New Toxoplasma gondii genotypes isolated from free-range chickens from the Fernando de Noronha, Brazil: unexpected findings

USDA-ARS?s Scientific Manuscript database

Worldwide comparison of Toxoplasma gondii isolates from free range chickens has indicated that T. gondii isolates from Brazil are phenotypically and genetically different than isolates from other countries; most strains from Brazil are pathogenic to mice, there is great genetic variability, most iso...

Unexpected consequences of genetic selection in broilers and turkeys: problems and solutions.

PubMed

Hocking, P M

2014-02-01

1. Genetic theory leads to the expectation that unexpected consequences of genetic selection for production traits will inevitably occur and that these changes are likely to be undesirable. 2. Both artificial selection for production efficiency and "natural" selection for adaptation to the production environment result in selection sweeps that increase the frequencies of rare recessive alleles that have a negative effect on fitness. 3. Fitness is broadly defined as any trait that affects the ability to survive, reproduce and contribute to the next generation, such as musculoskeletal disease in growing broiler chickens and multiple ovulation in adult broiler parents. 4. Welfare concerns about the negative effects of genetic selection on bird welfare are sometimes exaggerated but are nevertheless real. Breeders have paid increasing attention to these traits over several decades and have demonstrated improvement in pedigree flocks. There is an urgent need to monitor changes in commercial flocks to ensure that genetic change is accompanied by improvements in that target population. 5. New technologies for trait measurement, whole genome selection and targeted genetic modification hold out the promise of efficient and rapid improvement of welfare traits in future breeding of broiler chickens and turkeys. The potential of targeted genetic modification for enhancing welfare traits is considerable, but the goal of achieving public acceptability for the progeny of transgenic poultry will be politically challenging.

Genetic structure and seed-mediated dispersal rates of an endangered shrub in a fragmented landscape: a case study for Juniperus communis in northwestern Europe

PubMed Central

2011-01-01

Background Population extinction risk in a fragmented landscape is related to the differential ability of the species to spread its genes across the landscape. The impact of landscape fragmentation on plant population dynamics will therefore vary across different spatial scales. We quantified successful seed-mediated dispersal of the dioecious shrub Juniperus communis in a fragmented landscape across northwestern Europe by using amplified fragment length polymorphism (AFLP) markers. Furthermore we investigated the genetic diversity and structure on two spatial scales: across northwestern Europe and across Flanders (northern Belgium). We also studied whether seed viability and populations size were correlated with genetic diversity. Results Unexpectedly, estimated seed-mediated dispersal rates were quite high and ranged between 3% and 14%. No population differentiation and no spatial genetic structure were detected on the local, Flemish scale. A significant low to moderate genetic differentiation between populations was detected at the regional, northwest European scale (PhiPT = 0.10). In general, geographically nearby populations were also genetically related. High levels of within-population genetic diversity were detected but no correlation was found between any genetic diversity parameter and population size or seed viability. Conclusions In northwestern Europe, landscape fragmentation has lead to a weak isolation-by-distance pattern but not to genetic impoverishment of common juniper. Substantial rates of successful migration by seed-mediated gene flow indicate a high dispersal ability which could enable Juniperus communis to naturally colonize suitable habitats. However, it is not clear whether the observed levels of migration will suffice to counterbalance the effects of genetic drift in small populations on the long run. PMID:21859457

Genetic structure and seed-mediated dispersal rates of an endangered shrub in a fragmented landscape: a case study for Juniperus communis in northwestern Europe.

PubMed

Vanden-Broeck, An; Gruwez, Robert; Cox, Karen; Adriaenssens, Sandy; Michalczyk, Inga M; Verheyen, Kris

2011-08-22

Population extinction risk in a fragmented landscape is related to the differential ability of the species to spread its genes across the landscape. The impact of landscape fragmentation on plant population dynamics will therefore vary across different spatial scales. We quantified successful seed-mediated dispersal of the dioecious shrub Juniperus communis in a fragmented landscape across northwestern Europe by using amplified fragment length polymorphism (AFLP) markers. Furthermore we investigated the genetic diversity and structure on two spatial scales: across northwestern Europe and across Flanders (northern Belgium). We also studied whether seed viability and populations size were correlated with genetic diversity. Unexpectedly, estimated seed-mediated dispersal rates were quite high and ranged between 3% and 14%. No population differentiation and no spatial genetic structure were detected on the local, Flemish scale. A significant low to moderate genetic differentiation between populations was detected at the regional, northwest European scale (PhiPT = 0.10). In general, geographically nearby populations were also genetically related. High levels of within-population genetic diversity were detected but no correlation was found between any genetic diversity parameter and population size or seed viability. In northwestern Europe, landscape fragmentation has lead to a weak isolation-by-distance pattern but not to genetic impoverishment of common juniper. Substantial rates of successful migration by seed-mediated gene flow indicate a high dispersal ability which could enable Juniperus communis to naturally colonize suitable habitats. However, it is not clear whether the observed levels of migration will suffice to counterbalance the effects of genetic drift in small populations on the long run.

High unexpected genetic diversity of a narrow endemic terrestrial mollusc

PubMed Central

Madeira, Pedro M.; Chefaoui, Rosa M.; Cunha, Regina L.; Moreira, Francisco; Dias, Susana; Calado, Gonçalo

2017-01-01

The Iberian Peninsula has an extensive record of species displaying strong genetic structure as a result of their survival in isolated pockets throughout the Pleistocene ice ages. We used mitochondrial and nuclear sequence data to analyze phylogeographic patterns in endemic land snails from a valley of central Portugal (Vale da Couda), putatively assigned to Candidula coudensis, that show an exceptionally narrow distributional range. The genetic survey presented here shows the existence of five main mitochondrial lineages in Vale da Couda that do not cluster together suggesting independent evolutionary histories. Our results also indicate a departure from the expectation that species with restricted distributions have low genetic variability. The putative past and contemporary models of geographic distribution of Vale da Couda lineages are compatible with a scenario of species co-existence in more southern locations during the last glacial maximum (LGM) followed by a post-LGM northern dispersal tracking the species optimal thermal, humidity and soil physical conditions. PMID:28321363

Genetic selection for a highly functional cysteine-less membrane protein using site-saturation mutagenesis

PubMed Central

Arendt, Cassandra S.; Ri, Keirei; Yates, Phillip A.; Ullman, Buddy

2007-01-01

We describe an efficient method for generating highly functional membrane proteins with variant amino acids at defined positions that couples a modified site-saturation strategy with functional genetic selection. We applied this method to the production of a cysteine-less variant of the Crithidia fasciculata inosine-guanosine permease CfNT2, in order to facilitate biochemical studies using thiol-specific modifying reagents. Of ten endogenous cysteine residues in CfNT2, two cannot be replaced with serine or alanine without loss of function. High-quality single- and double-mutant libraries were produced by combining a previously reported site-saturation mutagenesis scheme based on the Quikchange method with a novel gel purification step that effectively eliminated template DNA from the products. Following selection for functional complementation in S. cerevisiae cells auxotrophic for purines, several highly functional non-cysteine substitutions were efficiently identified at each desired position, allowing the construction of cysteine-less variants of CfNT2 that retained wild-type affinity for inosine. This combination of an improved site-saturation mutagenesis technique and positive genetic selection provides a simple and efficient means to identify functional and perhaps unexpected amino acid variants at a desired position. PMID:17481563

Hereditary breast/ovarian cancer--pitfalls in genetic counseling.

PubMed

Dagan, E; Gershoni-Baruch, R

2001-10-01

Genetic counseling and risk assessment, given to women with a family history of breast/ovarian cancer, are regularly based on pedigree analysis. In the Ashkenazi Jewish population, hereditary breast/ovarian cancer is mainly attributed to three founder mutations, namely, 185delAG, 5382insC, and 6174delT, in BRCA1/2 genes. The overall frequency of these mutations, in the Jewish Ashkenazi population, is as high as 2.5%. Based on clinical and family history data, the results of BRCA molecular testing, in Ashkenazi individuals at risk, are appropriately anticipated in most cases. Here we report on five families, in which the segregation of BRCA1/2 mutations, in affected and unaffected family members, was unexpected, emphasizing the need to test, for founder mutations, every Ashkenazi individual at risk, irrespective of the genotype of affected family members. Ultimately, risk assessments and recommendations, in Ashkenazi women, should be invariably based on the results of genetic testing.

The domestication and evolutionary ecology of apples.

PubMed

Cornille, Amandine; Giraud, Tatiana; Smulders, Marinus J M; Roldán-Ruiz, Isabel; Gladieux, Pierre

2014-02-01

The cultivated apple is a major fruit crop in temperate zones. Its wild relatives, distributed across temperate Eurasia and growing in diverse habitats, represent potentially useful sources of diversity for apple breeding. We review here the most recent findings on the genetics and ecology of apple domestication and its impact on wild apples. Genetic analyses have revealed a Central Asian origin for cultivated apple, together with an unexpectedly large secondary contribution from the European crabapple. Wild apple species display strong population structures and high levels of introgression from domesticated apple, and this may threaten their genetic integrity. Recent research has revealed a major role of hybridization in the domestication of the cultivated apple and has highlighted the value of apple as an ideal model for unraveling adaptive diversification processes in perennial fruit crops. We discuss the implications of this knowledge for apple breeding and for the conservation of wild apples. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of Linkage Disequilibrium on the Identification of Functional Variants

PubMed Central

Thomas, Alun; Abel, Haley J; Di, Yanming; Faye, Laura L; Jin, Jing; Liu, Jin; Wu, Zheyan; Paterson, Andrew D

2011-01-01

We summarize the contributions of Group 9 of Genetic Analysis Workshop 17. This group addressed the problems of linkage disequilibrium and other longer range forms of allelic association when evaluating the effects of genotypes on phenotypes. Issues raised by long-range associations, whether a result of selection, stratification, possible technical errors, or chance, were less expected but proved to be important. Most contributors focused on regression methods of various types to illustrate problematic issues or to develop adaptations for dealing with high-density genotype assays. Study design was also considered, as was graphical modeling. Although no method emerged as uniformly successful, most succeeded in reducing false-positive results either by considering clusters of loci within genes or by applying smoothing metrics that required results from adjacent loci to be similar. Two unexpected results that questioned our assumptions of what is required to model linkage disequilibrium were observed. The first was that correlations between loci separated by large genetic distances can greatly inflate single-locus test statistics, and, whether the result of selection, stratification, possible technical errors, or chance, these correlations seem overabundant. The second unexpected result was that applying principal components analysis to genome-wide genotype data can apparently control not only for population structure but also for linkage disequilibrium. PMID:22128051

Widespread inbreeding and unexpected geographic patterns of genetic variation in eastern hemlock (Tsuga canadensis), an imperiled North American conifer

Treesearch

Kevin M. Potter; Robert M. Jetton; William S. Dvorak; Valerie D. Hipkins; Rusty Rhea; W. Andrew Whittier

2012-01-01

Eastern hemlock (Tsuga canadensis [L.] Carr.) is an ecologically important tree species experiencing severe mortality across much of its eastern North American distribution, caused by infestation of the exotic hemlock woolly adelgid (Adelges tsugae Annand). To guide gene conservation strategies for this imperiled conifer, we conducted a range-wide genetic variation...

Mitochondrial genetic variability of Didelphis albiventris (Didelphimorphia, Didelphidae) in Brazilian localities

PubMed Central

Sousa, Luciene C.C.; Gontijo, Célia M.F.; Botelho, Helbert A.; Fonseca, Cleusa G.

2012-01-01

Didelphis albiventris is a well-known and common marsupial. Due to its high adaptability, this very widespread generalist species occurs under various environmental conditions, this even including protected regions and disturbed urban areas. We studied a 653 bp fragment of cytochrome oxidase c (COI) from 93 biological samples from seven Brazilian localities, with linear distances ranging between 58 and about 1800 km to analyze the effects of geographic distances on variability and genetic differentiation. The haplotype network presented nine haplotypes and two genetic clusters compatible with the two most distant geographic areas of the states of Minas Gerais, in the southeast, and Rio Grande do Sul, in the extreme south. As each cluster was characterized by low nucleotide and high haplotype diversities, their populations were obviously composed of closely related haplotypes. Surprisingly, moderate to high FST differentiation values and a very weak phylogeographic signal characterizes interpopulation comparisons within Minas Gerais interdemes, these being correlated with the presence of privative haplotypes. On a large rgeographic scale, a comparison between demes from Minas Gerais and Rio Grande do Sul presented high FST values and a robust phylogeographic pattern. This unexpected scenario implies that mtDNA gene flow was insufficient to maintain population cohesion, reflected by the observed high differentiation. PMID:22888303

Genetic variation of loci potentially under selection confounds species-genetic diversity correlations in a fragmented habitat.

PubMed

Bertin, Angeline; Gouin, Nicolas; Baumel, Alex; Gianoli, Ernesto; Serratosa, Juan; Osorio, Rodomiro; Manel, Stephanie

2017-01-01

Positive species-genetic diversity correlations (SGDCs) are often thought to result from the parallel influence of neutral processes on genetic and species diversity. Yet, confounding effects of non-neutral mechanisms have not been explored. Here, we investigate the impact of non-neutral genetic diversity on SGDCs in high Andean wetlands. We compare correlations between plant species diversity and genetic diversity (GD) calculated with and without loci potentially under selection (outlier loci). The study system includes 2188 specimens from five species (three common aquatic macroinvertebrate and two dominant plant species) that were genotyped for 396 amplified fragment length polymorphism loci. We also appraise the importance of neutral processes on SGDCs by investigating the influence of habitat fragmentation features. Significant positive SGDCs were detected for all five species (mean SGDC = 0.52 ± 0.05). While only a few outlier loci were detected in each species, they resulted in significant decreases in GD and in SGDCs. This supports the hypothesis that neutral processes drive species-genetic diversity relationships in high Andean wetlands. Unexpectedly, the effects on genetic diversity GD of the habitat fragmentation characteristics in this study increased with the presence of outlier loci in two species. Overall, our results reveal pitfalls in using habitat features to infer processes driving SGDCs and show that a few loci potentially under selection are enough to cause a significant downward bias in SGDC. Investigating confounding effects of outlier loci thus represents a useful approach to evidence the contribution of neutral processes on species-genetic diversity relationships. © 2016 John Wiley & Sons Ltd.

Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma.

PubMed

Orlando, Domenico; Miele, Evelina; De Angelis, Biagio; Guercio, Marika; Boffa, Iolanda; Sinibaldi, Matilde; Po, Agnese; Caruana, Ignazio; Abballe, Luana; Carai, Andrea; Caruso, Simona; Camera, Antonio; Moseley, Annemarie; Hagedoorn, Renate S; Heemskerk, Mirjam H M; Giangaspero, Felice; Mastronuzzi, Angela; Ferretti, Elisabetta; Locatelli, Franco; Quintarelli, Concetta

2018-04-03

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients. Copyright ©2018, American Association for Cancer Research.

Microsatellite marker analysis of the genetic variability in Hanoverian Hounds.

PubMed

Lüpke, L; Distl, O

2005-04-01

Genetic variability of the dog breed Hanoverian Hound was analysed using a set of 16 microsatellites. The sample of 92 dogs was representative for the total current population [n=334, inbreeding coefficient 9.2%, relationship coefficient 11.2%] with respect to the level and distribution of the inbreeding and relationship coefficients. All microsatellites used were in Hardy-Weinberg equilibrium. The average number of alleles was 6.4. The average observed heterozygosity (H(O)) was slightly higher than the expected heterozygosity (H(E)). Dinucleotide microsatellites exhibited lower polymorphism information content (PIC) than tetranucleotide microsatellites (0.52 versus 0.66). The average PIC was 0.61. The individual inbreeding coefficient was negatively related to the average H(O) of all microsatellites, whereas the proportion of genes from introducing of Hanoverian Hounds from abroad showed no relationships to H(O). We found that the genetic variability in the Hanoverian Hounds analysed here was unexpectedly higher than that previously published for dog breeds of similar population size. Even in dog breeds of larger population size heterogyzosity was seldom higher than that observed here. The rather high genetic variability as quantified by polymorphic microsatellites in Hanoverian Hounds may be due to a large genetic variation in the founder animals of this breed and to the fact that this genetic diversity could be maintained despite genetic bottlenecks experienced by this breed in the 1920s and 1950s and despite the presence of high inbreeding and relationship coefficients for more than 50 years.

Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention.

PubMed

Goldman, Alica M; Behr, Elijah R; Semsarian, Christopher; Bagnall, Richard D; Sisodiya, Sanjay; Cooper, Paul N

2016-01-01

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Implications of nonadventitious rhizome spread on reproduction, inbreeding, and conservation for a rare grassland legume.

PubMed

Severns, Paul M; Liston, Aaron; Wilson, Mark V

2011-01-01

Small population size, genetic diversity, and spatial patterns of vegetative spread are important aspects to consider when managing populations of rare clonal plant species. We used 5 variable nuclear simple sequence repeat nDNA loci to determine the extent of genet rhizome spread, examine the possibility of very small population sizes, and project how Bombus spp. (bumblebee) foraging may impact selfing (through geitonogamy) for a threatened lupine (Lupinus oreganus Heller) that sprawls through nonadventitious rhizomes. Genotyping identified 1 genet (27 × 13 m) that dominated about 30% of a study site, whereas 15 genets spread a maximum average distance of about 5.5 m (range 1.6 -27.1 m) and appeared to be well integrated with intervening genets. We found unexpectedly high genotype diversity, no evidence of a recent genetic bottleneck, and 5 of 6 patches had mean fixation index values that were near Hardy-Weinberg Equilibrium expectations. If the median maximum Bombus foraging distance observed in lupine patches (1.2 m) occurred within genotyped populations, a typical foraging flight would have >80% chance of occurring between different genets. Our study demonstrates that inferences associated with clonality, small population size, and inbreeding depression should be directly evaluated for rare vegetatively spreading plants.

Hybridization Leads to Loss of Genetic Integrity in Shortleaf Pine: Unexpected Consequences of Pine Management and Fire Suppression

Treesearch

Charles G. Tauer; John F. Stewart; Rodney E. Will; Curtis J. Lilly; James M. Guldin; C. Dana Nelson

2012-01-01

Hybridization between shortleaf pine and loblolly pine is causing loss of genetic integrity (the tendency of a population to maintain its genotypes over generations) in shortleaf pine, a species already exhibiting dramatic declines due to land-use changes. Recent findings indicate hybridization has increased in shortleaf pine stands from 3% during the 1950s to 45% for...

Unexpectedly Low Rangewide Population Genetic Structure of the Imperiled Eastern Box Turtle Terrapene c. carolina

PubMed Central

Kimble, Steven J. A.; Rhodes Jr., O. E.; Williams, Rod N.

2014-01-01

Rangewide studies of genetic parameters can elucidate patterns and processes that operate only over large geographic scales. Herein, we present a rangewide population genetic assessment of the eastern box turtle Terrapene c. carolina, a species that is in steep decline across its range. To inform conservation planning for this species, we address the hypothesis that disruptions to demographic and movement parameters associated with the decline of the eastern box turtle has resulted in distinctive genetic signatures in the form of low genetic diversity, high population structuring, and decreased gene flow. We used microsatellite genotype data from (n = 799) individuals from across the species range to perform two Bayesian population assignment approaches, two methods for comparing historical and contemporary migration among populations, an evaluation of isolation by distance, and a method for detecting barriers to gene flow. Both Bayesian methods of population assignment indicated that there are two populations rangewide, both of which have maintained high levels of genetic diversity (HO = 0.756). Evidence of isolation by distance was detected in this species at a spatial scale of 300 – 500 km, and the Appalachian Mountains were identified as the primary barrier to gene flow across the species range. We also found evidence for historical but not contemporary migration between populations. Our prediction of many, highly structured populations across the range was not supported. This may point to cryptic contemporary gene flow, which might in turn be explained by the presence of rare transients in populations. However these data may be influenced by historical signatures of genetic connectivity because individuals of this species can be long-lived. PMID:24647580

New product trial, use of edibles, and unexpected highs among marijuana and hashish users in Colorado.

PubMed

Allen, Jane A; Davis, Kevin C; Duke, Jennifer C; Nonnemaker, James M; Bradfield, Brian R; Farrelly, Matthew C

2017-07-01

This study examines the relationships between trial of new marijuana or hashish products and unexpected highs, and use of edible products and unexpected highs. We conducted an online survey of 634 adult, past-year marijuana users in Colorado. We used logistic regression models to examine the relationship between new product trial or edible use and unexpected highs. In the first year that recreational marijuana was legal in Colorado, 71.4% of respondents tried a new marijuana or hashish product, and 53.6% used an edible product. Trial of new products was associated with greater odds of experiencing an unexpected high after controlling for age, gender, education, mental health status, current marijuana or hashish use, and mean amount of marijuana or hashish consumed in the past month (OR=2.13, p<0.001). Individuals who reported having used edibles had greater odds of experiencing an unexpected high, after controlling for the same set of variables (OR=1.56, p<0.05). People who try new marijuana or hashish products, or use edible marijuana or hashish products, are at greater risk for an unexpected high. It is possible that some negative outcomes associated with marijuana use and unexpected highs may be averted through a better understanding of how to use product packaging to communicate with consumers. Copyright © 2017 Elsevier B.V. All rights reserved.

High interpopulation homogeneity in Central Argentina as assessed by Ancestry Informative Markers (AIMs)

PubMed Central

García, Angelina; Dermarchi, Darío A.; Tovo-Rodrigues, Luciana; Pauro, Maia; Callegari-Jacques, Sidia M.; Salzano, Francisco M.; Hutz, Mara H.

2015-01-01

The population of Argentina has already been studied with regard to several genetic markers, but much more data are needed for the appropriate definition of its genetic profile. This study aimed at investigating the admixture patterns and genetic structure in Central Argentina, using biparental markers and comparing the results with those previously obtained by us with mitochondrial DNA (mtDNA) in the same samples. A total of 521 healthy unrelated individuals living in 13 villages of the Córdoba and San Luis provinces were tested. The individuals were genotyped for ten autosomal ancestry informative markers (AIMs). Allele frequencies were compared with those of African, European and Native American populations, chosen to represent parental contributions. The AIM estimates indicated a greater influence of the Native American ancestry as compared to previous studies in the same or other Argentinean regions, but smaller than that observed with the mtDNA tests. These differences can be explained, respectively, by different genetic contributions between rural and urban areas, and asymmetric gene flow occurred in the past. But a most unexpected finding was the marked interpopulation genetic homogeneity found in villages located in diverse geographic environments across a wide territory, suggesting considerable gene flow. PMID:26500436

Mitochondrial DNA variability among eight Tikúna villages: evidence for an intratribal genetic heterogeneity pattern.

