address the issue of edmontosaur diversity for the first time using rigorous morphometric analyses of virtually all known complete edmontosaur skulls. Results suggest only two valid species, Edmontosaurus regalis from the late Campanian, and E. annectens from the late Maastrichtian, with previously named taxa, including the controversial Anatotitan copei, erected on hypothesized transitional morphologies associated with ontogenetic size increase and allometric growth. A revision of North American hadrosaurid taxa suggests a decrease in both hadrosaurid diversity and disparity from the early to late Maastrichtian, a pattern likely also present in ceratopsid dinosaurs. A decline in the disparity of dominant megaherbivores in the latest Maastrichtian interval supports the hypothesis that dinosaur diversity decreased immediately preceding the end Cretaceous extinction event

Contributions of high- and low-quality patches to a metapopulation with stochastic disturbance

© The Author(s), 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Theoretical Ecology 5 (2012): 167-179, doi:10.1007/s12080-010-0106-9.Studies of time-invariant matrix metapopulation models indicate that metapopulation growth rate is usually more sensitive to the vital rates of individuals in high-quality (i.e., good) patches than in low-quality (i.e., bad) patches. This suggests that, given a choice, management efforts should focus on good rather than bad patches. Here, we examine the sensitivity of metapopulation growth rate for a two-patch matrix metapopulation model with and without stochastic disturbance and found cases where managers can more efficiently increase metapopulation growth rate by focusing efforts on the bad patch. In our model, net reproductive rate differs between the two patches so that in the absence of dispersal, one patch is high quality and the other low quality. Disturbance, when present, reduces net reproductive rate with equal frequency and intensity in both patches. The stochastic disturbance model gives qualitatively similar results to the deterministic model. In most cases, metapopulation growth rate was elastic to changes in net reproductive rate of individuals in the good patch than the bad patch. However, when the majority of individuals are located in the bad patch, metapopulation growth rate can be most elastic to net reproductive rate in the bad patch. We expand the model to include two stages and parameterize the patches using data for the softshell clam, Mya arenaria. With a two-stage demographic model, the elasticities of metapopulation growth rate to parameters in the bad patch increase, while elasticities to the same parameters in the good patch decrease. Metapopulation growth rate is most elastic to adult survival in the population of the good patch for all scenarios we examine. If the majority of the metapopulation is located in the bad patch, the elasticity to parameters of that population increase but do not surpass elasticity to parameters in the good patch. This model can be expanded to include additional patches, multiple stages, stochastic dispersal, and complex demography.Financial support was provided by the Woods Hole Oceanographic Institution Academic Programs Office; National Science Foundation grants OCE-0326734, OCE- 0215905, OCE-0349177, DEB-0235692, DEB-0816514, DMS- 0532378, OCE-1031256, and ATM-0428122; and by National Oceanic and Atmospheric Administration National Sea Grant College Program Office, Department of Commerce, under Grant No. NA86RG0075 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-32), and Grant No. NA16RG2273 (Woods Hole Oceanographic Institution Sea Grant Project No. R/0-35)

Nutritional and environmental regulation of the synthesis of highly unsaturated fatty acids and of fatty-acid oxidation in Atlantic salmon (Salmo salar L.) enterocytes and hepatocytes

The aim was to determine if highly unsaturated fatty acid (HUFA) synthesis and fatty acid oxidation in Atlantic salmon (Salmo salar L.) intestine was under environmental and/or seasonal regulation. Triplicate groups of salmon were grown through a full two-year cycle on two diets containing either fish oil (FO), or a diet with 75% of the FO replaced by a vegetable oil (VO) blend containing rapeseed, palm and linseed oils. At key points in the life cycle, fatty acyl desaturation/elongation (HUFA synthesis) and oxidation activities were determined in enterocytes and hepatocytes using [1-14C]18:3n-3 as substrate. As observed previously, HUFA synthesis in hepatocytes showed peak activity at seawater transfer and declined thereafter, with activity consistently greater in fish fed the VO diet. In fish fed FO, HUFA synthesis in enterocytes in the freshwater stage was at a similar level to that in hepatocytes. However, HUFA synthesis in enterocytes increased rapidly after seawater transfer and remained high for some months after transfer before decreasing to levels that were again similar to those observed in hepatocytes. Generally, enterocyte HUFA synthesis was higher in fish fed the VO diet compared to the FO diet. Oxidation of [1-14C]18:3n-3 in hepatocytes from fish fed FO tended to decrease during the freshwater phase but then increased steeply, peaking just after transfer before decreasing during the remaining seawater phase. At the peak in oxidation activity around seawater transfer, activity was significantly lower in fish fed VO compared to fish fed FO. In enterocytes, oxidation of [1-14C]18:3 in fish fed FO showed a peak in activity just prior to seawater transfer. In fish fed VO, other than high activity at 9 months, the pattern was similar to that obtained in enterocytes from fish fed FO with a high activity around seawater transfer and declining activity in seawater. In conclusion, fatty acid metabolism in intestinal cells appeared to be under dual nutritional and environmental or seasonal regulation. The temporal patterns for fatty acid oxidation were generally similar in the two cell types, but HUFA synthesis in enterocytes peaked over the summer seawater phase rather than at transfer, as with hepatocytes, suggesting possibly different regulatory cues