PubMed

Mendes-Junior, Celso Teixeira; Simões, Aguinaldo Luiz

2009-11-01

To study the genetic structure of the Tikúna tribe, four major Native American mitochondrial DNA (mtDNA) founder haplogroups were analyzed in 187 Amerindians from eight Tikúna villages located in the Brazilian Amazon. The central position of these villages in the continent makes them relevant for attempts to reconstruct population movements in South America. In this geographic region, there is particular concern regarding the genetic structure of the Tikúna tribe, formerly designated "enigmatic" due to its remarkable degree of intratribal homogeneity and the scarcity of private protein variants. In spite of its large population size and geographic distribution, the Tikúna tribe presents marked genetic and linguistic isolation. All individuals presented indigenous mtDNA haplogroups. An intratribal genetic heterogeneity pattern characterized by two highly homogeneous Tikúna groups that differ considerably from each other was observed. Such a finding was unexpected, since the Tikúna tribe is characterized by a social system that favors intratribal exogamy and patrilocality that would lead to a higher female migration rate and homogenization of the mtDNA gene pool. Demographic explosions and religious events, which significantly changed the sizes and compositions of many Tikúna villages, may be reflected in the genetic results presented here.

Spatial genetic structuring of baobab (Adansonia digitata, Malvaceae) in the traditional agroforestry systems of West Africa.

PubMed

Kyndt, Tina; Assogbadjo, Achille E; Hardy, Olivier J; Glele Kakaï, Romain; Sinsin, Brice; Van Damme, Patrick; Gheysen, Godelieve

2009-05-01

This study evaluates the spatial genetic structure of baobab (Adansonia digitata) populations from West African agroforestry systems at different geographical scales using AFLP fingerprints. Eleven populations from four countries (Benin, Ghana, Burkina Faso, and Senegal) had comparable levels of genetic diversity, although the two populations in the extreme west (Senegal) had less diversity. Pairwise F(ST) ranged from 0.02 to 0.28 and increased with geographic distance, even at a regional scale. Gene pools detected by Bayesian clustering seem to be a byproduct of the isolation-by-distance pattern rather than representing actual discrete entities. The organization of genetic diversity appears to result essentially from spatially restricted gene flow, with some influences of human seed exchange. Despite the potential for relatively long-distance pollen and seed dispersal by bats within populations, statistically significant spatial genetic structuring within populations (SGS) was detected and gave a mean indirect estimate of neighborhood size of ca. 45. This study demonstrated that relatively high levels of genetic structuring are present in baobab at both large and within-population level, which was unexpected in regard to its dispersal by bats and the influence of human exchange of seeds. Implications of these results for the conservation of baobab populations are discussed.

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

PubMed

Fujita, Naonobu; Huang, Wilson; Lin, Tzu-Han; Groulx, Jean-Francois; Jean, Steve; Nguyen, Jen; Kuchitsu, Yoshihiko; Koyama-Honda, Ikuko; Mizushima, Noboru; Fukuda, Mitsunori; Kiger, Amy A

2017-01-07

Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.

PubMed

Leu, Costin; Balestrini, Simona; Maher, Bridget; Hernández-Hernández, Laura; Gormley, Padhraig; Hämäläinen, Eija; Heggeli, Kristin; Schoeler, Natasha; Novy, Jan; Willis, Joseph; Plagnol, Vincent; Ellis, Rachael; Reavey, Eleanor; O'Regan, Mary; Pickrell, William O; Thomas, Rhys H; Chung, Seo-Kyung; Delanty, Norman; McMahon, Jacinta M; Malone, Stephen; Sadleir, Lynette G; Berkovic, Samuel F; Nashef, Lina; Zuberi, Sameer M; Rees, Mark I; Cavalleri, Gianpiero L; Sander, Josemir W; Hughes, Elaine; Helen Cross, J; Scheffer, Ingrid E; Palotie, Aarno; Sisodiya, Sanjay M

2015-09-01

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

PubMed Central

Leu, Costin; Balestrini, Simona; Maher, Bridget; Hernández-Hernández, Laura; Gormley, Padhraig; Hämäläinen, Eija; Heggeli, Kristin; Schoeler, Natasha; Novy, Jan; Willis, Joseph; Plagnol, Vincent; Ellis, Rachael; Reavey, Eleanor; O'Regan, Mary; Pickrell, William O.; Thomas, Rhys H.; Chung, Seo-Kyung; Delanty, Norman; McMahon, Jacinta M.; Malone, Stephen; Sadleir, Lynette G.; Berkovic, Samuel F.; Nashef, Lina; Zuberi, Sameer M.; Rees, Mark I.; Cavalleri, Gianpiero L.; Sander, Josemir W.; Hughes, Elaine; Helen Cross, J.; Scheffer, Ingrid E.; Palotie, Aarno; Sisodiya, Sanjay M.

2015-01-01

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10− 3) and non-epilepsy disease controls (P = 1.2 × 10− 3). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP. PMID:26501104

[Ethical guidelines on genetic testing and gene therapy].

PubMed

Fukushima, Yoshimitsu

2005-03-01

According to the recent and rapid advances in molecular genetics research, genetic testing and gene therapy have a potential of giving unexpected influence to the human beings. To prevent and to solve various ethical, legal and social implementations (ELSI) of genetic testing and gene therapy, several guidelines have been established. In Japan, all researchers and all clinicians have to know and keep the following three guidelines on genetic testing and a guideline on gene therapy: 1) "Guidelines for Researches on Human Genome and Gene (2001)" by the three Ministries (Education, Health and Economy), 2) "Guidelines for Genetic Testing (2001)" by the Genetic--medicine--related 10 societies, 3) "Ethical Principles on Entrusted Genetic Testing (2001)" by the Japan Registered Clinical Laboratories Association, and 4) "Guidelines for Clinical Research on Gene Therapy (2002)" by the two Ministries (Health and Education).

Gene flow on ice: the role of sea ice and whaling in shaping Holarctic genetic diversity and population differentiation in bowhead whales (Balaena mysticetus)

PubMed Central

Elizabeth Alter, S; Rosenbaum, Howard C; Postma, Lianne D; Whitridge, Peter; Gaines, Cork; Weber, Diana; Egan, Mary G; Lindsay, Melissa; Amato, George; Dueck, Larry; Brownell, Robert L; Heide-Jørgensen, Mads-Peter; Laidre, Kristin L; Caccone, Gisella; Hancock, Brittany L

2012-01-01

Sea ice is believed to be a major factor shaping gene flow for polar marine organisms, but it remains unclear to what extent it represents a true barrier to dispersal for arctic cetaceans. Bowhead whales are highly adapted to polar sea ice and were targeted by commercial whalers throughout Arctic and subarctic seas for at least four centuries, resulting in severe reductions in most areas. Both changing ice conditions and reductions due to whaling may have affected geographic distribution and genetic diversity throughout their range, but little is known about range-wide genetic structure or whether it differed in the past. This study represents the first examination of genetic diversity and differentiation across all five putative stocks, including Baffin Bay-Davis Strait, Hudson Bay-Foxe Basin, Bering-Beaufort-Chukchi, Okhotsk, and Spitsbergen. We also utilized ancient specimens from Prince Regent Inlet (PRI) in the Canadian Arctic and compared them with modern stocks. Results from analysis of molecular variance and demographic simulations are consistent with recent and high gene flow between Atlantic and Pacific stocks in the recent past. Significant genetic differences between ancient and modern populations suggest PRI harbored unique maternal lineages in the past that have been recently lost, possibly due to loss of habitat during the Little Ice Age and/or whaling. Unexpectedly, samples from this location show a closer genetic relationship with modern Pacific stocks than Atlantic, supporting high gene flow between the central Canadian Arctic and Beaufort Sea over the past millennium despite extremely heavy ice cover over much of this period. PMID:23170222

Spatial patterns of AFLP diversity in Bulbophyllum occultum (Orchidaceae) indicate long-term refugial isolation in Madagascar and long-distance colonization effects in La Réunion.

PubMed

Jaros, U; Fischer, G A; Pailler, T; Comes, H P

2016-05-01

Bulbophyllum occultum, an epiphytic orchid mainly distributed in the rainforests of (north)eastern Madagascar and La Réunion, represents an interesting model case for testing the effects of anthropogenic vs historical (e.g., climate induced) habitat isolation and long-distance colonization on the genetic structure of plant species with disjunct distributions in the Madagascan region. To this aim, we surveyed amplified fragment length polymorphisms (AFLPs) across 13 populations in Madagascar and nine in La Réunion (206 individuals in total). We found overall high levels of population subdivision (Φ(PT)=0.387) and low within-population diversity (H(E), range: 0.026-0.124), indicating non-equilibrium conditions in a mainly selfing species. There was no impact of recent deforestation (Madagascar) or habitat disturbance (La Réunion) detectable on AFLP diversity. K-means clustering and BARRIER analyses identified multiple gene pools and several genetic breaks, both within and among islands. Inter-island levels of population genetic diversity and subdivision were similar, whereby inter-individual divergence in flower colour explained a significant part of gene pool divergence in La Réunion. Our results suggest that (i) B. occultum persisted across multiple isolated ('refugial') regions along the eastern rainforest corridor of Madagascar over recent climatic cycles and (ii) populations in La Réunion arose from either single or few independent introductions from Madagascar. High selfing rates and sufficient time for genetic drift likely promoted unexpectedly high population genetic and phenotypic (flower colour) differentiation in La Réunion. Overall, this study highlights a strong imprint of history on the genetic structure of a low-gene-dispersing epiphytic orchid from the Madagascan region.

Different gene expressions between cattle and yak provide insights into high-altitude adaptation.

PubMed

Wang, K; Yang, Y; Wang, L; Ma, T; Shang, H; Ding, L; Han, J; Qiu, Q

2016-02-01

DNA sequence variation has been widely reported as the genetic basis for adaptation, in both humans and other animals, to the hypoxic environment experienced at high altitudes. However, little is known about the patterns of gene expression underlying such hypoxic adaptations. In this study, we examined the differences in the transcriptomes of four organs (heart, kidney, liver and lung) between yak and cattle, a pair of closely related species distributed at high and low altitudes respectively. Of the four organs examined, heart shows the greatest differentiation between the two species in terms of gene expression profiles. Detailed analyses demonstrated that some genes associated with the oxygen supply system and the defense systems that respond to threats of hypoxia are differentially expressed. In addition, genes with significantly differentiated patterns of expression in all organs exhibited an unexpected uniformity of regulation along with an elevated frequency of nonsynonymous substitutions. This co-evolution of protein sequences and gene expression patterns is likely to be correlated with the optimization of the yak metabolic system to resist hypoxia. © 2015 Stichting International Foundation for Animal Genetics.

Physicians’ Perspectives on the Uncertainties and Implications of Chromosomal Microarray Testing of Children and Families

PubMed Central

Reiff, Marian; Ross, Kathryn; Mulchandani, Surabhi; Propert, Kathleen Joy; Pyeritz, Reed E.; Spinner, Nancy B.; Bernhardt, Barbara A.

2012-01-01

Chromosomal microarray analysis (CMA) has improved the diagnostic rate of genomic disorders in pediatric populations, but can produce uncertain and unexpected findings. This paper explores clinicians’ perspectives and identifies challenges in effectively interpreting results and communicating with families about CMA. Responses to an online survey were obtained from 40 clinicians who had ordered CMA. Content included practice characteristics and perceptions, and queries about a hypothetical case involving uncertain and incidental findings. Data were analyzed using non-parametric statistical tests. Clinicians’ comfort levels differed significantly for explaining uncertain, abnormal, and normal CMA results, with lowest levels for uncertain results. Despite clinical guidelines recommending informed consent, many clinicians did not consider it pertinent to discuss the potential for CMA to reveal information concerning biological parentage or predisposition to late-onset disease, in a hypothetical case. Many non-genetics professionals ordering CMA did not feel equipped to interpret the results for patients, and articulated needs for education and access to genetics professionals. This exploratory study highlights key challenges in the practice of genomic medicine, and identifies needs for education, disseminated practice guidelines, and access to genetics professionals, especially when dealing with uncertain or unexpected findings. PMID:22989118

Geographical parthenogenesis and population genetic structure in the alpine species Ranunculus kuepferi (Ranunculaceae).

PubMed

Cosendai, A-C; Wagner, J; Ladinig, U; Rosche, C; Hörandl, E

2013-06-01

Geographical parthenogenesis describes the enigmatic phenomenon that asexual organisms have larger distribution areas than their sexual relatives, especially in previously glaciated areas. Classical models suggest temporary advantages to asexuality in colonization scenarios because of uniparental reproduction and clonality. We analyzed population genetic structure and self-fertility of the plant species Ranunculus kuepferi on 59 populations from the whole distribution area (European Alps, Apennines and Corsica). Amplified fragment length polymorphisms (AFLPs) and five microsatellite loci revealed individual genotypes for all populations and mostly insignificant differences between diploid sexuals and tetraploid apomicts in all measures of genetic diversity. Low frequencies of private AFLP fragments/simple sequence repeat alleles, and character incompatibility analyses suggest that facultative recombination explains best the unexpectedly high genotypic diversity of apomicts. STRUCTURE analyses using AFLPs revealed a higher number of partitions and a stronger geographical subdivision for diploids than for tetraploids, which contradicts expectations of standard gene flow models, but indicates a reduction of genetic structure in asexuals. Apomictic populations exhibited high admixture near the sexual area, but appeared rather uniform in remote areas. Bagging experiments and analyses of pollen tube growth confirmed self-fertility for pollen-dependent apomicts, but self-sterility for diploid sexuals. Facultative apomixis combines advantages of both modes of reproduction: uniparental reproduction allows for rapid colonization of remote areas, whereas facultative sexuality and polyploidy maintains genetic diversity within apomictic populations. The density dependence of outcrossing limits range expansions of sexual populations.

Geographical parthenogenesis and population genetic structure in the alpine species Ranunculus kuepferi (Ranunculaceae)

PubMed Central

Cosendai, A-C; Wagner, J; Ladinig, U; Rosche, C; Hörandl, E

2013-01-01

Geographical parthenogenesis describes the enigmatic phenomenon that asexual organisms have larger distribution areas than their sexual relatives, especially in previously glaciated areas. Classical models suggest temporary advantages to asexuality in colonization scenarios because of uniparental reproduction and clonality. We analyzed population genetic structure and self-fertility of the plant species Ranunculus kuepferi on 59 populations from the whole distribution area (European Alps, Apennines and Corsica). Amplified fragment length polymorphisms (AFLPs) and five microsatellite loci revealed individual genotypes for all populations and mostly insignificant differences between diploid sexuals and tetraploid apomicts in all measures of genetic diversity. Low frequencies of private AFLP fragments/simple sequence repeat alleles, and character incompatibility analyses suggest that facultative recombination explains best the unexpectedly high genotypic diversity of apomicts. STRUCTURE analyses using AFLPs revealed a higher number of partitions and a stronger geographical subdivision for diploids than for tetraploids, which contradicts expectations of standard gene flow models, but indicates a reduction of genetic structure in asexuals. Apomictic populations exhibited high admixture near the sexual area, but appeared rather uniform in remote areas. Bagging experiments and analyses of pollen tube growth confirmed self-fertility for pollen-dependent apomicts, but self-sterility for diploid sexuals. Facultative apomixis combines advantages of both modes of reproduction: uniparental reproduction allows for rapid colonization of remote areas, whereas facultative sexuality and polyploidy maintains genetic diversity within apomictic populations. The density dependence of outcrossing limits range expansions of sexual populations. PMID:23403961

Population genomic analysis of elongated skulls reveals extensive female-biased immigration in Early Medieval Bavaria

PubMed Central

Veeramah, Krishna R.; Rott, Andreas; Groß, Melanie; López, Saioa; Kirsanow, Karola; Sell, Christian; Blöcher, Jens; Link, Vivian; Hofmanová, Zuzana; Peters, Joris; Trautmann, Bernd; Gairhos, Anja; Haberstroh, Jochen; Päffgen, Bernd; Hellenthal, Garrett; Haas-Gebhard, Brigitte; Harbeck, Michaela; Burger, Joachim

2018-01-01

Modern European genetic structure demonstrates strong correlations with geography, while genetic analysis of prehistoric humans has indicated at least two major waves of immigration from outside the continent during periods of cultural change. However, population-level genome data that could shed light on the demographic processes occurring during the intervening periods have been absent. Therefore, we generated genomic data from 41 individuals dating mostly to the late 5th/early 6th century AD from present-day Bavaria in southern Germany, including 11 whole genomes (mean depth 5.56×). In addition we developed a capture array to sequence neutral regions spanning a total of 5 Mb and 486 functional polymorphic sites to high depth (mean 72×) in all individuals. Our data indicate that while men generally had ancestry that closely resembles modern northern and central Europeans, women exhibit a very high genetic heterogeneity; this includes signals of genetic ancestry ranging from western Europe to East Asia. Particularly striking are women with artificial skull deformations; the analysis of their collective genetic ancestry suggests an origin in southeastern Europe. In addition, functional variants indicate that they also differed in visible characteristics. This example of female-biased migration indicates that complex demographic processes during the Early Medieval period may have contributed in an unexpected way to shape the modern European genetic landscape. Examination of the panel of functional loci also revealed that many alleles associated with recent positive selection were already at modern-like frequencies in European populations ∼1,500 years ago. PMID:29531040

Landscape attributes and life history variability shape genetic structure of trout populations in a stream network

USGS Publications Warehouse

Neville, H.M.; Dunham, J.B.; Peacock, M.M.

2006-01-01

Spatial and temporal landscape patterns have long been recognized to influence biological processes, but these processes often operate at scales that are difficult to study by conventional means. Inferences from genetic markers can overcome some of these limitations. We used a landscape genetics approach to test hypotheses concerning landscape processes influencing the demography of Lahontan cutthroat trout in a complex stream network in the Great Basin desert of the western US. Predictions were tested with population- and individual-based analyses of microsatellite DNA variation, reflecting patterns of dispersal, population stability, and local effective population sizes. Complementary genetic inferences suggested samples from migratory corridors housed a mixture of fish from tributaries, as predicted based on assumed migratory life histories in those habitats. Also as predicted, populations presumed to have greater proportions of migratory fish or from physically connected, large, or high quality habitats had higher genetic variability and reduced genetic differentiation from other populations. Populations thought to contain largely non-migratory individuals generally showed the opposite pattern, suggesting behavioral isolation. Estimated effective sizes were small, and we identified significant and severe genetic bottlenecks in several populations that were isolated, recently founded, or that inhabit streams that desiccate frequently. Overall, this work suggested that Lahontan cutthroat trout populations in stream networks are affected by a combination of landscape and metapopulation processes. Results also demonstrated that genetic patterns can reveal unexpected processes, even within a system that is well studied from a conventional ecological perspective. ?? Springer 2006.

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin.

PubMed

Troggio, Michela; Surbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the 'Golden Delicious' genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies.

Unexpected Genetic Diversity among and within Populations of the Toxic Dinoflagellate Alexandrium catenella as Revealed by Nuclear Microsatellite Markers▿

PubMed Central

Masseret, Estelle; Grzebyk, Daniel; Nagai, Satoshi; Genovesi, Benjamin; Lasserre, Bernard; Laabir, Mohamed; Collos, Yves; Vaquer, André; Berrebi, Patrick

2009-01-01

Since 1998, blooms of Alexandrium catenella associated with paralytic shellfish poisoning have been repeatedly reported for Thau Lagoon (French Mediterranean coast). Based on data obtained for rRNA gene markers, it has been suggested that the strains involved could be closely related to the Japanese temperate Asian ribotype of the temperate Asian clade. In order to gain more insight into the origin of these organisms, we carried out a genetic analysis of 61 Mediterranean and 23 Japanese strains using both ribosomal and microsatellite markers. Whereas the phylogeny based on ribosomal markers tended to confirm the previous findings, the analysis of microsatellite sequences revealed an unexpected distinction between the French and Japanese populations. This analysis also highlighted great intraspecific diversity that was not detected with the classical rRNA gene markers. The Japanese strains are divided into two differentiated A. catenella lineages: the Sea of Japan lineage and the east coast lineage, which includes populations from the Inland Sea and the Pacific Ocean. A. catenella strains isolated from Thau Lagoon belong to another lineage. These findings indicate that microsatellite markers are probably better suited to investigations of the population genetics of this species that is distributed worldwide. Finally, application of the population genetics concepts available for macroorganisms could support new paradigms for speciation and migration in phytoplankton assemblages. PMID:19201972

Complex postglacial recolonization inferred from population genetic structure of mottled sculpin Cottus bairdii in tributaries of eastern Lake Michigan, U.S.A.

PubMed

Homola, J J; Ruetz, C R; Kohler, S L; Thum, R A

2016-11-01

This study used analyses of the genetic structure of a non-game fish species, the mottled sculpin Cottus bairdii to hypothesize probable recolonization routes used by cottids and possibly other Laurentian Great Lakes fishes following glacial recession. Based on samples from 16 small streams in five major Lake Michigan, U.S.A., tributary basins, significant interpopulation differentiation was documented (overall F ST = 0·235). Differentiation was complex, however, with unexpectedly high genetic similarity among basins as well as occasionally strong differentiation within basins, despite relatively close geographic proximity of populations. Genetic dissimilarities were identified between eastern and western populations within river basins, with similarities existing between eastern and western populations across basins. Given such patterns, recolonization is hypothesized to have occurred on three occasions from more than one glacial refugium, with a secondary vicariant event resulting from reduction in the water level of ancestral Lake Michigan. By studying the phylogeography of a small, non-game fish species, this study provides insight into recolonization dynamics of the region that could be difficult to infer from game species that are often broadly dispersed by humans. © 2016 The Fisheries Society of the British Isles.

Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity

PubMed Central

Andersen, Erik C.; Gerke, Justin P.; Shapiro, Joshua A.; Crissman, Jonathan R.; Ghosh, Rajarshi; Bloom, Joshua S.; Félix, Marie-Anne; Kruglyak, Leonid

2011-01-01

The nematode Caenorhabditis elegans is central to research in molecular, cell, and developmental biology, but nearly all of this research has been conducted on a single strain. Comparatively little is known about the population genomic and evolutionary history of this species. We characterized C. elegans genetic variation by high-throughput selective sequencing of a worldwide collection of 200 wild strains, identifying 41,188 single nucleotide polymorphisms. Unexpectedly, C. elegans genome variation is dominated by a set of commonly shared haplotypes on four of the six chromosomes, each spanning many megabases. Population-genetic modeling shows that this pattern was generated by chromosome-scale selective sweeps that have reduced variation worldwide; at least one of these sweeps likely occurred in the past few hundred years. These sweeps, which we hypothesize to be a result of human activity, have dramatically reshaped the global C. elegans population in the recent past. PMID:22286215

[Pharmacogenetics in primary health care: implementation and future expectations].

PubMed

Houwink, Elisa J F; Rigter, Tessel; Swen, Jesse J; Cornel, Martina C; Kienhuis, Anne; Rodenburg, Wendy; Weda, Marjolein

2015-01-01

Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care.

Unravelling the mysteries of sudden unexpected death in epilepsy.

PubMed

Hampel, K G; Rocamora Zuñiga, R; Quesada, C M

2017-04-18

Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of premature death in epileptic patients. Most SUDEP events occur at night and frequently go unnoticed; the exact pathophysiological mechanisms of this phenomenon therefore remain undetermined. Nevertheless, most cases of SUDEP are attributed to an infrequent yet extremely severe complication of epileptic seizures. We conducted a systematic literature search on PubMed. Our review article summarises scientific evidence on the classification, pathophysiological mechanisms, risk factors, biomarkers, and prevention of SUDEP. Likewise, we propose new lines of research and critically analyse findings that are relevant to clinical practice. Current knowledge suggests that SUDEP is a heterogeneous phenomenon caused by multiple factors. In most cases, however, SUDEP is thought to be due to postictal cardiorespiratory failure triggered by generalised tonic-clonic seizures and ultimately leading to cardiac arrest. The underlying pathophysiological mechanism involves multiple factors, ranging from genetic predisposition to environmental factors. Risk of SUDEP is higher in young adults with uncontrolled generalised tonic-clonic seizures. However, patients apparently at lower risk may also experience SUDEP. Current research focuses on identifying genetic and neuroimaging biomarkers that may help determine which patients are at high risk for SUDEP. Antiepileptic treatment is the only preventive measure proven effective to date. Night-time monitoring together with early resuscitation may reduce the risk of SUDEP. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Global population genetic dynamics of a highly migratory, apex predator shark.

PubMed

Bernard, Andrea M; Feldheim, Kevin A; Heithaus, Michael R; Wintner, Sabine P; Wetherbee, Bradley M; Shivji, Mahmood S

2016-11-01

Knowledge of genetic connectivity dynamics in the world's large-bodied, highly migratory, apex predator sharks across their global ranges is limited. One such species, the tiger shark (Galeocerdo cuvier), occurs worldwide in warm temperate and tropical waters, uses remarkably diverse habitats (nearshore to pelagic) and possesses a generalist diet that can structure marine ecosystems through top-down processes. We investigated the phylogeography and the global population structure of this exploited, phylogenetically enigmatic shark by using 10 nuclear microsatellites (n = 380) and sequences from the mitochondrial control region (CR, n = 340) and cytochrome oxidase I gene (n = 100). All three marker classes showed the genetic differentiation between tiger sharks from the western Atlantic and Indo-Pacific ocean basins (microsatellite F ST  > 0.129; CR Φ ST  > 0.497), the presence of North vs. southwestern Atlantic differentiation and the isolation of tiger sharks sampled from Hawaii from other surveyed locations. Furthermore, mitochondrial DNA revealed high levels of intraocean basin matrilineal population structure, suggesting female philopatry and sex-biased gene flow. Coalescent- and genetic distance-based estimates of divergence from CR sequences were largely congruent (d corr  = 0.0015-0.0050), indicating a separation of Indo-Pacific and western Atlantic tiger sharks <1 million years ago. Mitochondrial haplotype relationships suggested that the western South Atlantic Ocean was likely a historical connection for interocean basin linkages via the dispersal around South Africa. Together, the results reveal unexpectedly high levels of population structure in a highly migratory, behaviourally generalist, cosmopolitan ocean predator, calling for management and conservation on smaller-than-anticipated spatial scales. © 2016 John Wiley & Sons Ltd.

Wybutosine biosynthesis: Structural and mechanistic overview

PubMed Central

Perche-Letuvée, Phanélie; Molle, Thibaut; Forouhar, Farhad; Mulliez, Etienne; Atta, Mohamed

2014-01-01

Over the last 10 years, significant progress has been made in understanding the genetics, enzymology and structural components of the wybutosine (yW) biosynthetic pathway. These studies have played a key role in expanding our understanding of yW biosynthesis and have revealed unexpected evolutionary ties, which are presently being unraveled. The enzymes catalyzing the 5 steps of this pathway, from genetically encoded guanosine to wybutosine base, provide an ensemble of amazing reaction mechanisms that are to be discussed in this review article. PMID:25629788

Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments

PubMed Central

Eicher, John D.; Gruen, Jeffrey R.

2013-01-01

Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in-depth look at the recent imaging-genetics investigations of dyslexia. PMID:23916419

Slowly dispersing neotenic beetles can speciate on a penny coin and generate space-limited diversity in the tropical mountains

NASA Astrophysics Data System (ADS)

Bray, Timothy C.; Bocak, Ladislav

2016-09-01

We demonstrate the controversial origin of a biological species within an area of a few kilometres in the absence of physical barriers. We employed nuclear rRNA/mitochondrial and genome-wide SNP approaches to infer relationships of four species of net-winged beetles characterised by female neoteny. Three species are distributed at low elevations and a single population colonised a 40 km2 highland plateau and established distinct biological species despite incomplete genetic isolation. The speciation process is extreme in the highly localised spatial scale, due to the low dispersal power of neotenics, and provides clear support for a microallopatric model based on ecological conditions. In contrast with neutral evolution in a homogenous environment, as demonstrated by the genetic divergence and morphological similarity of two widely distributed low-mountain species, the environmental characteristics of the high-mountain plateau led to the origin of a species adapted to the local mimetic pattern and characterised by morphologically distinct genitalia. We conclude that the low dispersal propensity promotes neutral genetic differentiation in the first stage, but environmental characteristics play an important role the final phase of the speciation process. The unexpected speciation at such an extreme geographic scale points to the in situ origin and uniqueness of the mountain fauna.

Critical roles for a genetic code alteration in the evolution of the genus Candida.

PubMed

Silva, Raquel M; Paredes, João A; Moura, Gabriela R; Manadas, Bruno; Lima-Costa, Tatiana; Rocha, Rita; Miranda, Isabel; Gomes, Ana C; Koerkamp, Marian J G; Perrot, Michel; Holstege, Frank C P; Boucherie, Hélian; Santos, Manuel A S

2007-10-31

During the last 30 years, several alterations to the standard genetic code have been discovered in various bacterial and eukaryotic species. Sense and nonsense codons have been reassigned or reprogrammed to expand the genetic code to selenocysteine and pyrrolysine. These discoveries highlight unexpected flexibility in the genetic code, but do not elucidate how the organisms survived the proteome chaos generated by codon identity redefinition. In order to shed new light on this question, we have reconstructed a Candida genetic code alteration in Saccharomyces cerevisiae and used a combination of DNA microarrays, proteomics and genetics approaches to evaluate its impact on gene expression, adaptation and sexual reproduction. This genetic manipulation blocked mating, locked yeast in a diploid state, remodelled gene expression and created stress cross-protection that generated adaptive advantages under environmental challenging conditions. This study highlights unanticipated roles for codon identity redefinition during the evolution of the genus Candida, and strongly suggests that genetic code alterations create genetic barriers that speed up speciation.

Added value measures in education show genetic as well as environmental influence.

PubMed

Haworth, Claire M A; Asbury, Kathryn; Dale, Philip S; Plomin, Robert

2011-02-02

Does achievement independent of ability or previous attainment provide a purer measure of the added value of school? In a study of 4000 pairs of 12-year-old twins in the UK, we measured achievement with year-long teacher assessments as well as tests. Raw achievement shows moderate heritability (about 50%) and modest shared environmental influences (25%). Unexpectedly, we show that for indices of the added value of school, genetic influences remain moderate (around 50%), and the shared (school) environment is less important (about 12%). The pervasiveness of genetic influence in how and how much children learn is compatible with an active view of learning in which children create their own educational experiences in part on the basis of their genetic propensities.

Cellular Force Microscopy for in Vivo Measurements of Plant Tissue Mechanics1[W][OA

PubMed Central

Routier-Kierzkowska, Anne-Lise; Weber, Alain; Kochova, Petra; Felekis, Dimitris; Nelson, Bradley J.; Kuhlemeier, Cris; Smith, Richard S.

2012-01-01

Although growth and morphogenesis are controlled by genetics, physical shape change in plant tissue results from a balance between cell wall loosening and intracellular pressure. Despite recent work demonstrating a role for mechanical signals in morphogenesis, precise measurement of mechanical properties at the individual cell level remains a technical challenge. To address this challenge, we have developed cellular force microscopy (CFM), which combines the versatility of classical microindentation techniques with the high automation and resolution approaching that of atomic force microscopy. CFM’s large range of forces provides the possibility to map the apparent stiffness of both plasmolyzed and turgid tissue as well as to perform micropuncture of cells using very high stresses. CFM experiments reveal that, within a tissue, local stiffness measurements can vary with the level of turgor pressure in an unexpected way. Altogether, our results highlight the importance of detailed physically based simulations for the interpretation of microindentation results. CFM’s ability to be used both to assess and manipulate tissue mechanics makes it a method of choice to unravel the feedbacks between mechanics, genetics, and morphogenesis. PMID:22353572

Progress in Understanding Autism: 2007-2010

ERIC Educational Resources Information Center

Rutter, Michael L.

2011-01-01

Scientific progress is discussed in relation to clinical issues; genetic issues; environmental issues; and the state of play on psychological treatments. It is concluded that substantial gains in knowledge have been achieved during the last 3 years, and there have been some unexpected findings, but major puzzles remain. We should be hopeful of…

Gene dosage induction of silencing directed against an Arabidopsis Myb transgene in tobacco

USDA-ARS?s Scientific Manuscript database

An unexpected reduction in petal pigmentation on petunia plants genetically engineered for enhanced flower color was one of the first experimental demonstrations of the natural process of RNA-associated gene silencing. The obvious visual nature of such alterations to pigment patterns of transgenic ...

NON-TARGET AND ECOSYSTEM IMPACTS FROM GENETICALLY MODIFIED CROPS CONTAINING PLANT INCORPORATED PROTECTANTS (PIPS)

EPA Science Inventory

The risk of unintended and unexpected adverse impacts on non-target organisms and ecosystems is a key issue in environmental risk assessment of PIP crop plants. While there has been considerable examination of the effects of insect resistant crops on certain non-target organisms...

Genetic basis and selection for life-history trait plasticity on alternative host plants for the cereal aphid Sitobion avenae.

PubMed

Dai, Xinjia; Gao, Suxia; Liu, Deguang

2014-01-01

Sitobion avenae (F.) can survive on various plants in the Poaceae, which may select for highly plastic genotypes. But phenotypic plasticity was often thought to be non-genetic, and of little evolutionary significance historically, and many problems related to adaptive plasticity, its genetic basis and natural selection for plasticity have not been well documented. To address these questions, clones of S. avenae were collected from three plants, and their phenotypic plasticity under alternative environments was evaluated. Our results demonstrated that nearly all tested life-history traits showed significant plastic changes for certain S. avenae clones with the total developmental time of nymphs and fecundity tending to have relatively higher plasticity for most clones. Overall, the level of plasticity for S. avenae clones' life-history traits was unexpectedly low. The factor 'clone' alone explained 27.7-62.3% of the total variance for trait plasticities. The heritability of plasticity was shown to be significant in nearly all the cases. Many significant genetic correlations were found between trait plasticities with a majority of them being positive. Therefore, it is evident that life-history trait plasticity involved was genetically based. There was a high degree of variation in selection coefficients for life-history trait plasticity of different S. avenae clones. Phenotypic plasticity for barley clones, but not for oat or wheat clones, was frequently found to be under significant selection. The directional selection of alternative environments appeared to act to decrease the plasticity of S. avenae clones in most cases. G-matrix comparisons showed significant differences between S. avenae clones, as well as quite a few negative covariances (i.e., trade-offs) between trait plasticities. Genetic basis and evolutionary significance of life-history trait plasticity were discussed.

The Change of a Medically Important Genus: Worldwide Occurrence of Genetically Diverse Novel Brucella Species in Exotic Frogs.

PubMed

Scholz, Holger C; Mühldorfer, Kristin; Shilton, Cathy; Benedict, Suresh; Whatmore, Adrian M; Blom, Jochen; Eisenberg, Tobias

2016-01-01

The genus Brucella comprises various species of both veterinary and human medical importance. All species are genetically highly related to each other, sharing intra-species average nucleotide identities (ANI) of > 99%. Infections occur among various warm-blooded animal species, marine mammals, and humans. Until recently, amphibians had not been recognized as a host for Brucella. In this study, however, we show that novel Brucella species are distributed among exotic frogs worldwide. Comparative recA gene analysis of 36 frog isolates from various continents and different frog species revealed an unexpected high genetic diversity, not observed among classical Brucella species. In phylogenetic reconstructions the isolates consequently formed various clusters and grouped together with atypical more distantly related brucellae, like B. inopinata, strain BO2, and Australian isolates from rodents, some of which were isolated as human pathogens. Of one frog isolate (10RB9215) the genome sequence was determined. Comparative genome analysis of this isolate and the classical Brucella species revealed additional genetic material, absent from classical Brucella species but present in Ochrobactrum, the closest genetic neighbor of Brucella, and in other soil associated genera of the Alphaproteobacteria. The presence of gene clusters encoding for additional metabolic functions, flanked by tRNAs and mobile genetic elements, as well as by bacteriophages is suggestive for a different ecology compared to classical Brucella species. Furthermore it suggests that amphibian isolates may represent a link between free living soil saprophytes and the pathogenic Brucella with a preferred intracellular habitat. We therefore assume that brucellae from frogs have a reservoir in soil and, in contrast to classical brucellae, undergo extensive horizontal gene transfer.

A high-throughput label-free nanoparticle analyser.

PubMed

Fraikin, Jean-Luc; Teesalu, Tambet; McKenney, Christopher M; Ruoslahti, Erkki; Cleland, Andrew N

2011-05-01

Synthetic nanoparticles and genetically modified viruses are used in a range of applications, but high-throughput analytical tools for the physical characterization of these objects are needed. Here we present a microfluidic analyser that detects individual nanoparticles and characterizes complex, unlabelled nanoparticle suspensions. We demonstrate the detection, concentration analysis and sizing of individual synthetic nanoparticles in a multicomponent mixture with sufficient throughput to analyse 500,000 particles per second. We also report the rapid size and titre analysis of unlabelled bacteriophage T7 in both salt solution and mouse blood plasma, using just ~1 × 10⁻⁶ l of analyte. Unexpectedly, in the native blood plasma we discover a large background of naturally occurring nanoparticles with a power-law size distribution. The high-throughput detection capability, scalable fabrication and simple electronics of this instrument make it well suited for diverse applications.

Allozyme electrophoresis as a tool for distinguishing different zooxanthellae symbiotic with giant clams

PubMed Central

Baillie, B. K.; Monje, V.; Silvestre, V.; Sison, M.; Belda-Baillie, C. A.

1998-01-01

The taxonomy of zooxanthellae in marine invertebrate symbioses is not well understood owing mainly to their lack of reliable morphological differences. Nevertheless, previous work using protein and DNA electrophoreses has set the stage for advancing our taxonomic understanding of cnidarian zooxanthellae. Here we present the use of allozymes as genetic markers for distinguishing algal isolates from tridacnid hosts. Zooxanthellae from seven Tridacna and Hippopus species were isolated and maintained in axenic clonal cultures over many generations. Of 16 enzyme systems, α- and β-esterase (EST), esterase-F (EST-F), glucose phosphate isomerase (GPI), and malate dehydrogenase (MDH) were found suitable polymorphic markers of genetic differences among clonal cultures. Of 39 clonal isolates, 97% were found to be genetically distinguishable. This high extent of genetic variation in zooxanthellae within and between clam species was unexpected, and is difficult to explain based solely on the general notion of asexual reproduction in symbiotic zooxanthellae. Our results are also consistent with the occurrence of sexual reproduction in clam zooxanthellae. The close genetic similarity of the symbionts of Tridacna gigas, the largest and fastest-growing clam species, and the difficulty of initiating their clonal cultures in the given nutrient medium, compared with the symbionts of other clam species, are further indicative of possibly distinct algal symbionts in T. gigas. These findings are discussed in light of current taxonomic understanding of these organisms.

Population Genetics of an Ecosystem-Defining Reef Coral Pocillopora damicornis in the Tropical Eastern Pacific

PubMed Central

Combosch, David J.; Vollmer, Steven V.

2011-01-01

Background Coral reefs in the Tropical Eastern Pacific (TEP) are amongst the most peripheral and geographically isolated in the world. This isolation has shaped the biology of TEP organisms and lead to the formation of numerous endemic species. For example, the coral Pocillopora damicornis is a minor reef-builder elsewhere in the Indo-West Pacific, but is the dominant reef-building coral in the TEP, where it forms large, mono-specific stands, covering many hectares of reef. Moreover, TEP P. damicornis reproduces by broadcast spawning, while it broods mostly parthenogenetic larvae throughout the rest of the Indo-West Pacific. Population genetic surveys for P. damicornis from across its Indo-Pacific range indicate that gene flow (i.e. larval dispersal) is generally limited over hundreds of kilometers or less. Little is known about the population genetic structure and the dispersal potential of P. damicornis in the TEP. Methodology Using multilocus microsatellite data, we analyzed the population structure of TEP P. damicornis among and within nine reefs and test for significant genetic structure across three geographically and ecologically distinct regions in Panama. Principal Findings/Conclusions We detected significant levels of population genetic structure (global RST = 0.162), indicating restricted gene flow (i.e. larvae dispersal), both among the three regions (RRT = 0.081) as well as within regions (RSR = 0.089). Limited gene flow across a distinct environmental cline, like the regional upwelling gradient in Panama, indicates a significant potential for differential adaptation and population differentiation. Individual reefs were characterized by unexpectedly high genet diversity (avg. 94%), relatively high inbreeding coefficients (global FIS = 0.183), and localized spatial genetic structure among individuals (i.e. unique genets) over 10 m intervals. These findings suggest that gene flow is limited in TEP P. damicornis populations, particularly among regions, but even over meter scales within populations. PMID:21857900

Sudden unexpected death under acute influence of cannabis.

PubMed

Hartung, Benno; Kauferstein, Silke; Ritz-Timme, Stefanie; Daldrup, Thomas

2014-04-01

The acute toxicity of cannabinoids is said to be low and there is little public awareness of the potentially hazardous cardiovascular effects of cannabis, e.g. marked increase in heart rate or supine blood pressure. We describe the cases of two young, putative healthy men who died unexpectedly under the acute influence of cannabinoids. To our knowledge, these are the first cases of suspected fatal cannabis intoxications where full postmortem investigations, including autopsy, toxicological, histological, immunohistochemical and genetical examinations, were carried out. The results of these examinations are presented. After exclusion of other causes of death we assume that the young men experienced fatal cardiovascular complications evoked by smoking cannabis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Advances in Dyslexia Genetics-New Insights Into the Role of Brain Asymmetries.

PubMed

Paracchini, S; Diaz, R; Stein, J

2016-01-01

Dyslexia is a common condition affecting up to 10% school-aged children. There is strong evidence that genetics plays an important role in dyslexia and is expected to be complex in nature. Few specific susceptibility factors have been identified so far, but their functional characterization has provided novel insights into the biology of dyslexia. In particular, they point to an unexpected role of candidate genes for dyslexia in the biology of cilia, cellular organelles required in many processes including the establishment of left-right asymmetries early in development. This observation has brought back into the spotlight the old idea of a link between dyslexia and handedness. Yet much of the genetics contributing to dyslexia remains unexplained. The lack of biological markers, clear diagnostic criteria, and homogeneous assessment strategies are just some of the factors preventing the collection of the cohorts powered enough for large-scale genetic studies. While the technology and methods to generate and handle large-scale data have reached unprecedented potential, the main challenge remains in establishing universal guidelines to collect suitable phenotype information across independent studies. These difficulties reflect the complex nature of dyslexia which is highly heterogeneous and often co-occurs with other neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Environmental and genetic sources of diversification in the timing of seed germination: implications for the evolution of bet hedging.

PubMed

Simons, Andrew M; Johnston, Mark O

2006-11-01

Environmental variation that is not predictably related to cues is expected to drive the evolution of bet-hedging strategies. The high variance observed in the timing of seed germination has led to it being the most cited diversification strategy in the theoretical bet-hedging literature. Despite this theoretical focus, virtually nothing is known about the mechanisms responsible for the generation of individual-level diversification. Here we report analyses of sources of variation in timing of germination within seasons, germination fraction over two generations and three sequential seasons, and the genetic correlation structure of these traits using almost 10,000 seeds from more than 100 genotypes of the monocarpic perennial Lobelia inflata. Microenvironmental analysis of time to germination suggests that extreme sensitivity to environmental gradients, or microplasticity, even within a homogeneous growth chamber, may act as an effective individual-level diversification mechanism and explains more than 30% of variance in time to germination. The heritability of within-season timing of germination was low (h(2) = 0.07) but significant under homogeneous conditions. Consistent with individual-level diversification, this low h(2) was attributable not to low additive genetic variance, but to an unusually high coefficient of residual variation in time to germination. Despite high power to detect additive genetic variance in within-season diversification, it was low and indistinguishable from zero. Restricted maximum likelihood detected significant genetic variation for germination fraction (h(2) = 0.18) under homogeneous conditions. Unexpectedly, this heritability was positive when measured within a generation by sibling analysis and negative when measured across generations by offspring-on-parent regression. The consistency of dormancy fraction over multiple delays, a major premise of Cohen's classic model, was supported by a strong genetic correlation (r = 0.468) observed for a cohort's germination fraction over two seasons. We discuss implications of the results for the evolution of bet hedging and highlight the need for further empirical study of the causal components of diversification.

Analysis of HIV-1 intersubtype recombination breakpoints suggests region with high pairing probability may be a more fundamental factor than sequence similarity affecting HIV-1 recombination.

PubMed

Jia, Lei; Li, Lin; Gui, Tao; Liu, Siyang; Li, Hanping; Han, Jingwan; Guo, Wei; Liu, Yongjian; Li, Jingyun

2016-09-21

With increasing data on HIV-1, a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades. Currently an incomplete structural understanding of the copy choice mechanism along with several other issues in the field that lack elucidation led us to perform an analysis of the correlation between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarity to further explore structural mechanisms. Near full length sequences of URFs from Asia, Europe, and Africa (one sequence/patient), and representative sequences of worldwide CRFs were retrieved from the Los Alamos HIV database. Their recombination patterns were analyzed by jpHMM in detail. Then the relationships between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarities were investigated. Pearson correlation test showed that all URF groups and the CRF group exhibit the same breakpoint distribution pattern. Additionally, the Wilcoxon two-sample test indicated a significant and inexplicable limitation of recombination in regions with high pairing probability. These regions have been found to be strongly conserved across distinct biological states (i.e., strong intersubtype similarity), and genetic similarity has been determined to be a very important factor promoting recombination. Thus, the results revealed an unexpected disagreement between intersubtype similarity and breakpoint distribution, which were further confirmed by genetic similarity analysis. Our analysis reveals a critical conflict between results from natural HIV-1 isolates and those from HIV-1-based assay vectors in which genetic similarity has been shown to be a very critical factor promoting recombination. These results indicate the region with high-pairing probabilities may be a more fundamental factor affecting HIV-1 recombination than sequence similarity in natural HIV-1 infections. Our findings will be relevant in furthering the understanding of HIV-1 recombination mechanisms.

Field Measurements Indicate Unexpected, Serious Underestimation of Mussel Heart Rates and Thermal Tolerance by Laboratory Studies

PubMed Central

Tagliarolo, Morgana; McQuaid, Christopher D.

2016-01-01

Attempts to predict the response of species to long-term environmental change are generally based on extrapolations from laboratory experiments that inevitably simplify the complex interacting effects that occur in the field. We recorded heart rates of two genetic lineages of the brown mussel Perna perna over a full tidal cycle in-situ at two different sites in order to evaluate the cardiac responses of the two genetic lineages present on the South African coast to temperature and the immersion/emersion cycle. “Robomussel” temperature loggers were used to monitor thermal conditions at the two sites over one year. Comparison with live animals showed that robomussels provided a good estimate of mussel body temperatures. A significant difference in estimated body temperatures was observed between the sites and the results showed that, under natural conditions, temperatures regularly approach or exceed the thermal limits of P. perna identified in the laboratory. The two P. perna lineages showed similar tidal and diel patterns of heart rate, with higher cardiac activity during daytime immersion and minimal values during daytime emersion. Comparison of the heart rates measured in the field with data previously measured in the laboratory indicates that laboratory results seriously underestimate heart rate activity, by as much as 75%, especially during immersion. Unexpectedly, field estimates of body temperatures indicated an ability to tolerate temperatures considered lethal on the basis of laboratory measurements. This suggests that the interaction of abiotic conditions in the field does not necessarily raise vulnerability to high temperatures. PMID:26840775

Mitochondrial DNA variability among six South American Amerindian villages from the Pano linguistic group.

PubMed

Mendes-Junior, Celso T; Simoes, Aguinaldo L

2014-01-01

Although scattered throughout a large geographic area, the members of the Pano linguistic group present strong ethnic, linguistic, and cultural homogeneity, a feature that causes them to be considered components of a same "Pano" tribe. Nevertheless, the genetic homogeneity between Pano villages has not yet been examined. To study the genetic structure of the Pano linguistic group, four major Native American mitochondrial DNA (mtDNA) founder haplogroups were analyzed in 77 Amerindians from six villages of four Pano tribes (Katukina, Kaxináwa, Marúbo, and Yaminawa) located in the Brazilian Amazon. The central position of these tribes in the continent makes them relevant for attempts to reconstruct population movements in South America. Except for a single individual that presented an African haplogroup L, all remaining individuals presented one of the four Native American haplogroups. Significant heterogeneity was observed across the six Pano villages. Although Amerindian populations are usually characterized by considerable interpopulational diversity, the high heterogeneity level observed is unexpected if the strong ethnic, linguistic, and cultural homogeneity of the Pano linguistic group is taken into account. The present findings indicate that the ethnic, linguistic, and cultural homogeneity does not imply genetic homogeneity. Even though the genetic heterogeneity uncovered may be a female-specific process, the most probable explanation for that is the joint action of isolation and genetic drift as major factors influencing the genetic structure of the Pano linguistic group. Copyright © 2014 Wayne State University Press, Detroit, Michigan 48201-1309.

The nature of schizotypy among multigenerational multiplex schizophrenia families

PubMed Central

Tarbox, Sarah I.; Almasy, Laura; Gur, Raquel E.; Nimgaonkar, Vishwajit L.; Pogue-Geile, Michael F.

2012-01-01

Identification of endophenotypes (Gottesman & Gould, 2003; Gottesman & Shields, 1972) that genetically correlate with schizophrenia and are genetically homogeneous is an important strategy for detecting genes that affect schizophrenia risk. Symptoms of schizotypy may familially correlate with schizophrenia; however, there are critical limitations of the current literature concerning this association. The present study examined the genetic architecture and genetic associations between schizotypy and schizophrenia among multigenerational, multiplex schizophrenia families. Genetic schizotypy factor scales were developed that genetically correlated with schizophrenia, although some relations were unexpected in direction suggesting minimization of “psychotic-like” symptoms. These genetic schizotypy factor scales did not genetically correlate with major depressive disorder or substance dependence indicating specificity to schizophrenia. The results highlight the possibility of significant response bias in schizophrenia families, particularly among close relatives, and suggest an important consideration when acquiring self-report information. This is a topic that deserves future study as the origins of this putative bias in relatives are unclear. In addition, the results support the identification of genetic schizotypy factors as a promising technique for maximizing genetic correlation of endophenotypes with schizophrenia. PMID:22288909

Genetic Diversity Among Botulinum Neurotoxin-Producing Clostridial Strains

DTIC Science & Technology

2007-02-01

analysis. John Wiley & Sons, Inc., New York, NY. 25. Keto -Timonen, R., M. Nevas, and H. Korkeala. 2005. Efficient DNA finger- printing of Clostridium...G botulinal toxin in humans: report of five sudden unexpected deaths. J. Infect. Dis. 143 :22–27. 41. Sonnabend, O. A., W. F. Sonnabend, U. Krech, G

Hypervariable minisatellites: recombinators or innocent bystanders?

PubMed

Jarman, A P; Wells, R A

1989-11-01

It has become apparent in recent years that unexpectedly large numbers of minisatellites exist within the eukaryotic genome. Their use in genetics is well known, but as with any new class of sequence, there is also much speculation about their involvement in a range of biological processes. How much is known of their biology?

Effects of genetic strain on stress-induced weight and body fat loss in rats: Application to air pollution research

EPA Science Inventory

Exposure to some air pollutants is suspected of contributing to obesity. Hazelton chambers are commonly used in air pollution studies but we found unexpected reductions in body weight and body fat of rats housed in Hazelton chambers under control conditions. We suspect that stres...

Development of antinuclear antibodies and a genetic linkage in pigs infected with porcine circovirus type 2

USDA-ARS?s Scientific Manuscript database

Objectives. Prominent nuclear immunohistochemical staining of a PCV-2 free porcine kidney cell line (PK-15) was detected with a rabbit polyclonal antibody produced against a conserved PCV2 Rep-protein peptide. This unexpected finding led us to retrospectively test sera from gnotobiotic pigs for the ...

A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

PubMed

Sauer, Charles W; Marc-Aurele, Krishelle L

2016-07-28

BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby.

XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.

PubMed

Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen; Uzel, Gulbu; Matthews, Helen; Lenardo, Michael J

2014-04-03

Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.

Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns.

PubMed

Sack, Laura Magill; Davoli, Teresa; Li, Mamie Z; Li, Yuyang; Xu, Qikai; Naxerova, Kamila; Wooten, Eric C; Bernardi, Ronald J; Martin, Timothy D; Chen, Ting; Leng, Yumei; Liang, Anthony C; Scorsone, Kathleen A; Westbrook, Thomas F; Wong, Kwok-Kin; Elledge, Stephen J

2018-04-05

Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

Phylogeography of microbial phototrophs in the dry valleys of the high Himalayas and Antarctica.

PubMed

Schmidt, S K; Lynch, R C; King, A J; Karki, D; Robeson, M S; Nagy, L; Williams, M W; Mitter, M S; Freeman, K R

2011-03-07

High-elevation valleys in dry areas of the Himalayas are among the most extreme, yet least explored environments on Earth. These barren, rocky valleys are subjected to year-round temperature fluctuations across the freezing point and very low availability of water and nutrients, causing previous workers to hypothesize that no photoautotrophic life (primary producers) exists in these locations. However, there has been no work using modern biogeochemical or culture-independent molecular methods to test the hypothesis that photoautotrophs are absent from high Himalayan soil systems. Here, we show that although microbial biomass levels are as low as those of the Dry Valleys of Antarctica, there are abundant microbial photoautotrophs, displaying unexpected phylogenetic diversity, in barren soils from just below the permanent ice line of the central Himalayas. Furthermore, we discovered that one of the dominant algal clades from the high Himalayas also contains the dominant algae in culture-independent surveys of both soil and ice samples from the Dry Valleys of Antarctica, revealing an unexpected link between these environmentally similar but geographically very distant systems. Phylogenetic and biogeographic analyses demonstrated that although this algal clade is globally distributed to other high-altitude and high-latitude soils, it shows significant genetic isolation by geographical distance patterns, indicating local adaptation and perhaps speciation in each region. Our results are the first to demonstrate the remarkable similarities of microbial life of arid soils of Antarctica and the high Himalayas. Our findings are a starting point for future comparative studies of the dry valleys of the Himalayas and Antarctica that will yield new insights into the cold and dry limits to life on Earth.

A potentially fatal mix of herpes in zoos.

PubMed

Greenwood, Alex D; Tsangaras, Kyriakos; Ho, Simon Y W; Szentiks, Claudia A; Nikolin, Veljko M; Ma, Guanggang; Damiani, Armando; East, Marion L; Lawrenz, Arne; Hofer, Heribert; Osterrieder, Nikolaus

2012-09-25

Pathogens often have a limited host range, but some can opportunistically jump to new species. Anthropogenic activities that mix reservoir species with novel, hence susceptible, species can provide opportunities for pathogens to spread beyond their normal host range. Furthermore, rapid evolution can produce new pathogens by mechanisms such as genetic recombination. Zoos unintentionally provide pathogens with a high diversity of species from different continents and habitats assembled within a confined space. Institutions alert to the problem of pathogen spread to unexpected hosts can monitor the emergence of pathogens and take preventative measures. However, asymptomatic infections can result in the causative pathogens remaining undetected in their reservoir host. Furthermore, pathogen spread to unexpected hosts may remain undiagnosed if the outcome of infection is limited, as in the case of compromised fertility, or if more severe outcomes are restricted to less charismatic species that prompt only limited investigation. We illustrate this problem here with a recombinant zebra herpesvirus infecting charismatic species including zoo polar bears over at least four years. The virus may cause fatal encephalitis and infects at least five mammalian orders, apparently without requiring direct contact with infected animals. Copyright © 2012 Elsevier Ltd. All rights reserved.

Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.

PubMed

Moreno-Moral, Aida; Pesce, Francesco; Behmoaras, Jacques; Petretto, Enrico

2017-01-01

Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures

PubMed Central

Nishino, Jo; Kochi, Yuta; Shigemizu, Daichi; Kato, Mamoru; Ikari, Katsunori; Ochi, Hidenori; Noma, Hisashi; Matsui, Kota; Morizono, Takashi; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Matsui, Shigeyuki

2018-01-01

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases. PMID:29740473

Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas.

PubMed

Abou-El-Ardat, Khalil; Seifert, Michael; Becker, Kerstin; Eisenreich, Sophie; Lehmann, Matthias; Hackmann, Karl; Rump, Andreas; Meijer, Gerrit; Carvalho, Beatriz; Temme, Achim; Schackert, Gabriele; Schröck, Evelin; Krex, Dietmar; Klink, Barbara

2017-04-01

The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management.

PubMed

Chandler, Natalie; Best, Sunayna; Hayward, Jane; Faravelli, Francesca; Mansour, Sahar; Kivuva, Emma; Tapon, Dagmar; Male, Alison; DeVile, Catherine; Chitty, Lyn S

2018-03-29

PurposeUnexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar.MethodsParents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias.ResultsDefinitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty.ConclusionTrio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2018.30.

Ambiguous genetic relationships among coconut (Cocos nucifera L.) cultivars: the effects of outcrossing, sample source and size, and method of analysis.

USDA-ARS?s Scientific Manuscript database

A prior analysis of eight coconut cultivars with 15 microsatellite (SSR) markers drew unexpected relationships between two of the out-crossing tall cultivars evaluated: ‘Atlantic Tall’ and ‘Panama Tall’. We further investigated the relationships between these eight cultivars by increasing the number...

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin

PubMed Central

Troggio, Michela; Šurbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the ‘Golden Delicious’ genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies. PMID:23826289

Science, Sentiment, and the State

PubMed Central

Gibbon, Sahra Elizabeth

2013-01-01

Contributing to an emerging field of social science literature by examining the translation of genomic medicine across global and transnational fields of research and medicine, this article examines how genetics is allied to public health in Cuba. It examines the sociopolitical and cultural discourses and practices that constitute community genetics or challenge or impede the translation and expansion of genomics as public health. Focusing on the experience of health practitioners, the article explores how their work is circumscribed by cultural values and social ideologies that collectively reveal an unexpected heterogeneity in how genetics is being constituted and reproduced. Although the Western quest for genomics as “personal medicine” is revealed here as both ideologically and practically problematic, such challenges paradoxically work to reinforce a commitment to maintaining the distinctive field of Cuban community genetics in its orientation to collective public health. PMID:24213970

Population-genetic nature of copy number variations in the human genome.

PubMed

Kato, Mamoru; Kawaguchi, Takahisa; Ishikawa, Shumpei; Umeda, Takayoshi; Nakamichi, Reiichiro; Shapero, Michael H; Jones, Keith W; Nakamura, Yusuke; Aburatani, Hiroyuki; Tsunoda, Tatsuhiko

2010-03-01

Copy number variations (CNVs) are universal genetic variations, and their association with disease has been increasingly recognized. We designed high-density microarrays for CNVs, and detected 3000-4000 CNVs (4-6% of the genomic sequence) per population that included CNVs previously missed because of smaller sizes and residing in segmental duplications. The patterns of CNVs across individuals were surprisingly simple at the kilo-base scale, suggesting the applicability of a simple genetic analysis for these genetic loci. We utilized the probabilistic theory to determine integer copy numbers of CNVs and employed a recently developed phasing tool to estimate the population frequencies of integer copy number alleles and CNV-SNP haplotypes. The results showed a tendency toward a lower frequency of CNV alleles and that most of our CNVs were explained only by zero-, one- and two-copy alleles. Using the estimated population frequencies, we found several CNV regions with exceptionally high population differentiation. Investigation of CNV-SNP linkage disequilibrium (LD) for 500-900 bi- and multi-allelic CNVs per population revealed that previous conflicting reports on bi-allelic LD were unexpectedly consistent and explained by an LD increase correlated with deletion-allele frequencies. Typically, the bi-allelic LD was lower than SNP-SNP LD, whereas the multi-allelic LD was somewhat stronger than the bi-allelic LD. After further investigation of tag SNPs for CNVs, we conclude that the customary tagging strategy for disease association studies can be applicable for common deletion CNVs, but direct interrogation is needed for other types of CNVs.

Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

NASA Astrophysics Data System (ADS)

Soundararajan, Venky; Aravamudan, Murali

2014-12-01

The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action - inspired by the Google page rank algorithm that unearths most ``globally connected'' websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs - up to 20Å from the ATP binding site, but within 5Å of the phosphorylation site - encode the Gibbs free energy of inhibition (ΔGinhibition) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis

DOE PAGES

Sakhanenko, Nikita A.; Kunert-Graf, James; Galas, David J.

2017-10-13

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. Here, we present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discretemore » variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis—that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. Finally, we illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.« less

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakhanenko, Nikita A.; Kunert-Graf, James; Galas, David J.

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. Here, we present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discretemore » variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis—that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. Finally, we illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.« less

The Information Content of Discrete Functions and Their Application in Genetic Data Analysis.

PubMed

Sakhanenko, Nikita A; Kunert-Graf, James; Galas, David J

2017-12-01

The complex of central problems in data analysis consists of three components: (1) detecting the dependence of variables using quantitative measures, (2) defining the significance of these dependence measures, and (3) inferring the functional relationships among dependent variables. We have argued previously that an information theory approach allows separation of the detection problem from the inference of functional form problem. We approach here the third component of inferring functional forms based on information encoded in the functions. We present here a direct method for classifying the functional forms of discrete functions of three variables represented in data sets. Discrete variables are frequently encountered in data analysis, both as the result of inherently categorical variables and from the binning of continuous numerical variables into discrete alphabets of values. The fundamental question of how much information is contained in a given function is answered for these discrete functions, and their surprisingly complex relationships are illustrated. The all-important effect of noise on the inference of function classes is found to be highly heterogeneous and reveals some unexpected patterns. We apply this classification approach to an important area of biological data analysis-that of inference of genetic interactions. Genetic analysis provides a rich source of real and complex biological data analysis problems, and our general methods provide an analytical basis and tools for characterizing genetic problems and for analyzing genetic data. We illustrate the functional description and the classes of a number of common genetic interaction modes and also show how different modes vary widely in their sensitivity to noise.

Impact of genetic targets on therapy in head and neck squamous cell carcinoma.

PubMed

Chaikhoutdinov, Irina; Goldenberg, David

2013-01-01

Despite advances in surgical technique, radiation therapy and chemotherapy, the mortality from head and neck squamous cell carcinoma (HNSCC) has not improved significantly. Squamous cell carcinoma is caused by tobacco use, alcohol consumption and infection with high-risk types of human papillomavirus. It is the 6th most common cancer in the world, with upwards of 45,000 new cases reported yearly in the United States alone.In recent years, there has been a significant increase in the understanding of the molecular and genetic pathogenesis of head and neck cancer, shedding light on the unexpected heterogeneity of the disease. Genetic analysis has led to new classification schemes for HNSCC, with different subgroups exhibiting different prognoses. In addition, multiple targets in aberrant signaling pathways have been identified using increasingly sophisticated bio-informatics tools. Advances in technology have allowed for novel delivery mechanisms to introduce genetic material into cells to produce a therapeutic effect by targeting cancer cells via a number of different approaches.A pressing need to develop novel therapies to augment current treatment modalities has led to a number of translational studies involving gene therapy in the treatment of HNSCC. This article will focus on a review of the most recent developments in molecular biology of head and neck squamous cell carcinoma in regards to possible targets for gene therapy, as well as the array of novel therapeutic strategies directed at these targets.

MOSAIC: a chemical-genetic interaction data repository and web resource for exploring chemical modes of action.

PubMed

Nelson, Justin; Simpkins, Scott W; Safizadeh, Hamid; Li, Sheena C; Piotrowski, Jeff S; Hirano, Hiroyuki; Yashiroda, Yoko; Osada, Hiroyuki; Yoshida, Minoru; Boone, Charles; Myers, Chad L

2018-04-01

Chemical-genomic approaches that map interactions between small molecules and genetic perturbations offer a promising strategy for functional annotation of uncharacterized bioactive compounds. We recently developed a new high-throughput platform for mapping chemical-genetic (CG) interactions in yeast that can be scaled to screen large compound collections, and we applied this system to generate CG interaction profiles for more than 13 000 compounds. When integrated with the existing global yeast genetic interaction network, CG interaction profiles can enable mode-of-action prediction for previously uncharacterized compounds as well as discover unexpected secondary effects for known drugs. To facilitate future analysis of these valuable data, we developed a public database and web interface named MOSAIC. The website provides a convenient interface for querying compounds, bioprocesses (Gene Ontology terms) and genes for CG information including direct CG interactions, bioprocesses and gene-level target predictions. MOSAIC also provides access to chemical structure information of screened molecules, chemical-genomic profiles and the ability to search for compounds sharing structural and functional similarity. This resource will be of interest to chemical biologists for discovering new small molecule probes with specific modes-of-action as well as computational biologists interested in analysing CG interaction networks. MOSAIC is available at http://mosaic.cs.umn.edu. hisyo@riken.jp, yoshidam@riken.jp, charlie.boone@utoronto.ca or chadm@umn.edu. Supplementary data are available at Bioinformatics online.

Animacy, perceptual load, and inattentional blindness.

PubMed

Calvillo, Dustin P; Jackson, Russell E

2014-06-01

Inattentional blindness is the failure to notice unexpected objects in a visual scene while engaging in an attention-demanding task. We examined the effects of animacy and perceptual load on inattentional blindness. Participants searched for a category exemplar under low or high perceptual load. On the last trial, the participants were exposed to an unexpected object that was either animate or inanimate. Unexpected objects were detected more frequently when they were animate rather than inanimate, and more frequently with low than with high perceptual loads. We also measured working memory capacity and found that it predicted the detection of unexpected objects, but only with high perceptual loads. The results are consistent with the animate-monitoring hypothesis, which suggests that animate objects capture attention because of the importance of the detection of animate objects in ancestral hunter-gatherer environments.

New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.

PubMed

Penco, Silvana; Buscema, Massimo; Patrosso, Maria Cristina; Marocchi, Alessandro; Grossi, Enzo

2008-05-30

Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks to identify a possible genetic background predisposing to the disease. A DNA multiarray panel was applied to genotype more than 60 polymorphisms within 35 genes selected from pathways of lipid and homocysteine metabolism, regulation of blood pressure, coagulation, inflammation, cellular adhesion and matrix integrity, in 54 sporadic ALS patients and 208 controls. Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis. An unexpected discovery of a strong genetic background in sporadic ALS using a DNA multiarray panel and analytical processing of the data with advanced artificial neural networks was found. The predictive accuracy obtained with Linear Discriminant Analysis and Standard Artificial Neural Networks ranged from 70% to 79% (average 75.31%) and from 69.1 to 86.2% (average 76.6%) respectively. The corresponding value obtained with Advanced Intelligent Systems reached an average of 96.0% (range 94.4 to 97.6%). This latter approach allowed the identification of seven genetic variants essential to differentiate cases from controls: apolipoprotein E arg158cys; hepatic lipase -480 C/T; endothelial nitric oxide synthase 690 C/T and glu298asp; vitamin K-dependent coagulation factor seven arg353glu, glycoprotein Ia/IIa 873 G/A and E-selectin ser128arg. This study provides an alternative and reliable method to approach complex diseases. Indeed, the application of a novel artificial intelligence-based method offers a new insight into genetic markers of sporadic ALS pointing out the existence of a strong genetic background.

Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing

PubMed Central

Dijamco, Cheri; Kiefer, Amy K.; Eriksson, Nicholas; Moiseff, Bianca; Tung, Joyce Y.; Mountain, Joanna L.

2013-01-01

Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown. Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation-negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned. Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered. PMID:23638402

Structural imaging biomarkers of sudden unexpected death in epilepsy

PubMed Central

Wandschneider, Britta; Koepp, Matthias; Scott, Catherine; Micallef, Caroline; Balestrini, Simona; Sisodiya, Sanjay M.; Thom, Maria; Harper, Ronald M.; Sander, Josemir W.; Vos, Sjoerd B.; Duncan, John S.; Lhatoo, Samden

2015-01-01

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies. PMID:26264515

Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).

PubMed

Mishra, Vikas; Karumuri, Bharat K; Gautier, Nicole M; Liu, Rui; Hutson, Timothy N; Vanhoof-Villalba, Stephanie L; Vlachos, Ioannis; Iasemidis, Leonidas; Glasscock, Edward

2017-06-01

People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Redefining the genetics of Murine Gammaherpesvirus 68 via transcriptome-based annotation

PubMed Central

Johnson, L. Steven; Willert, Erin K.; Virgin, Herbert W.

2010-01-01

Summary Viral genetic studies often focus on large open reading frames (ORFs) identified during genome annotation (ORF-based annotation). Here we provide a tool and software set for defining gene expression by murine gammaherpesvirus 68 (γHV68) nucleotide-by-nucleotide across the 119,450 basepair (bp) genome. These tools allowed us to determine that viral RNA expression was significantly more complex than predicted from ORF-based annotation, including over 73,000 nucleotides of unexpected transcription within 30 expressed genomic regions (EGRs). Approximately 90% of this RNA expression was antisense to genomic regions containing known large ORFs. We verified the existence of novel transcripts in three EGRs using standard methods to validate the approach and determined which parts of the transcriptome depend on protein or viral DNA synthesis. This redefines the genetic map of γHV68, indicates that herpesviruses contain significantly more genetic complexity than predicted from ORF-based genome annotations, and provides new tools and approaches for viral genetic studies. PMID:20542255

Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

PubMed Central

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2015-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

High-throughput discovery of novel developmental phenotypes.

PubMed

Dickinson, Mary E; Flenniken, Ann M; Ji, Xiao; Teboul, Lydia; Wong, Michael D; White, Jacqueline K; Meehan, Terrence F; Weninger, Wolfgang J; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N; Bower, Lynette; Brown, James M; Caddle, L Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J; Denegre, James M; Doe, Brendan; Dolan, Mary E; Edie, Sarah M; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R; Hsu, Chih-Wei; Johnson, Sara J; Kalaga, Sowmya; Keith, Lance C; Lanoue, Louise; Lawson, Thomas N; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L; Newbigging, Susan; Nutter, Lauryl M J; Peterson, Kevin A; Ramirez-Solis, Ramiro; Rowland, Douglas J; Ryder, Edward; Samocha, Kaitlin E; Seavitt, John R; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G; Tocchini-Valentini, Glauco P; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C; Justice, Monica J; Parkinson, Helen E; Moore, Mark; Wells, Sara; Braun, Robert E; Svenson, Karen L; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R Mark; Brown, Steve D M; Adams, David J; Lloyd, K C Kent; McKerlie, Colin; Beaudet, Arthur L; Bućan, Maja; Murray, Stephen A

2016-09-22

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

High-throughput discovery of novel developmental phenotypes

PubMed Central

Dickinson, Mary E.; Flenniken, Ann M.; Ji, Xiao; Teboul, Lydia; Wong, Michael D.; White, Jacqueline K.; Meehan, Terrence F.; Weninger, Wolfgang J.; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N.; Bower, Lynette; Brown, James M.; Caddle, L. Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J.; Denegre, James M.; Doe, Brendan; Dolan, Mary E.; Edie, Sarah M.; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R.; Hsu, Chih-wei; Johnson, Sara J.; Kalaga, Sowmya; Keith, Lance C.; Lanoue, Louise; Lawson, Thomas N.; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L.; Newbigging, Susan; Nutter, Lauryl M.J.; Peterson, Kevin A.; Ramirez-Solis, Ramiro; Rowland, Douglas J.; Ryder, Edward; Samocha, Kaitlin E.; Seavitt, John R.; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B.; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G.; Tocchini-Valentini, Glauco P.; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C.; Justice, Monica J.; Parkinson, Helen E.; Moore, Mark; Wells, Sara; Braun, Robert E.; Svenson, Karen L.; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R. Mark; Brown, Steve D.M.; Adams, David J.; Lloyd, K.C. Kent; McKerlie, Colin; Beaudet, Arthur L.; Bucan, Maja; Murray, Stephen A.

2016-01-01

Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts. PMID:27626380

Compound Heterozygosity of Dominant and Recessive COL7A Alleles in a Severely Affected Patient with a Family History of Dystrophic Epidermolysis Bullosa: Clinical Findings, Genetic Testing, and Treatment Implications.

PubMed

Watson, Kendra D; Schoch, Jennifer J; Beek, Geoffrey J; Hand, Jennifer L

2017-03-01

An 8-year-old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life-threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB-affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history. © 2017 Wiley Periodicals, Inc.

Do cryptic species exist in Hoplobatrachus rugulosus? An examination using four nuclear genes, the cyt b gene and the complete MT genome.

PubMed

Yu, Danna; Zhang, Jiayong; Li, Peng; Zheng, Rongquan; Shao, Chen

2015-01-01

he Chinese tiger frog Hoplobatrachus rugulosus is widely distributed in southern China, Malaysia, Myanmar, Thailand, and Vietnam. It is listed in Appendix II of CITES as the only Class II nationally-protected frog in China. The bred tiger frog known as the Thailand tiger frog, is also identified as H. rugulosus. Our analysis of the Cyt b gene showed high genetic divergence (13.8%) between wild and bred samples of tiger frog. Unexpected genetic divergence of the complete mt genome (14.0%) was also observed between wild and bred samples of tiger frog. Yet, the nuclear genes (NCX1, Rag1, Rhod, Tyr) showed little divergence between them. Despite this and their very similar morphology, the features of the mitochondrial genome including genetic divergence of other genes, different three-dimensional structures of ND5 proteins, and gene rearrangements indicate that H. rugulosus may be a cryptic species complex. Using Bayesian inference, maximum likelihood, and maximum parsimony analyses, Hoplobatrachus was resolved as a sister clade to Euphlyctis, and H. rugulosus (BT) as a sister clade to H. rugulosus (WT). We suggest that we should prevent Thailand tiger frogs (bred type) from escaping into wild environments lest they produce hybrids with Chinese tiger frogs (wild type).

Do Cryptic Species Exist in Hoplobatrachus rugulosus? An Examination Using Four Nuclear Genes, the Cyt b Gene and the Complete MT Genome

PubMed Central

Li, Peng; Zheng, Rongquan; Shao, Chen

2015-01-01

he Chinese tiger frog Hoplobatrachus rugulosus is widely distributed in southern China, Malaysia, Myanmar, Thailand, and Vietnam. It is listed in Appendix II of CITES as the only Class II nationally-protected frog in China. The bred tiger frog known as the Thailand tiger frog, is also identified as H. rugulosus. Our analysis of the Cyt b gene showed high genetic divergence (13.8%) between wild and bred samples of tiger frog. Unexpected genetic divergence of the complete mt genome (14.0%) was also observed between wild and bred samples of tiger frog. Yet, the nuclear genes (NCX1, Rag1, Rhod, Tyr) showed little divergence between them. Despite this and their very similar morphology, the features of the mitochondrial genome including genetic divergence of other genes, different three-dimensional structures of ND5 proteins, and gene rearrangements indicate that H. rugulosus may be a cryptic species complex. Using Bayesian inference, maximum likelihood, and maximum parsimony analyses, Hoplobatrachus was resolved as a sister clade to Euphlyctis, and H. rugulosus (BT) as a sister clade to H. rugulosus (WT). We suggest that we should prevent Thailand tiger frogs (bred type) from escaping into wild environments lest they produce hybrids with Chinese tiger frogs (wild type). PMID:25875761

Targeted thermal therapy with genetically engineered magnetite magnetosomes@RGD: Photothermia is far more efficient than magnetic hyperthermia.

PubMed

Plan Sangnier, Anouchka; Preveral, Sandra; Curcio, Alberto; K A Silva, Amanda; Lefèvre, Chistopher T; Pignol, David; Lalatonne, Yoann; Wilhelm, Claire

2018-06-10

Providing appropriate means for heat generation by low intratumoral nanoparticle concentrations is a major challenge for cancer nanotherapy. Here we propose RGD-tagged magnetosomes (magnetosomes@RGD) as a biogenic, genetically engineered, inorganic platform for multivalent thermal cancer treatment. Magnetosomes@RGD are biomagnetite nanoparticles synthesized by genetically modified magnetotactic bacteria thanks to a translational fusion of the RGD peptide with the magnetosomal protein MamC. Magnetosomes@RGD thus combine the high crystallinity of their magnetite core with efficient surface functionalization. The specific affinity of RGD was first quantified by single-cell magnetophoresis with a variety of cell types, including immune, muscle, endothelial, stem and cancer cells. The highest affinity and cellular uptake was observed with PC3 prostatic and HeLa uterine cancer cells. The efficiency of photothermia and magnetic hyperthermia was then compared on PC3 cells. Unexpectedly, photothermia was far more efficient than magnetic hyperthermia, which was almost totally inhibited by the cellular environment. RGD targeting was then assessed in vivo at tumor site, in mice bearing PC3 tumors. As a result, we demonstrate that targeted magnetic nanoparticles could generate heat on a therapeutic level after systemic administration, but only under laser excitation, and successfully inhibit tumor progression. Copyright © 2018 Elsevier B.V. All rights reserved.

Occupational exposure to antineoplastic agents induces a high level of chromosome damage. Lack of an effect of GST polymorphisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Testa, Antonella; Giachelia, Manuela; Palma, Selena

The aim of our study was to investigate whether occupational exposure to antineoplastic drugs (AND) resulted in genetic damage, possibly indicative of adverse health effects in the long term. We performed a chromosomal aberrations (CA) analysis in peripheral blood lymphocytes (PBL) of a group of 76 trained nurses occupationally exposed to AND. Furthermore, we analysed whether genetic polymorphisms in four metabolic genes of the glutathione S-transferase (GST) family involved in antineoplastic drugs detoxification (GSTM1, GSTT1, GSTP1, GSTA1) had any effect on the yield of chromosomal aberrations in nurses exposed to antineoplastic agents. The exposed group showed a very significant increasemore » of genetic damage (p < 0.0001) potentially indicative of an increased risk of cancer. Unexpectedly, besides the elevated level of chromatid-type aberrations usually related to exposure to chemical agents, we found also severe chromosome damages such as chromosome deletions and dicentric chromosomes, usually related to radiation exposure. No significant association was detected between all GSTs genotypes and chromosome damage. In conclusion, our data show how the occupational exposure to AND is associated to a potential cancer risk, suggesting that current prevention methods do not completely eliminate opportunities for exposure and supporting the need to improve the actual safety practices.« less

Sequence analysis of Jembrana disease virus strains reveals a genetically stable lentivirus.

PubMed

Desport, Moira; Stewart, Meredith E; Mikosza, Andrew S; Sheridan, Carol A; Peterson, Shane E; Chavand, Olivier; Hartaningsih, Nining; Wilcox, Graham E

2007-06-01

Jembrana disease virus (JDV) is a lentivirus associated with an acute disease syndrome with a 20% case fatality rate in Bos javanicus (Bali cattle) in Indonesia, occurring after a short incubation period and with no recurrence of the disease after recovery. Partial regions of gag and pol and the entire env were examined for sequence variation in DNA samples from cases of Jembrana disease obtained from Bali, Sumatra and South Kalimantan in Indonesian Borneo. A high level of nucleotide conservation (97-100%) was observed in gag sequences from samples taken in Bali and Sumatra, indicating that the source of JDV in Sumatra was most likely to have originated from Bali. The pol sequences and, unexpectedly, the env sequences from Bali samples were also well conserved with low nucleotide (96-99%) and amino acid substitutions (95-99%). However, the sample from South Kalimantan (JDV(KAL/01)) contained more divergent sequences, particularly in env (88% identity). Phylogenetic analysis revealed that the JDV(KAL/01)env sequences clustered with the sequence from the Pulukan sample (Bali) from 2001. JDV appears to be remarkably stable genetically and has undergone minor genetic changes over a period of nearly 20 years in Bali despite becoming endemic in the cattle population of the island.

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.

PubMed

Lalonde, Emilie; Albrecht, Steffen; Ha, Kevin C H; Jacob, Karine; Bolduc, Nathalie; Polychronakos, Constantin; Dechelotte, Pierre; Majewski, Jacek; Jabado, Nada

2010-08-01

Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity.

Evidence for weak genetic recombination at the PTP2 locus of Nosema ceranae.

PubMed

Gómez-Moracho, Tamara; Bartolomé, Carolina; Martín-Hernández, Raquel; Higes, Mariano; Maside, Xulio

2015-04-01

The microsporidian Nosema ceranae is an emergent pathogen that threatens the health of honeybees and other pollinators all over the world. Its recent rapid spread across a wide variety of host species and environments demonstrated an enhanced ability of adaptation, which seems to contradict the lack of evidence for genetic recombination and the absence of a sexual stage in its life cycle. Here we retrieved fresh data of the patterns of genetic variation at the PTP2 locus in naturally infected Apis mellifera colonies, by means of single genome amplification. This technique, designed to prevent the formation of chimeric haplotypes during polymerase chain reaction (PCR), provides more reliable estimates of the diversity levels and haplotype structure than standard PCR-cloning methods. Our results are consistent with low but significant rates of recombination in the history of the haplotypes detected: estimates of the population recombination rate are of the order of 30 and support recent evidence for unexpectedly high levels of variation of the parasites within honeybee colonies. These observations suggest the existence of a diploid stage at some point in the life cycle of this parasite and are relevant for our understanding of the dynamics of its expanding population. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

PubMed Central

2009-01-01

In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort) was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA) program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9%) reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8%) had an estimated lifetime risk of breast cancer ≥ 20% and 214 (23.7%) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7%). The overall prevalence of a hereditary breast cancer phenotype was 6.2% (95%CI: 5.67-6.65). These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3%) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers. PMID:21637504

Unexpected Relationships and Inbreeding in HapMap Phase III Populations

PubMed Central

Stevens, Eric L.; Baugher, Joseph D.; Shirley, Matthew D.; Frelin, Laurence P.; Pevsner, Jonathan

2012-01-01

Correct annotation of the genetic relationships between samples is essential for population genomic studies, which could be biased by errors or omissions. To this end, we used identity-by-state (IBS) and identity-by-descent (IBD) methods to assess genetic relatedness of individuals within HapMap phase III data. We analyzed data from 1,397 individuals across 11 ethnic populations. Our results support previous studies (Pemberton et al., 2010; Kyriazopoulou-Panagiotopoulou et al., 2011) assessing unknown relatedness present within this population. Additionally, we present evidence for 1,657 novel pairwise relationships across 9 populations. Surprisingly, significant Cotterman's coefficients of relatedness K1 (IBD1) values were detected between pairs of known parents. Furthermore, significant K2 (IBD2) values were detected in 32 previously annotated parent-child relationships. Consistent with a hypothesis of inbreeding, regions of homozygosity (ROH) were identified in the offspring of related parents, of which a subset overlapped those reported in previous studies (Gibson et al. 2010; Johnson et al. 2011). In total, we inferred 28 inbred individuals with ROH that overlapped areas of relatedness between the parents and/or IBD2 sharing at a different genomic locus between a child and a parent. Finally, 8 previously annotated parent-child relationships had unexpected K0 (IBD0) values (resulting from a chromosomal abnormality or genotype error), and 10 previously annotated second-degree relationships along with 38 other novel pairwise relationships had unexpected IBD2 (indicating two separate paths of recent ancestry). These newly described types of relatedness may impact the outcome of previous studies and should inform the design of future studies relying on the HapMap Phase III resource. PMID:23185369

Effects of hydrostatic pressure on yeasts isolated from deep-sea hydrothermal vents.

PubMed

Burgaud, Gaëtan; Hué, Nguyen Thi Minh; Arzur, Danielle; Coton, Monika; Perrier-Cornet, Jean-Marie; Jebbar, Mohamed; Barbier, Georges

2015-11-01

Hydrostatic pressure plays a significant role in the distribution of life in the biosphere. Knowledge of deep-sea piezotolerant and (hyper)piezophilic bacteria and archaea diversity has been well documented, along with their specific adaptations to cope with high hydrostatic pressure (HHP). Recent investigations of deep-sea microbial community compositions have shown unexpected micro-eukaryotic communities, mainly dominated by fungi. Molecular methods such as next-generation sequencing have been used for SSU rRNA gene sequencing to reveal fungal taxa. Currently, a difficult but fascinating challenge for marine mycologists is to create deep-sea marine fungus culture collections and assess their ability to cope with pressure. Indeed, although there is no universal genetic marker for piezoresistance, physiological analyses provide concrete relevant data for estimating their adaptations and understanding the role of fungal communities in the abyss. The present study investigated morphological and physiological responses of fungi to HHP using a collection of deep-sea yeasts as a model. The aim was to determine whether deep-sea yeasts were able to tolerate different HHP and if they were metabolically active. Here we report an unexpected taxonomic-based dichotomic response to pressure with piezosensitve ascomycetes and piezotolerant basidiomycetes, and distinct morphological switches triggered by pressure for certain strains. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Testing the link between population genetic differentiation and clade diversification in Costa Rican orchids.

PubMed

Kisel, Yael; Moreno-Letelier, Alejandra C; Bogarín, Diego; Powell, Martyn P; Chase, Mark W; Barraclough, Timothy G

2012-10-01

Species population genetics could be an important factor explaining variation in clade species richness. Here, we use newly generated amplified fragment length polymorphism (AFLP) data to test whether five pairs of sister clades of Costa Rican orchids that differ greatly in species richness also differ in average neutral genetic differentiation within species, expecting that if the strength of processes promoting differentiation within species is phylogenetically heritable, then clades with greater genetic differentiation should diversify more. Contrary to expectation, neutral genetic differentiation does not correlate directly with total diversification in the clades studied. Neutral genetic differentiation varies greatly among species and shows no heritability within clades. Half of the variation in neutral genetic differentiation among populations can be explained by ecological variables, and species-level traits explain the most variation. Unexpectedly, we find no isolation by distance in any species, but genetic differentiation is greater between populations occupying different niches. This pattern corresponds with those observed for microscopic eukaryotes and could reflect effective widespread dispersal of tiny and numerous orchid seeds. Although not providing a definitive answer to whether population genetics processes affect clade diversification, this work highlights the potential for addressing new macroevolutionary questions using a comparative population genetic approach. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

Genetically modified α-amylase inhibitor peas are not specifically allergenic in mice.

PubMed

Lee, Rui-Yun; Reiner, Daniela; Dekan, Gerhard; Moore, Andrew E; Higgins, T J V; Epstein, Michelle M

2013-01-01

Weevils can devastate food legumes in developing countries, but genetically modified peas (Pisum sativum), chickpeas and cowpeas expressing the gene for alpha-amylase inhibitor-1 (αAI) from the common bean (Phaseolus vulgaris) are completely protected from weevil destruction. αAI is seed-specific, accumulated at high levels and undergoes post-translational modification as it traverses the seed endomembrane system. This modification was thought to be responsible for the reported allergenicity in mice of the transgenic pea but not the bean. Here, we observed that transgenic αAI peas, chickpeas and cowpeas as well as non-transgenic beans were all allergenic in BALB/c mice. Even consuming non-transgenic peas lacking αAI led to an anti-αAI response due to a cross-reactive response to pea lectin. Our data demonstrate that αAI transgenic peas are not more allergenic than beans or non-transgenic peas in mice. This study illustrates the importance of repeat experiments in independent laboratories and the potential for unexpected cross-reactive allergic responses upon consumption of plant products in mice.

Genetically Modified α-Amylase Inhibitor Peas Are Not Specifically Allergenic in Mice

PubMed Central

Dekan, Gerhard; Moore, Andrew E.; Higgins, T. J. V.; Epstein, Michelle M.

2013-01-01

Weevils can devastate food legumes in developing countries, but genetically modified peas (Pisum sativum), chickpeas and cowpeas expressing the gene for alpha-amylase inhibitor-1 (αAI) from the common bean (Phaseolus vulgaris) are completely protected from weevil destruction. αAI is seed-specific, accumulated at high levels and undergoes post-translational modification as it traverses the seed endomembrane system. This modification was thought to be responsible for the reported allergenicity in mice of the transgenic pea but not the bean. Here, we observed that transgenic αAI peas, chickpeas and cowpeas as well as non-transgenic beans were all allergenic in BALB/c mice. Even consuming non-transgenic peas lacking αAI led to an anti-αAI response due to a cross-reactive response to pea lectin. Our data demonstrate that αAI transgenic peas are not more allergenic than beans or non-transgenic peas in mice. This study illustrates the importance of repeat experiments in independent laboratories and the potential for unexpected cross-reactive allergic responses upon consumption of plant products in mice. PMID:23326368

Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana.

PubMed

Lin, X; Kaul, S; Rounsley, S; Shea, T P; Benito, M I; Town, C D; Fujii, C Y; Mason, T; Bowman, C L; Barnstead, M; Feldblyum, T V; Buell, C R; Ketchum, K A; Lee, J; Ronning, C M; Koo, H L; Moffat, K S; Cronin, L A; Shen, M; Pai, G; Van Aken, S; Umayam, L; Tallon, L J; Gill, J E; Adams, M D; Carrera, A J; Creasy, T H; Goodman, H M; Somerville, C R; Copenhaver, G P; Preuss, D; Nierman, W C; White, O; Eisen, J A; Salzberg, S L; Fraser, C M; Venter, J C

1999-12-16

Arabidopsis thaliana (Arabidopsis) is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA. Here we report the sequence of chromosome 2 from the Columbia ecotype in two gap-free assemblies (contigs) of 3.6 and 16 megabases (Mb). The latter represents the longest published stretch of uninterrupted DNA sequence assembled from any organism to date. Chromosome 2 represents 15% of the genome and encodes 4,037 genes, 49% of which have no predicted function. Roughly 250 tandem gene duplications were found in addition to large-scale duplications of about 0.5 and 4.5 Mb between chromosomes 2 and 1 and between chromosomes 2 and 4, respectively. Sequencing of nearly 2 Mb within the genetically defined centromere revealed a low density of recognizable genes, and a high density and diverse range of vestigial and presumably inactive mobile elements. More unexpected is what appears to be a recent insertion of a continuous stretch of 75% of the mitochondrial genome into chromosome 2.

Predicting Gene Structure Changes Resulting from Genetic Variants via Exon Definition Features.

PubMed

Majoros, William H; Holt, Carson; Campbell, Michael S; Ware, Doreen; Yandell, Mark; Reddy, Timothy E

2018-04-25

Genetic variation that disrupts gene function by altering gene splicing between individuals can substantially influence traits and disease. In those cases, accurately predicting the effects of genetic variation on splicing can be highly valuable for investigating the mechanisms underlying those traits and diseases. While methods have been developed to generate high quality computational predictions of gene structures in reference genomes, the same methods perform poorly when used to predict the potentially deleterious effects of genetic changes that alter gene splicing between individuals. Underlying that discrepancy in predictive ability are the common assumptions by reference gene finding algorithms that genes are conserved, well-formed, and produce functional proteins. We describe a probabilistic approach for predicting recent changes to gene structure that may or may not conserve function. The model is applicable to both coding and noncoding genes, and can be trained on existing gene annotations without requiring curated examples of aberrant splicing. We apply this model to the problem of predicting altered splicing patterns in the genomes of individual humans, and we demonstrate that performing gene-structure prediction without relying on conserved coding features is feasible. The model predicts an unexpected abundance of variants that create de novo splice sites, an observation supported by both simulations and empirical data from RNA-seq experiments. While these de novo splice variants are commonly misinterpreted by other tools as coding or noncoding variants of little or no effect, we find that in some cases they can have large effects on splicing activity and protein products, and we propose that they may commonly act as cryptic factors in disease. The software is available from geneprediction.org/SGRF. bmajoros@duke.edu. Supplementary information is available at Bioinformatics online.

The Evolution of Polymorphic Hybrid Incompatibilities in House Mice.

PubMed

Larson, Erica L; Vanderpool, Dan; Sarver, Brice A J; Callahan, Colin; Keeble, Sara; Provencio, Lorraine P; Kessler, Michael D; Stewart, Vanessa; Nordquist, Erin; Dean, Matthew D; Good, Jeffrey M

2018-04-24

Resolving the mechanistic and genetic bases of reproductive barriers between species is essential to understanding the evolutionary forces that shape speciation. Intrinsic hybrid incompatibilities are often treated as fixed between species, yet there can be considerable variation in the strength of reproductive isolation between populations. The extent and causes of this variation remain poorly understood in most systems. We investigated the genetic basis of variable hybrid male sterility (HMS) between two recently diverged subspecies of house mice, Mus musculus domesticus and M. m. musculus We found that polymorphic HMS has a surprisingly complex genetic basis, with contributions from at least five autosomal loci segregating between two closely related wild-derived strains of M. m. musculus One of the HMS-linked regions on Chromosome 4 also showed extensive introgression among inbred laboratory strains and transmission ratio distortion (TRD) in hybrid crosses. Using additional crosses and whole genome sequencing of sperm pools, we showed that TRD was limited to hybrid crosses and was not due to differences in sperm motility between M. m. musculus strains. Based on these results, we argue that TRD likely reflects additional incompatibilities that reduce hybrid embryonic viability. In some common inbred strains of mice, selection against deleterious interactions appears to have unexpectedly driven introgression at loci involved in epistatic hybrid incompatibilities. The highly variable genetic basis to F1 hybrid incompatibilities between closely related mouse lineages argues that a thorough dissection of reproductive isolation will require much more extensive sampling of natural variation than has been commonly utilized in mice and other model systems. Copyright © 2018, Genetics.

Sudden and unexpected childhood deaths investigated at the Pretoria Medico-Legal Laboratory, South Africa, 2007 - 2011.

PubMed

Van Deventer, B S; Rossouw, S H; Du Toit-Prinsloo, L

2016-09-06

 Sudden and unexpected death is well known to occur in infants, and although sudden deaths are less frequent after the first birthday, they still account for a significant proportion of childhood deaths. In 2009, 1.9% of the total deaths in the USA were childhood deaths. In South Africa (SA) this proportion was much higher at 11.85%. According to the law, sudden and unexpected deaths are generally investigated as unnatural deaths. Establishing an exact underlying anatomical cause of death will depend on available resources and can be difficult in a substantial proportion of cases.  A retrospective descriptive case audit was conducted at the Pretoria Medico-Legal Laboratory (PMLL), SA, from 1 January 2007 through to 31 December 2011. All children aged 1 - 18 years who died suddenly and unexpectedly were included.  Ninety-eight cases were identified, which constituted nearly 1% of total admissions to the PMLL. The majority of the deaths were of children aged 1 - 5 years, and the male/female ratio was 1.04:1. In the largest proportion of cases (n=28, 28.6%), the medicolegal investigation, including autopsy and ancillary investigations, did not establish an underlying anatomical cause of death. In the cases where a cause of death was established, pneumonia was the most common diagnosis (n=22, 22.4%).  The fact that the cause of the largest proportion of deaths could not be ascertained emphasises the need for consideration of additional investigative techniques, such as molecular/genetic screening, which have provided an underlying cause of death in a significant number of cases in other countries. There is a lack of published research on the causes and incidence of sudden unexpected deaths in children in SA, and further research in this area is needed.

REC-1 and HIM-5 distribute meiotic crossovers and function redundantly in meiotic double-strand break formation in Caenorhabditis elegans

PubMed Central

Chung, George; Rose, Ann M.; Petalcorin, Mark I.R.; Martin, Julie S.; Kessler, Zebulin; Sanchez-Pulido, Luis; Ponting, Chris P.; Yanowitz, Judith L.; Boulton, Simon J.

2015-01-01

The Caenorhabditis elegans gene rec-1 was the first genetic locus identified in metazoa to affect the distribution of meiotic crossovers along the chromosome. We report that rec-1 encodes a distant paralog of HIM-5, which was discovered by whole-genome sequencing and confirmed by multiple genome-edited alleles. REC-1 is phosphorylated by cyclin-dependent kinase (CDK) in vitro, and mutation of the CDK consensus sites in REC-1 compromises meiotic crossover distribution in vivo. Unexpectedly, rec-1; him-5 double mutants are synthetic-lethal due to a defect in meiotic double-strand break formation. Thus, we uncovered an unexpected robustness to meiotic DSB formation and crossover positioning that is executed by HIM-5 and REC-1 and regulated by phosphorylation. PMID:26385965

Mammalian skin cell biology: at the interface between laboratory and clinic.

PubMed

Watt, Fiona M

2014-11-21

Mammalian skin research represents the convergence of three complementary disciplines: cell biology, mouse genetics, and dermatology. The skin provides a paradigm for current research in cell adhesion, inflammation, and tissue stem cells. Here, I discuss recent insights into the cell biology of skin. Single-cell analysis has revealed that human epidermal stem cells are heterogeneous and differentiate in response to multiple extrinsic signals. Live-cell imaging, optogenetics, and cell ablation experiments show skin cells to be remarkably dynamic. High-throughput, genome-wide approaches have yielded unprecedented insights into the circuitry that controls epidermal stem cell fate. Last, integrative biological analysis of human skin disorders has revealed unexpected functions for elements of the skin that were previously considered purely structural. Copyright © 2014, American Association for the Advancement of Science.

Comparative analysis of bat genomes provides insight into the evolution of flight and immunity.

PubMed

Zhang, Guojie; Cowled, Christopher; Shi, Zhengli; Huang, Zhiyong; Bishop-Lilly, Kimberly A; Fang, Xiaodong; Wynne, James W; Xiong, Zhiqiang; Baker, Michelle L; Zhao, Wei; Tachedjian, Mary; Zhu, Yabing; Zhou, Peng; Jiang, Xuanting; Ng, Justin; Yang, Lan; Wu, Lijun; Xiao, Jin; Feng, Yue; Chen, Yuanxin; Sun, Xiaoqing; Zhang, Yong; Marsh, Glenn A; Crameri, Gary; Broder, Christopher C; Frey, Kenneth G; Wang, Lin-Fa; Wang, Jun

2013-01-25

Bats are the only mammals capable of sustained flight and are notorious reservoir hosts for some of the world's most highly pathogenic viruses, including Nipah, Hendra, Ebola, and severe acute respiratory syndrome (SARS). To identify genetic changes associated with the development of bat-specific traits, we performed whole-genome sequencing and comparative analyses of two distantly related species, fruit bat Pteropus alecto and insectivorous bat Myotis davidii. We discovered an unexpected concentration of positively selected genes in the DNA damage checkpoint and nuclear factor κB pathways that may be related to the origin of flight, as well as expansion and contraction of important gene families. Comparison of bat genomes with other mammalian species has provided new insights into bat biology and evolution.

Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

PubMed Central

Soundararajan, Venky; Aravamudan, Murali

2014-01-01

The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action – inspired by the Google page rank algorithm that unearths most “globally connected” websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs – up to 20Å from the ATP binding site, but within 5Å of the phosphorylation site – encode the Gibbs free energy of inhibition (ΔGinhibition) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows. PMID:25465236

Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population

PubMed Central

Villanueva, Pia; Newbury, Dianne F; Jara, Lilian; De Barbieri, Zulema; Mirza, Ghazala; Palomino, Hernán M; Fernández, María Angélica; Cazier, Jean-Baptiste; Monaco, Anthony P; Palomino, Hernán

2011-01-01

Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL=6.73, P=4.0 × 10−11). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P=0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments. PMID:21248734

Length Distributions of Identity by Descent Reveal Fine-Scale Demographic History

PubMed Central

Palamara, Pier Francesco; Lencz, Todd; Darvasi, Ariel; Pe’er, Itsik

2012-01-01

Data-driven studies of identity by descent (IBD) were recently enabled by high-resolution genomic data from large cohorts and scalable algorithms for IBD detection. Yet, haplotype sharing currently represents an underutilized source of information for population-genetics research. We present analytical results on the relationship between haplotype sharing across purportedly unrelated individuals and a population’s demographic history. We express the distribution of IBD sharing across pairs of individuals for segments of arbitrary length as a function of the population’s demography, and we derive an inference procedure to reconstruct such demographic history. The accuracy of the proposed reconstruction methodology was extensively tested on simulated data. We applied this methodology to two densely typed data sets: 500 Ashkenazi Jewish (AJ) individuals and 56 Kenyan Maasai (MKK) individuals (HapMap 3 data set). Reconstructing the demographic history of the AJ cohort, we recovered two subsequent population expansions, separated by a severe founder event, consistent with previous analysis of lower-throughput genetic data and historical accounts of AJ history. In the MKK cohort, high levels of cryptic relatedness were detected. The spectrum of IBD sharing is consistent with a demographic model in which several small-sized demes intermix through high migration rates and result in enrichment of shared long-range haplotypes. This scenario of historically structured demographies might explain the unexpected abundance of runs of homozygosity within several populations. PMID:23103233

Geography and end use drive the diversification of worldwide winter rye populations.

PubMed

Parat, Florence; Schwertfirm, Grit; Rudolph, Ulrike; Miedaner, Thomas; Korzun, Viktor; Bauer, Eva; Schön, Chris-Carolin; Tellier, Aurélien

2016-01-01

To meet the current challenges in human food production, improved understanding of the genetic diversity of crop species that maximizes the selection efficacy in breeding programs is needed. The present study offers new insights into the diversity, genetic structure and demographic history of cultivated rye (Secale cereale L.). We genotyped 620 individuals from 14 global rye populations with a different end use (grain or forage) at 32 genome-wide simple sequence repeat markers. We reveal the relationships among these populations, their sizes and the timing of domestication events using population genetics and model-based inference with approximate Bayesian computation. Our main results demonstrate (i) a high within-population variation and genetic diversity, (ii) an unexpected absence of reduction in diversity with an increasing improvement level and (iii) patterns suggestive of multiple domestication events. We suggest that the main drivers of diversification of winter rye are the end use of rye in two early regions of cultivation: rye forage in the Mediterranean area and grain in northeast Europe. The lower diversity and stronger differentiation of eastern European populations were most likely due to more intensive cultivation and breeding of rye in this region, in contrast to the Mediterranean region where it was considered a secondary crop or even a weed. We discuss the relevance of our results for the management of gene bank resources and the pitfalls of inference methods applied to crop domestication due to violation of model assumptions and model complexity. © 2015 John Wiley & Sons Ltd.

Spontaneous Chloroplast Mutants Mostly Occur by Replication Slippage and Show a Biased Pattern in the Plastome of Oenothera[OPEN

PubMed Central

Massouh, Amid; Schubert, Julia; Yaneva-Roder, Liliya; Ulbricht-Jones, Elena S.; Johnson, Marc T.J.; Wright, Stephen I.; Pellizzer, Tommaso; Sobanski, Johanna; Greiner, Stephan

2016-01-01

Spontaneous plastome mutants have been used as a research tool since the beginning of genetics. However, technical restrictions have severely limited their contributions to research in physiology and molecular biology. Here, we used full plastome sequencing to systematically characterize a collection of 51 spontaneous chloroplast mutants in Oenothera (evening primrose). Most mutants carry only a single mutation. Unexpectedly, the vast majority of mutations do not represent single nucleotide polymorphisms but are insertions/deletions originating from DNA replication slippage events. Only very few mutations appear to be caused by imprecise double-strand break repair, nucleotide misincorporation during replication, or incorrect nucleotide excision repair following oxidative damage. U-turn inversions were not detected. Replication slippage is induced at repetitive sequences that can be very small and tend to have high A/T content. Interestingly, the mutations are not distributed randomly in the genome. The underrepresentation of mutations caused by faulty double-strand break repair might explain the high structural conservation of seed plant plastomes throughout evolution. In addition to providing a fully characterized mutant collection for future research on plastid genetics, gene expression, and photosynthesis, our work identified the spectrum of spontaneous mutations in plastids and reveals that this spectrum is very different from that in the nucleus. PMID:27053421

Marked augmentation of PLGA nanoparticle-induced metabolically beneficial impact of γ-oryzanol on fuel dyshomeostasis in genetically obese-diabetic ob/ob mice.

PubMed

Kozuka, Chisayo; Shimizu-Okabe, Chigusa; Takayama, Chitoshi; Nakano, Kaku; Morinaga, Hidetaka; Kinjo, Ayano; Fukuda, Kotaro; Kamei, Asuka; Yasuoka, Akihito; Kondo, Takashi; Abe, Keiko; Egashira, Kensuke; Masuzaki, Hiroaki

2017-11-01

Our previous works demonstrated that brown rice-specific bioactive substance, γ-oryzanol acts as a chaperone, attenuates exaggerated endoplasmic reticulum (ER) stress in brain hypothalamus and pancreatic islets, thereby ameliorating metabolic derangement in high fat diet (HFD)-induced obese diabetic mice. However, extremely low absorption efficiency from intestine of γ-oryzanol is a tough obstacle for the clinical application. Therefore, in this study, to overcome extremely low bioavailability of γ-oryzanol with super-high lipophilicity, we encapsulated γ-oryzanol in polymer poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Nano-Orz), and evaluated its metabolically beneficial impact in genetically obese-diabetic ob/ob mice, the best-known severest diabetic model in mice. To our surprise, Nano-Orz markedly ameliorated fuel metabolism with an unexpected magnitude (∼1000-fold lower dose) compared with regular γ-oryzanol. Furthermore, such a conspicuous impact was achievable by its administration once every 2 weeks. Besides the excellent impact on dysfunction of hypothalamus and pancreatic islets, Nano-Orz markedly decreased ER stress and inflammation in liver and adipose tissue. Collectively, nanotechnology-based developments of functional foods oriented toward γ-oryzanol shed light on the novel approach for the treatment of a variety of metabolic diseases in humans.

Ancestral genetic diversity associated with the rapid spread of stress-tolerant coral symbionts in response to Holocene climate change.

PubMed

Hume, Benjamin C C; Voolstra, Christian R; Arif, Chatchanit; D'Angelo, Cecilia; Burt, John A; Eyal, Gal; Loya, Yossi; Wiedenmann, Jörg

2016-04-19

Coral communities in the Persian/Arabian Gulf (PAG) withstand unusually high salinity levels and regular summer temperature maxima of up to ∼35 °C that kill conspecifics elsewhere. Due to the recent formation of the PAG and its subsequent shift to a hot climate, these corals have had only <6,000 y to adapt to these extreme conditions and can therefore inform on how coral reefs may respond to global warming. One key to coral survival in the world's warmest reefs are symbioses with a newly discovered alga,Symbiodinium thermophilum Currently, it is unknown whether this symbiont originated elsewhere or emerged from unexpectedly fast evolution catalyzed by the extreme environment. Analyzing genetic diversity of symbiotic algae across >5,000 km of the PAG, the Gulf of Oman, and the Red Sea coastline, we show thatS. thermophilumis a member of a highly diverse, ancient group of symbionts cryptically distributed outside the PAG. We argue that the adjustment to temperature extremes by PAG corals was facilitated by the positive selection of preadapted symbionts. Our findings suggest that maintaining the largest possible pool of potentially stress-tolerant genotypes by protecting existing biodiversity is crucial to promote rapid adaptation to present-day climate change, not only for coral reefs, but for ecosystems in general.

Uniparental ancestry markers in Chilean populations

PubMed Central

Vieira-Machado, Camilla Dutra; Tostes, Maluah; Alves, Gabrielle; Nazer, Julio; Martinez, Liliana; Wettig, Elisabeth; Pizarro Rivadeneira, Oscar; Diaz Caamaño, Marcela; Larenas Ascui, Jessica; Pavez, Pedro; Dutra, Maria da Graça; Castilla, Eduardo Enrique; Orioli, Ieda Maria

2016-01-01

Abstract The presence of Native Americans, Europeans, and Africans has led to the development of a multi-ethnic, admixed population in Chile. This study aimed to contribute to the characterization of the uniparental genetic structure of three Chilean regions. Newborns from seven hospitals in Independencia, Providencia, Santiago, Curicó, Cauquenes, Valdívia, and Puerto Montt communes, belonging to the Chilean regions of Santiago, Maule, and Los Lagos, were studied. The presence of Native American mitochondrial DNA (mtDNA) haplogroups and two markers present in the non-recombinant region of the Y chromosome, DYS199 and DYS287, indicative of Native American and African ancestry, respectively, was determined. A high Native American matrilineal contribution and a low Native American and African patrilineal contributions were found in all three studied regions. As previously found in Chilean admixed populations, the Native American matrilineal contribution was lower in Santiago than in the other studied regions. However, there was an unexpectedly higher contribution of Native American ancestry in one of the studied communes in Santiago, probably due to the high rate of immigration from other regions of the country. The population genetic sub-structure we detected in Santiago using few uniparental markers requires further confirmation, owing to possible stratification for autosomal and X-chromosome markers. PMID:27561109

The N400 and the P300 are not all that independent.

PubMed

Arbel, Yael; Spencer, Kevin M; Donchin, Emanuel

2011-06-01

This study assessed whether two ERP components that are elicited by unexpected events interact. The conditions that are known to elicit the N400 and the P300 ERP components were applied separately and in combination to terminal-words in sentences. Each sentence ended with a terminal-word that was highly expected, semantically unexpected, physically deviant, or both semantically unexpected and physically deviant. In addition, we varied the level of semantic relatedness between the unexpected terminal-words and the expected exemplars. Physically deviant words elicited a P300, whereas semantically unexpected words elicited an N400, whose amplitude was sensitive to the level of semantic relatedness. Words that were both semantically unexpected and physically deviant elicited both an N400 with enhanced amplitude, and a P300 with reduced amplitude. These results suggest an interaction between the processes manifested by the two components. Copyright © 2010 Society for Psychophysiological Research.

Digging up the roots of an insular hotspot of genetic diversity: decoupled mito-nuclear histories in the evolution of the Corsican-Sardinian endemic lizard Podarcis tiliguerta.

PubMed

Salvi, Daniele; Pinho, Catarina; Harris, D James

2017-03-02

Mediterranean islands host a disproportionately high level of biodiversity and endemisms. Growing phylogeographic evidence on island endemics has unveiled unexpectedly complex patterns of intra-island diversification, which originated at diverse spatial and temporal scales. We investigated multilocus genetic variation of the Corsican-Sardinian endemic lizard Podarcis tiliguerta with the aim of shedding more light on the evolutionary processes underlying the origin of Mediterranean island biodiversity. We analysed DNA sequences of mitochondrial (12S and nd4) and nuclear (acm4 and mc1r) gene fragments in 174 individuals of P. tiliguerta from 81 localities across the full range of the species in a geographic and genealogical framework. We found surprisingly high genetic diversity both at mitochondrial and nuclear loci. Seventeen reciprocally monophyletic allopatric mitochondrial haplogroups were sharply divided into four main mitochondrial lineages (two in Corsica and two in Sardinia) of Miocene origin. In contrast, shallow divergence and shared diversity within and between islands was observed at the nuclear loci. We evaluated alternative biogeographic and evolutionary scenarios to explain such profound discordance in spatial and phylogenetic patterning between mitochondrial and nuclear genomes. While neutral models provided unparsimonious explanations for the observed pattern, the hypothesis of environmental selection driving mitochondrial divergence in the presence of nuclear gene flow is favoured. Our study on the genetic variation of P. tiliguerta reveals surprising levels of diversity underlining a complex phylogeographic pattern with a striking example of mito-nuclear discordance. These findings have profound implications, not only for the taxonomy and conservation of P. tiliguerta. Growing evidence on deep mitochondrial breaks in absence of geographic barriers and of climatic factors associated to genetic variation of Corsican-Sardinian endemics warrants additional investigation on the potential role of environmental selection driving the evolution of diversity hotspots within Mediterranean islands.

Microevolutionary dynamics of a macroevolutionary key innovation in a Lepidopteran herbivore

PubMed Central

2010-01-01

Background A molecular population genetics understanding is central to the study of ecological and evolutionary functional genomics. Population genetics identifies genetic variation and its distribution within and among populations, it reveals the demographic history of the populations studied, and can provide indirect insights into historical selection dynamics. Here we use this approach to examine the demographic and selective dynamics acting of a candidate gene involved in plant-insect interactions. Previous work documents the macroevolutionary and historical ecological importance of the nitrile-specifier protein (Nsp), which facilitated the host shift of Pieridae butterflies onto Brassicales host plants ~80 Myr ago. Results Here we assess the microevolutionary dynamics of the Nsp gene by studying the within and among-population variation at Nsp and reference genes in the butterfly Pieris rapae (Small Cabbage White). Nsp exhibits unexpectedly high amounts of amino acid polymorphism, unequally distributed across the gene. The vast majority of genetic variation exists within populations, with little to no genetic differentiation among four populations on two continents. A comparison of synonymous and nonsynonymous substitutions in 70 randomly chosen genes among P. rapae and its close relative Pieris brassicae (Large Cabbage White) finds Nsp to have a significantly relaxed functional constraint compared to housekeeping genes. We find strong evidence for a recent population expansion and no role for strong purifying or directional selection upon the Nsp gene. Conclusions The microevolutionary dynamics of the Nsp gene in P. rapae are dominated by recent population expansion and variation in functional constraint across the repeated domains of the Nsp gene. While the high amounts of amino acid diversity suggest there may be significant functional differences among allelic variants segregating within populations, indirect tests of selection could not conclusively identify a signature of historical selection. The importance of using this information for planning future studies of potential performance and fitness consequences of the observed variation is discussed. PMID:20181249

Bioethics commission to review gene patenting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rothenburg, L.

1995-12-01

In October, in an unexpected development, U.S. President Bill Clinton created a national ethics advisory board, the National Bioethics Advisory Commission (NBAC, Washington, DC), to study both research ethics and the management and use of genetic information. Of particular interest to biotechnology companies and researchers is the fact that the commission`s brief encompasses issues about human gene patenting, a subject not contained in earlier proposals for the commission.

Bone and muscle endocrine functions: Unexpected paradigms of inter-organ communication

PubMed Central

Karsenty, Gerard; Olson, Eric N.

2016-01-01

Most physiological functions originate with the communication between organs. Mouse genetics has revived this holistic view of physiology through the identification of inter-organ communications that are unanticipated, functionally important and would have been difficult to uncover otherwise. This review highlights this point by showing how two tissues usually not seen as endocrine ones, bone and striated muscles, influence in a significant manner several physiological processes. PMID:26967290

Do whole-food animal feeding studies have any value in the safety assessment of GM crops?

PubMed

Herman, Rod A; Ekmay, Ricardo

2014-02-01

The use of whole-food (grain meal contained in feed) animal-feeding studies to support the safety assessment of genetically modified crops has been contentious. This may be, in part, a consequence of poorly agreed upon study objectives. Whole-food animal-feeding studies have been postulated to be useful in detecting both expected and unexpected effects on the composition of genetically modified crops. While the justification of animal feeding studies to detect unexpected effects may be inadequately supported, there may be better justification to conduct such studies in specific cases to investigate the consequences of expected compositional effects including expression of transgenic proteins. Such studies may be justified when (1) safety cannot reasonably be predicted from other evidence, (2) reasonable hypothesis for adverse effects are postulated, (3) the compositional component in question cannot be isolated or enriched in an active form for inclusion in animal feeding studies, and (4) reasonable multiples of exposure can be accomplished relative to human diets. The study design for whole-food animal-feeding studies should be hypotheses-driven, and the types of data collected should be consistent with adverse effects that are known to occur from dietary components of biological origin. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Sudden Unexpected Death in Fetal Life Through Early Childhood

PubMed Central

Kinney, Hannah C.; Willinger, Marian

2016-01-01

In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled “Sudden Unexpected Death in Fetal Life Through Early Childhood: New Opportunities.” Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term “SIDS” in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and “omics” approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of “SIDS” as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research. PMID:27230764

Genealogy of wine grape cultivars: "Pinot" is related to "Syrah".

PubMed

Vouillamoz, J F; Grando, M S

2006-08-01

Since the domestication of wild grapes ca 6000 years ago, numerous cultivars have been generated by spontaneous or deliberate crosses, and up to 10 000 are still in existence today. Just as in human paternity analysis, DNA typing can reveal unexpected parentage of grape cultivars. In this study, we have analysed 89 grape cultivars with 60 microsatellite markers in order to accurately calculate the identity-by-descent (IBD) and relatedness (r) coefficients among six putatively related cultivars from France ("Pinot", "Syrah" and "Dureza") and northern Italy ("Teroldego", "Lagrein" and "Marzemino"). Using a recently developed likelihood-based approach to analyse kinship in grapes, we provide the first evidence of a genetic link between grapes across the Alps: "Dureza" and "Teroldego" turn out to be full-siblings (FS). For the first time in grapevine genetics we were able to detect FS without knowing one of the parents and identify unexpected second-degree relatives. We reconstructed the most likely pedigree that revealed a third-degree relationship between the worldwide-cultivated "Pinot" from Burgundy and "Syrah" from the Rhone Valley. Our finding was totally unsuspected by classical ampelography and it challenges the commonly assumed independent origins of these grape cultivars. Our results and this new approach in grape genetics will (a) help grape breeders to avoid choosing closely related varieties for new crosses, (b) provide pedigrees of cultivars in order to detect inheritance of disease-resistance genes and (c) open the way for future discoveries of first- and second-degree relationships between grape cultivars in order to better understand viticultural migrations.

High-Throughput Characterization of Cascade type I-E CRISPR Guide Efficacy Reveals Unexpected PAM Diversity and Target Sequence Preferences.

PubMed

Fu, Becky Xu Hua; Wainberg, Michael; Kundaje, Anshul; Fire, Andrew Z

2017-08-01

Interactions between Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs and CRISPR-associated (Cas) proteins form an RNA-guided adaptive immune system in prokaryotes. The adaptive immune system utilizes segments of the genetic material of invasive foreign elements in the CRISPR locus. The loci are transcribed and processed to produce small CRISPR RNAs (crRNAs), with degradation of invading genetic material directed by a combination of complementarity between RNA and DNA and in some cases recognition of adjacent motifs called PAMs (Protospacer Adjacent Motifs). Here we describe a general, high-throughput procedure to test the efficacy of thousands of targets, applying this to the Escherichia coli type I-E Cascade (CRISPR-associated complex for antiviral defense) system. These studies were followed with reciprocal experiments in which the consequence of CRISPR activity was survival in the presence of a lytic phage. From the combined analysis of the Cascade system, we found that (i) type I-E Cascade PAM recognition is more expansive than previously reported, with at least 22 distinct PAMs, with many of the noncanonical PAMs having CRISPR-interference abilities similar to the canonical PAMs; (ii) PAM positioning appears precise, with no evidence for tolerance to PAM slippage in interference; and (iii) while increased guanine-cytosine (GC) content in the spacer is associated with higher CRISPR-interference efficiency, high GC content (>62.5%) decreases CRISPR-interference efficiency. Our findings provide a comprehensive functional profile of Cascade type I-E interference requirements and a method to assay spacer efficacy that can be applied to other CRISPR-Cas systems. Copyright © 2017 by the Genetics Society of America.

High molecular diversity in the true service tree (Sorbus domestica) despite rareness: data from Europe with special reference to the Austrian occurrence.

PubMed

George, Jan-Peter; Konrad, Heino; Collin, Eric; Thevenet, Jean; Ballian, Dalibor; Idzojtic, Marilena; Kamm, Urs; Zhelev, Peter; Geburek, Thomas

2015-06-01

Sorbus domestica (Rosaceae) is one of the rarest deciduous tree species in Europe and is characterized by a scattered distribution. To date, no large-scale geographic studies on population genetics have been carried out. Therefore, the aims of this study were to infer levels of molecular diversity across the major part of the European distribution of S. domestica and to determine its population differentiation and structure. In addition, spatial genetic structure was examined together with the patterns of historic and recent gene flow between two adjacent populations. Leaf or cambium samples were collected from 17 populations covering major parts of the European native range from north-west France to south-east Bulgaria. Seven nuclear microsatellites and one chloroplast minisatellite were examined and analysed using a variety of methods. Allelic richness was unexpectedly high for both markers within populations (mean per locus: 3·868 for nSSR and 1·647 for chloroplast minisatellite). Moreover, there was no evidence of inbreeding (mean Fis = -0·047). The Italian Peninsula was characterized as a geographic region with comparatively high genetic diversity for both genomes. Overall population differentiation was moderate (FST = 0·138) and it was clear that populations formed three groups in Europe, namely France, Mediterranean/Balkan and Austria. Historic gene flow between two local Austrian populations was high and asymmetric, while recent gene flow seemed to be disrupted. It is concluded that molecular mechanisms such as self-incompatibility and high gene flow distances are responsible for the observed level of allelic richness as well as for population differentiation. However, human influence could have contributed to the present genetic pattern, especially in the Mediterranean region. Comparison of historic and recent gene flow may mirror the progress of habitat fragmentation in eastern Austria. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Genetic mechanism for designing new generation of buildings from data obtained by sensor agent robots

NASA Astrophysics Data System (ADS)

Ono, Chihiro; Mita, Akira

2012-04-01

Due to an increase in an elderly-people household, and global warming, the design of building spaces requires delicate consideration of the needs of elderly-people. Studies of intelligent spaces that can control suitable devices for residents may provide some of functions needed. However, these intelligent spaces are based on predefined scenarios so that it is difficult to handle unexpected circumstances and adapt to the needs of people. This study aims to suggest a Genetic adaption algorithm for building spaces. The feasibility of the algorithm is tested by simulation. The algorithm extend the existing design methodology by reflecting ongoing living information quickly in the variety of patterns.

Comparison of the physiological characteristics of transgenic insect-resistant cotton and conventional lines.

PubMed

Li, Xiaogang; Ding, Changfeng; Wang, Xingxiang; Liu, Biao

2015-03-04

The introduction of transgenic insect-resistant cotton into agricultural ecosystems has raised concerns regarding its ecological effects. Many studies have been conducted to compare the differences in characteristics between transgenic cotton and conventional counterparts. However, few studies have focused on the different responses of transgenic cotton to stress conditions, especially to the challenges of pathogens. The aim of this work is to determine the extent of variation in physiological characteristics between transgenic insect-resistant cotton and the conventional counterpart infected by cotton soil-borne pathogens. The results showed that the difference in genetic backgrounds is the main factor responsible for the effects on biochemical characteristics of transgenic cotton when incubating with cotton Fusarium oxysporum. However, genetic modification had a significantly greater influence on the stomatal structure of transgenic cotton than the effects of cotton genotypes. Our results highlight that the differences in genetic background and/or genetic modifications may introduce variations in physiological characteristics and should be considered to explore the potential unexpected ecological effects of transgenic cotton.

Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability.

PubMed

Bonnet, Amandine; Grosso, Ana R; Elkaoutari, Abdessamad; Coleno, Emeline; Presle, Adrien; Sridhara, Sreerama C; Janbon, Guilhem; Géli, Vincent; de Almeida, Sérgio F; Palancade, Benoit

2017-08-17

Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage. Copyright © 2017 Elsevier Inc. All rights reserved.

Explosive genetic evidence for explosive human population growth

PubMed Central

Gao, Feng; Keinan, Alon

2016-01-01

The advent of next-generation sequencing technology has allowed the collection of vast amounts of genetic variation data. A recurring discovery from studying larger and larger samples of individuals had been the extreme, previously unexpected, excess of very rare genetic variants, which has been shown to be mostly due to the recent explosive growth of human populations. Here, we review recent literature that inferred recent changes in population size in different human populations and with different methodologies, with many pointing to recent explosive growth, especially in European populations for which more data has been available. We also review the state-of-the-art methods and software for the inference of historical population size changes that lead to these discoveries. Finally, we discuss the implications of recent population growth on personalized genomics, on purifying selection in the non-equilibrium state it entails and, as a consequence, on the genetic architecture underlying complex disease and the performance of mapping methods in discovering rare variants that contribute to complex disease risk. PMID:27710906

Genetically engineered mouse models for studying inflammatory bowel disease.

PubMed

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2016-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ancient deuterostome origins of vertebrate brain signalling centres.

PubMed

Pani, Ariel M; Mullarkey, Erin E; Aronowicz, Jochanan; Assimacopoulos, Stavroula; Grove, Elizabeth A; Lowe, Christopher J

2012-03-14

Neuroectodermal signalling centres induce and pattern many novel vertebrate brain structures but are absent, or divergent, in invertebrate chordates. This has led to the idea that signalling-centre genetic programs were first assembled in stem vertebrates and potentially drove morphological innovations of the brain. However, this scenario presumes that extant cephalochordates accurately represent ancestral chordate characters, which has not been tested using close chordate outgroups. Here we report that genetic programs homologous to three vertebrate signalling centres-the anterior neural ridge, zona limitans intrathalamica and isthmic organizer-are present in the hemichordate Saccoglossus kowalevskii. Fgf8/17/18 (a single gene homologous to vertebrate Fgf8, Fgf17 and Fgf18), sfrp1/5, hh and wnt1 are expressed in vertebrate-like arrangements in hemichordate ectoderm, and homologous genetic mechanisms regulate ectodermal patterning in both animals. We propose that these genetic programs were components of an unexpectedly complex, ancient genetic regulatory scaffold for deuterostome body patterning that degenerated in amphioxus and ascidians, but was retained to pattern divergent structures in hemichordates and vertebrates. © 2012 Macmillan Publishers Limited. All rights reserved

Long-Distance Dispersal Shaped Patterns of Human Genetic Diversity in Eurasia

PubMed Central

Alves, Isabel; Arenas, Miguel; Currat, Mathias; Sramkova Hanulova, Anna; Sousa, Vitor C.; Ray, Nicolas; Excoffier, Laurent

2016-01-01

Most previous attempts at reconstructing the past history of human populations did not explicitly take geography into account or considered very simple scenarios of migration and ignored environmental information. However, it is likely that the last glacial maximum (LGM) affected the demography and the range of many species, including our own. Moreover, long-distance dispersal (LDD) may have been an important component of human migrations, allowing fast colonization of new territories and preserving high levels of genetic diversity. Here, we use a high-quality microsatellite data set genotyped in 22 populations to estimate the posterior probabilities of several scenarios for the settlement of the Old World by modern humans. We considered models ranging from a simple spatial expansion to others including LDD and a LGM-induced range contraction, as well as Neolithic demographic expansions. We find that scenarios with LDD are much better supported by data than models without LDD. Nevertheless, we show evidence that LDD events to empty habitats were strongly prevented during the settlement of Eurasia. This unexpected absence of LDD ahead of the colonization wave front could have been caused by an Allee effect, either due to intrinsic causes such as an inbreeding depression built during the expansion or due to extrinsic causes such as direct competition with archaic humans. Overall, our results suggest only a relatively limited effect of the LGM contraction on current patterns of human diversity. This is in clear contrast with the major role of LDD migrations, which have potentially contributed to the intermingled genetic structure of Eurasian populations. PMID:26637555

REC-1 and HIM-5 distribute meiotic crossovers and function redundantly in meiotic double-strand break formation in Caenorhabditis elegans.

PubMed

Chung, George; Rose, Ann M; Petalcorin, Mark I R; Martin, Julie S; Kessler, Zebulin; Sanchez-Pulido, Luis; Ponting, Chris P; Yanowitz, Judith L; Boulton, Simon J

2015-09-15

The Caenorhabditis elegans gene rec-1 was the first genetic locus identified in metazoa to affect the distribution of meiotic crossovers along the chromosome. We report that rec-1 encodes a distant paralog of HIM-5, which was discovered by whole-genome sequencing and confirmed by multiple genome-edited alleles. REC-1 is phosphorylated by cyclin-dependent kinase (CDK) in vitro, and mutation of the CDK consensus sites in REC-1 compromises meiotic crossover distribution in vivo. Unexpectedly, rec-1; him-5 double mutants are synthetic-lethal due to a defect in meiotic double-strand break formation. Thus, we uncovered an unexpected robustness to meiotic DSB formation and crossover positioning that is executed by HIM-5 and REC-1 and regulated by phosphorylation. © 2015 Chung et al.; Published by Cold Spring Harbor Laboratory Press.

Idiopathic infantile arterial calcification: a rare cause of sudden unexpected death in childhood.

PubMed

Guimarães, Susana; Lopes, José Manuel; Oliveira, José Bessa; Santos, Agostinho

2010-07-27

Unexpected child death investigation is a difficult area of forensic practice in view of the wide range of possible genetic, congenital, and acquired natural and nonnatural causes. Idiopathic infantile arterial calcification (IIAC) is a rare autosomic recessive disease usually diagnosed postmortem. Inactivating mutations of the ENPP1 gene were described in 80% of the cases with IIAC. We report a case of a 5-year-old girl submitted to a forensic autopsy due to sudden death and possible medical negligence/parents child abuse. Major alterations found (intimal proliferation and deposition of calcium hydroxyapatite around the internal elastic lamina and media of arteries; acute myocardial infarct, stenotic and calcified coronary artery; perivascular and interstitial myocardial fibrosis; and subendocardial fibroelastosis) were diagnostic of IIAC. We reviewed IIAC cases published in the English literature and highlight the importance of adequate autopsy evaluation in cases of sudden child death.

Idiopathic Infantile Arterial Calcification: A Rare Cause of Sudden Unexpected Death in Childhood

PubMed Central

Guimarães, Susana; Lopes, José Manuel; Oliveira, José Bessa; Santos, Agostinho

2010-01-01

Unexpected child death investigation is a difficult area of forensic practice in view of the wide range of possible genetic, congenital, and acquired natural and nonnatural causes. Idiopathic infantile arterial calcification (IIAC) is a rare autosomic recessive disease usually diagnosed postmortem. Inactivating mutations of the ENPP1 gene were described in 80% of the cases with IIAC. We report a case of a 5-year-old girl submitted to a forensic autopsy due to sudden death and possible medical negligence/parents child abuse. Major alterations found (intimal proliferation and deposition of calcium hydroxyapatite around the internal elastic lamina and media of arteries; acute myocardial infarct, stenotic and calcified coronary artery; perivascular and interstitial myocardial fibrosis; and subendocardial fibroelastosis) were diagnostic of IIAC. We reviewed IIAC cases published in the English literature and highlight the importance of adequate autopsy evaluation in cases of sudden child death. PMID:21151691

The Mouse House: A brief history of the ORNL mouse-genetics program, 1947–2009

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, Liane B.

The large mouse genetics program at the Oak Ridge National Lab is often re-membered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutationsmore » and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-Chromosome s importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable source of mouse models for human genetic disorders.« less

The Mouse House: a brief history of the ORNL mouse-genetics program, 1947-2009.

PubMed

Russell, Liane B

2013-01-01

The large mouse genetics program at the Oak Ridge National Laboratory (ORNL) is often remembered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-chromosome's importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable source of mouse models for human genetic disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Portuguese crypto-Jews: the genetic heritage of a complex history

PubMed Central

Nogueiro, Inês; Teixeira, João C.; Amorim, António; Gusmão, Leonor; Alvarez, Luis

2015-01-01

The first documents mentioning Jewish people in Iberia are from the Visigothic period. It was also in this period that the first documented anti-Judaic persecution took place. Other episodes of persecution would happen again and again during the long troubled history of the Jewish people in Iberia and culminated with the Decrees of Expulsion and the establishment of the Inquisition: some Jews converted to Catholicism while others resisted and were forcedly baptized, becoming the first Iberian Crypto-Jews. In the 18th century the official discrimination and persecution carried out by the Inquisition ended and several Jewish communities emerged in Portugal. From a populational genetics point of view, the worldwide Diaspora of contemporary Jewish communities has been intensely studied. Nevertheless, very little information is available concerning Sephardic and Iberian Crypto-Jewish descendants. Data from the Iberian Peninsula, the original geographic source of Sephardic Jews, is limited to two populations in Portugal, Belmonte, and Bragança district, and the Chueta community from Mallorca. Belmonte was the first Jewish community studied for uniparental markers. The construction of a reference model for the history of the Portuguese Jewish communities, in which the genetic and classical historical data interplay dynamically, is still ongoing. Recently an enlarged sample covering a wide region in the Northeast Portugal was undertaken, allowing the genetic profiling of male and female lineages. A Jewish specific shared female lineage (HV0b) was detected between the community of Belmonte and Bragança. In contrast to what was previously described as a hallmark of the Portuguese Jews, an unexpectedly high polymorphism of lineages was found in Bragança, showing a surprising resistance to the erosion of genetic diversity typical of small-sized isolate populations, as well as signs of admixture with the Portuguese host population. PMID:25699075

Portuguese crypto-Jews: the genetic heritage of a complex history.

PubMed

Nogueiro, Inês; Teixeira, João C; Amorim, António; Gusmão, Leonor; Alvarez, Luis

2015-01-01

The first documents mentioning Jewish people in Iberia are from the Visigothic period. It was also in this period that the first documented anti-Judaic persecution took place. Other episodes of persecution would happen again and again during the long troubled history of the Jewish people in Iberia and culminated with the Decrees of Expulsion and the establishment of the Inquisition: some Jews converted to Catholicism while others resisted and were forcedly baptized, becoming the first Iberian Crypto-Jews. In the 18th century the official discrimination and persecution carried out by the Inquisition ended and several Jewish communities emerged in Portugal. From a populational genetics point of view, the worldwide Diaspora of contemporary Jewish communities has been intensely studied. Nevertheless, very little information is available concerning Sephardic and Iberian Crypto-Jewish descendants. Data from the Iberian Peninsula, the original geographic source of Sephardic Jews, is limited to two populations in Portugal, Belmonte, and Bragança district, and the Chueta community from Mallorca. Belmonte was the first Jewish community studied for uniparental markers. The construction of a reference model for the history of the Portuguese Jewish communities, in which the genetic and classical historical data interplay dynamically, is still ongoing. Recently an enlarged sample covering a wide region in the Northeast Portugal was undertaken, allowing the genetic profiling of male and female lineages. A Jewish specific shared female lineage (HV0b) was detected between the community of Belmonte and Bragança. In contrast to what was previously described as a hallmark of the Portuguese Jews, an unexpectedly high polymorphism of lineages was found in Bragança, showing a surprising resistance to the erosion of genetic diversity typical of small-sized isolate populations, as well as signs of admixture with the Portuguese host population.

Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing.

PubMed

Weber, Stefanie; Büscher, Anja K; Hagmann, Henning; Liebau, Max C; Heberle, Christian; Ludwig, Michael; Rath, Sabine; Alberer, Martin; Beissert, Antje; Zenker, Martin; Hoyer, Peter F; Konrad, Martin; Klein, Hanns-Georg; Hoefele, Julia

2016-01-01

Steroid-resistant nephrotic syndrome (SRNS) is a severe cause of progressive renal disease. Genetic forms of SRNS can present with autosomal recessive or autosomal dominant inheritance. Recent studies have identified mutations in multiple podocyte genes responsible for SRNS. Improved sequencing methods (next-generation sequencing, NGS) now promise rapid mutational testing of SRNS genes. In the present study, a simultaneous screening of ten SRNS genes in 37 SRNS patients was performed by NGS. In 38 % of the patients, causative mutations in one SRNS gene were found. In 22 % of the patients, in addition to these mutations, a secondary variant in a different gene was identified. This high incidence of accumulating sequence variants was unexpected but, although they might have modifier effects, the pathogenic potential of these additional sequence variants seems unclear so far. The example of molecular diagnostics by NGS in SRNS patients shows that these new sequencing technologies might provide further insight into molecular pathogenicity in genetic disorders but will also generate results, which will be difficult to interpret and complicate genetic counseling. Although NGS promises more frequent identification of disease-causing mutations, the identification of causative mutations, the interpretation of incidental findings and possible pitfalls might pose problems, which hopefully will decrease by further experience and elucidation of molecular interactions.

Genetic and Pharmacological Modulation of the Steroid Sulfatase Axis Improves Response Control; Comparison with Drugs Used in ADHD

PubMed Central

Davies, William; Humby, Trevor; Trent, Simon; Eddy, Jessica B; Ojarikre, Obah A; Wilkinson, Lawrence S

2014-01-01

Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,XY*O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent. PMID:24842408

COPA mutations impair ER-Golgi transport causing hereditary autoimmune-mediated lung disease and arthritis

PubMed Central

Watkin, Levi B.; Jessen, Birthe; Wiszniewski, Wojciech; Vece, Timothy; Jan, Max; Sha, Youbao; Thamsen, Maike; Santos-Cortez, Regie L. P.; Lee, Kwanghyuk; Gambin, Tomasz; Forbes, Lisa; Law, Christopher S.; Stray-Petersen, Asbjørg; Cheng, Mickie H.; Mace, Emily M.; Anderson, Mark S.; Liu, Dongfang; Tang, Ling Fung; Nicholas, Sarah K.; Nahmod, Karen; Makedonas, George; Canter, Debra; Kwok, Pui-Yan; Hicks, John; Jones, Kirk D.; Penney, Samantha; Jhangiani, Shalini N.; Rosenblum, Michael D.; Dell, Sharon D.; Waterfield, Michael R.; Papa, Feroz R.; Muzny, Donna M.; Zaitlen, Noah; Leal, Suzanne M.; Gonzaga-Jauregui, Claudia; Boerwinkle, Eric; Eissa, N. Tony; Gibbs, Richard A.; Lupski, James R.; Orange, Jordan S.; Shum, Anthony K.

2015-01-01

Advances in genomics have allowed unbiased genetic studies of human disease with unexpected insights into the molecular mechanisms of cellular immunity and autoimmunity1. We performed whole exome sequencing (WES) and targeted sequencing in patients with an apparent Mendelian syndrome of autoimmune disease characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease (ILD). In five families, we identified four unique deleterious variants in the Coatomer subunit alpha (COPA) gene all located within the same functional domain. We hypothesized that mutant COPA leads to a defect in intracellular transport mediated by coat protein complex I (COPI)2–4. We show that COPA variants impair binding of proteins targeted for retrograde Golgi to ER transport and demonstrate that expression of mutant COPA leads to ER stress and the upregulation of Th17 priming cytokines. Consistent with this pattern of cytokine expression, patients demonstrated a significant skewing of CD4+ T cells toward a T helper 17 (Th17) phenotype, an effector T cell population implicated in autoimmunity5,6. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease. These findings provide a unique opportunity to understand how alterations in cellular homeostasis caused by a defect in the intracellular trafficking pathway leads to the generation of human autoimmune disease. PMID:25894502

Impact of accelerated plant growth on seed variety development

NASA Astrophysics Data System (ADS)

Christophersen, Eric

1998-01-01

The commercial lives of agricultural seed products have steadily declined in recent years. The introduction of genetically engineered crop seeds in 1966 has accentuated that trend. Widespread grower demand for genetically engineered seed requires competitive response by industry followers in order to avert market share losses to the industry leaders. Limitations on plant transformation technology, regulatory requirements and patent impediments require companies to rapidly convert transformed lines into elite commercial products. Massive multigenerational backcrossing efforts are required to distribute genetically engineered traits into a broad product mix. Significant incidents of expression failures, or ``gene silencing,'' have occurred unexpectedly, requiring product substitution strategies. First-to-market strategies, competitive response, broad germplasm conversion and rescue of product failures all share the element of urgency. Technologies which reliably accelerate product development rates can expect favorable reception by commercial seed developers. A growth chamber which dramatically accelerates the rate of plant growth is described.

Unexpected absence of genetic separation of a highly diverse population of hookworms from geographically isolated hosts.

PubMed

Haynes, Benjamin T; Marcus, Alan D; Higgins, Damien P; Gongora, Jaime; Gray, Rachael; Šlapeta, Jan

2014-12-01

The high natal site fidelity of endangered Australian sea lions (Neophoca cinerea) along the southern Australian coast suggests that their maternally transmitted parasitic species, such as hookworms, will have restricted potential for dispersal. If this is the case, we would expect to find a hookworm haplotype structure corresponding to that of the host mtDNA haplotype structure; that is, restricted among geographically separated colonies. In this study, we used a fragment of the cytochrome c oxidase I mitochondrial DNA (mtDNA) gene to investigate the diversity of hookworms (Uncinaria sanguinis) in N. cinerea to assess the importance of host distribution and ecology on the evolutionary history of the parasite. High haplotype (h=0.986) and nucleotide diversity (π=0.013) were seen, with 45 unique hookworm mtDNA haplotypes across N. cinerea colonies; with most of the variation (78%) arising from variability within hookworms from individual colonies. This is supported by the low genetic differentiation co-efficient (GST=0.007) and a high gene flow (Nm=35.25) indicating a high migration rate between the populations of hookworms. The haplotype network demonstrated no clear distribution and delineation of haplotypes according to geographical location. Our data rejects the vicariance hypothesis; that female host natal site fidelity and the transmammary route of infection restrict hookworm gene flow between N. cinerea populations and highlights the value of studies of parasite diversity and dispersal to challenge our understanding of parasite and host ecology. Copyright © 2014 Elsevier B.V. All rights reserved.

Non-conventional protrusions: the diversity of cell interactions at short and long distance.

PubMed

Caviglia, Sara; Ober, Elke A

2018-06-08

Cells use different means to communicate within and between tissues and thereby coordinate their behaviours. Following the initial observations of enigmatic long filopodia unrelated to cell movement, it became clear that the roles of cellular protrusions are not restricted to sensing functions or motility and are much more diverse than previously appreciated. Advances in live-imaging and genetic tools revealed several types of non-conventional cell protrusions and their functions, ranging from tissue patterning, proliferation and differentiation control, tissue matching and cell spacing to more unexpected roles such as priming of cell adhesion as well as bidirectional coordination of tissue movements. Here, we will highlight exciting new insights into highly diverse cell behaviours elicited by protrusions and contact-dependent cell communication, essential for embryonic development across species. Copyright © 2018. Published by Elsevier Ltd.

[Headache case that responded to alendronate treatment in Paget's disease].

PubMed

Bozkurt, Dilek; Hiz, Fazilet; Çinar, Meral; Can, Meltem

2012-01-01

Paget's disease of the bone is a chronic, focal skeletal disease characterized by bone pain and deformity, pathological fractures and neurological symptoms such as headache, hearing loss and tinnitus, etc. The frequency of the disease increases in later ages. Viral and genetical factors play a role in the etiology. The majority of cases are asymptomatic. It is often diagnosed with an incidental finding on radiography or with an unexpected high serum alkaline phosphatase level. Bone fractures or neurological complications can negatively affect the quality of life. Early diagnosis and treatment are thus very important. Bisphosphonates are the most frequently used medication in the treatment. We present a case who sought medical help because of headache and was diagnosed as Paget's disease. Neurological complications and the diagnosis and treatment of Paget's disease are reviewed in the literature.

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing.

PubMed

Coll, Monica; Allegue, Catarina; Partemi, Sara; Mates, Jesus; Del Olmo, Bernat; Campuzano, Oscar; Pascali, Vincenzo; Iglesias, Anna; Striano, Pasquale; Oliva, Antonio; Brugada, Ramon

2016-03-01

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.

Biophysical model of prokaryotic diversity in geothermal hot springs.

PubMed

Klales, Anna; Duncan, James; Nett, Elizabeth Janus; Kane, Suzanne Amador

2012-02-01

Recent studies of photosynthetic bacteria living in geothermal hot spring environments have revealed surprisingly complex ecosystems with an unexpected level of genetic diversity. One case of particular interest involves the distribution along hot spring thermal gradients of genetically distinct bacterial strains that differ in their preferred temperatures for reproduction and photosynthesis. In such systems, a single variable, temperature, defines the relevant environmental variation. In spite of this, each region along the thermal gradient exhibits multiple strains of photosynthetic bacteria adapted to several distinct thermal optima, rather than a single thermal strain adapted to the local environmental temperature. Here we analyze microbiology data from several ecological studies to show that the thermal distribution data exhibit several universal features independent of location and specific bacterial strain. These include the distribution of optimal temperatures of different thermal strains and the functional dependence of the net population density on temperature. We present a simple population dynamics model of these systems that is highly constrained by biophysical data and by physical features of the environment. This model can explain in detail the observed thermal population distributions, as well as certain features of population dynamics observed in laboratory studies of the same organisms. © 2012 American Physical Society

Great majority of recombination events in Arabidopsis are gene conversion events

PubMed Central

Yang, Sihai; Yuan, Yang; Wang, Long; Li, Jing; Wang, Wen; Liu, Haoxuan; Chen, Jian-Qun; Hurst, Laurence D.; Tian, Dacheng

2012-01-01

The evolutionary importance of meiosis may not solely be associated with allelic shuffling caused by crossing-over but also have to do with its more immediate effects such as gene conversion. Although estimates of the crossing-over rate are often well resolved, the gene conversion rate is much less clear. In Arabidopsis, for example, next-generation sequencing approaches suggest that the two rates are about the same, which contrasts with indirect measures, these suggesting an excess of gene conversion. Here, we provide analysis of this problem by sequencing 40 F2 Arabidopsis plants and their parents. Small gene conversion tracts, with biased gene conversion content, represent over 90% (probably nearer 99%) of all recombination events. The rate of alteration of protein sequence caused by gene conversion is over 600 times that caused by mutation. Finally, our analysis reveals recombination hot spots and unexpectedly high recombination rates near centromeres. This may be responsible for the previously unexplained pattern of high genetic diversity near Arabidopsis centromeres. PMID:23213238

Neurological Complications of Cardiac Disease.

PubMed

Madan, Nandini; Carvalho, Karen S

2017-02-01

This article focuses on the complex interactions between the cardiovascular and neurologic systems. Initially, we focus on neurological complications in children with congenital heart disease both secondary to the underlying cardiac disease and complications of interventions. We later discuss diagnosis and management of common syncope syndromes with emphasis on vasovagal syncope. We also review the diagnosis, classification, and management of children and adolescents with postural orthostatic tachycardia syndrome. Lastly, we discuss long QT syndrome and sudden unexpected death in epilepsy (SUDEP), reviewing advances in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics, and current medical interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Ancestral genetic diversity associated with the rapid spread of stress-tolerant coral symbionts in response to Holocene climate change

PubMed Central

Hume, Benjamin C. C.; Voolstra, Christian R.; Arif, Chatchanit; D’Angelo, Cecilia; Burt, John A.; Eyal, Gal; Loya, Yossi; Wiedenmann, Jörg

2016-01-01

Coral communities in the Persian/Arabian Gulf (PAG) withstand unusually high salinity levels and regular summer temperature maxima of up to ∼35 °C that kill conspecifics elsewhere. Due to the recent formation of the PAG and its subsequent shift to a hot climate, these corals have had only <6,000 y to adapt to these extreme conditions and can therefore inform on how coral reefs may respond to global warming. One key to coral survival in the world’s warmest reefs are symbioses with a newly discovered alga, Symbiodinium thermophilum. Currently, it is unknown whether this symbiont originated elsewhere or emerged from unexpectedly fast evolution catalyzed by the extreme environment. Analyzing genetic diversity of symbiotic algae across >5,000 km of the PAG, the Gulf of Oman, and the Red Sea coastline, we show that S. thermophilum is a member of a highly diverse, ancient group of symbionts cryptically distributed outside the PAG. We argue that the adjustment to temperature extremes by PAG corals was facilitated by the positive selection of preadapted symbionts. Our findings suggest that maintaining the largest possible pool of potentially stress-tolerant genotypes by protecting existing biodiversity is crucial to promote rapid adaptation to present-day climate change, not only for coral reefs, but for ecosystems in general. PMID:27044109

Spontaneous Chloroplast Mutants Mostly Occur by Replication Slippage and Show a Biased Pattern in the Plastome of Oenothera.

PubMed

Massouh, Amid; Schubert, Julia; Yaneva-Roder, Liliya; Ulbricht-Jones, Elena S; Zupok, Arkadiusz; Johnson, Marc T J; Wright, Stephen I; Pellizzer, Tommaso; Sobanski, Johanna; Bock, Ralph; Greiner, Stephan

2016-04-01

Spontaneous plastome mutants have been used as a research tool since the beginning of genetics. However, technical restrictions have severely limited their contributions to research in physiology and molecular biology. Here, we used full plastome sequencing to systematically characterize a collection of 51 spontaneous chloroplast mutants in Oenothera (evening primrose). Most mutants carry only a single mutation. Unexpectedly, the vast majority of mutations do not represent single nucleotide polymorphisms but are insertions/deletions originating from DNA replication slippage events. Only very few mutations appear to be caused by imprecise double-strand break repair, nucleotide misincorporation during replication, or incorrect nucleotide excision repair following oxidative damage. U-turn inversions were not detected. Replication slippage is induced at repetitive sequences that can be very small and tend to have high A/T content. Interestingly, the mutations are not distributed randomly in the genome. The underrepresentation of mutations caused by faulty double-strand break repair might explain the high structural conservation of seed plant plastomes throughout evolution. In addition to providing a fully characterized mutant collection for future research on plastid genetics, gene expression, and photosynthesis, our work identified the spectrum of spontaneous mutations in plastids and reveals that this spectrum is very different from that in the nucleus. © 2016 American Society of Plant Biologists. All rights reserved.

42 CFR 493.861 - Standard; Unexpected antibody detection.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... for Laboratories Performing Tests of Moderate Complexity (including the Subcategory), High Complexity...

42 CFR 493.861 - Standard; Unexpected antibody detection.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 5 2011-10-01 2011-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... for Laboratories Performing Tests of Moderate Complexity (including the Subcategory), High Complexity...

Emotional reactivity to incentive downshift as a correlated response to selection of high and low alcohol preferring mice and an influencing factor on ethanol intake.

PubMed

Matson, Liana M; Grahame, Nicholas J

2015-11-01

Losing a job or significant other are examples of incentive loss that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking (Keyes, Hatzenbuehler, & Hasin, 2011). Further, certain genotypes are more likely to drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). Shared genetic factors may contribute to alcohol drinking and emotional reactivity, but this relationship is not currently well understood. We used an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. We also investigated if ethanol drinking is influenced in High Alcohol Preferring mice that had been exposed to an incentive downshift. Incentive downshift procedures have been widely utilized to model emotional reactivity, and involve shifting a high reward group to a low reward and comparing the shifted group to a consistently rewarded control group. Here, we show that replicate lines of selectively bred High Alcohol Preferring mice exhibited larger successive negative contrast effects than their corresponding replicate Low Alcohol Preferring lines, providing strong evidence for a genetic association between alcohol drinking and susceptibility to the emotional effects of negative contrast. These mice can be used to study the shared neurological and genetic underpinnings of emotional reactivity and alcohol preference. Unexpectedly, an incentive downshift suppressed ethanol drinking immediately following an incentive downshift. This could be due to a specific effect of negative contrast on ethanol consumption or a suppressive effect on consummatory behavior in general. These data suggest that either alcohol intake does not provide the anticipated negative reinforcement, or that a single test was insufficient for animals to learn to drink following incentive downshift. However, the emotional intensity following incentive downshift provides initial evidence that this type of emotional reactivity may be a predisposing factor in alcoholism. Copyright © 2015 Elsevier Inc. All rights reserved.

Mapping the mouse Allelome reveals tissue-specific regulation of allelic expression

PubMed Central

Andergassen, Daniel; Dotter, Christoph P; Wenzel, Daniel; Sigl, Verena; Bammer, Philipp C; Muckenhuber, Markus; Mayer, Daniela; Kulinski, Tomasz M; Theussl, Hans-Christian; Penninger, Josef M; Bock, Christoph; Barlow, Denise P; Pauler, Florian M; Hudson, Quanah J

2017-01-01

To determine the dynamics of allelic-specific expression during mouse development, we analyzed RNA-seq data from 23 F1 tissues from different developmental stages, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. We demonstrate that allelic expression arising from genetic or epigenetic differences is highly tissue-specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We also find that escape from X-inactivation is tissue-specific, with leg muscle showing an unexpectedly high rate of XCI escapers. By surveying a range of tissues during development, and performing extensive validation, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This shows that cluster size varies dynamically during development and can be substantially larger than previously thought, with the Igf2r cluster extending over 10 Mb in placenta. DOI: http://dx.doi.org/10.7554/eLife.25125.001 PMID:28806168

Is Bocourt’s Terrific Skink Really So Terrific? Trophic Myth and Reality

PubMed Central

Jowers, Michael J.; Boistel, Renaud; Ineich, Ivan

2013-01-01

Many scientists argue that our planet is undergoing a mass extinction event that is largely due to human influences. In this context, rediscoveries of species presumed to be extinct are encouraging and of great potential interest. During a 2003 expedition to New Caledonia, Bocourt’s terrific skink, Phoboscincus bocourti, was unexpectedly rediscovered on a small islet by one of us. This skink species had been described from a single specimen collected around 1872 in New Caledonia. Since that time, however, no data on the species’ biology, trophic interactions, or role in the ecosystem have been collected, making it difficult to follow the established conservation plan. In this study, we used a multidisciplinary approach involving natural history, anatomy, morphology, genetics, and stable isotopes to elucidate the ecology of Bocourt’s terrific skink. Over the course of three different expeditions to the islet (total of 55 days across 2005 and 2012), we captured 4 individuals and observed another 4 individuals. The species’ dentition and trophic ecology suggest that it is a top predator in its ecosystem and a major consumer of small terrestrial reptiles. Its high degree of genetic relatedness to another New Caledonian skink, which has a broad distribution, suggests that P. bocourti underwent genetic isolation at a geographical remote location, where dispersal or colonization was highly improbable. Moreover, the lack of genetic variation among the four individuals we captured may imply that a unique lineage, characterized by few inter-island exchanges, exists on the islet. Bocourt’s terrific skink may be the largest terrestrial squamate predator alive in New Caledonia today. As a result, it is likely vulnerable to habitat modifications and especially the invasive rodents found on this islet. Further information is necessary to assess the conservation plans and practices in place as no concrete changes have been made since the species’ rediscovery almost 10 years ago. PMID:24205285

Genetically Predicted Body Mass Index and Alzheimer’s Disease Related Phenotypes in Three Large Samples: Mendelian Randomization Analyses

PubMed Central

Mukherjee, Shubhabrata; Walter, Stefan; Kauwe, John S.K.; Saykin, Andrew J.; Bennett, David A.; Larson, Eric B.; Crane, Paul K.; Glymour, M. Maria

2015-01-01

Observational research shows that higher body mass index (BMI) increases Alzheimer’s disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian Randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9,613 controls), the Health and Retirement Study (HRS: 8,403 participants with algorithm-predicted dementia status) and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3,177 AD cases and 7,277 controls). No evidence from individual SNPs or polygenic scores indicated BMI increased AD risk. Mendelian Randomization effect estimates per BMI point (95% confidence intervals) were: ADGC OR=0.95 (0.90, 1.01); HRS OR=1.00 (0.75, 1.32); GERAD1 OR=0.96 (0.87, 1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk. PMID:26079416

Isocost Lines Describe the Cellular Economy of Genetic Circuits

PubMed Central

Gyorgy, Andras; Jiménez, José I.; Yazbek, John; Huang, Hsin-Ho; Chung, Hattie; Weiss, Ron; Del Vecchio, Domitilla

2015-01-01

Genetic circuits in living cells share transcriptional and translational resources that are available in limited amounts. This leads to unexpected couplings among seemingly unconnected modules, which result in poorly predictable circuit behavior. In this study, we determine these interdependencies between products of different genes by characterizing the economy of how transcriptional and translational resources are allocated to the production of proteins in genetic circuits. We discover that, when expressed from the same plasmid, the combinations of attainable protein concentrations are constrained by a linear relationship, which can be interpreted as an isocost line, a concept used in microeconomics. We created a library of circuits with two reporter genes, one constitutive and the other inducible in the same plasmid, without a regulatory path between them. In agreement with the model predictions, experiments reveal that the isocost line rotates when changing the ribosome binding site strength of the inducible gene and shifts when modifying the plasmid copy number. These results demonstrate that isocost lines can be employed to predict how genetic circuits become coupled when sharing resources and provide design guidelines for minimizing the effects of such couplings. PMID:26244745

Genetics behind barbed wire: Masuo Kodani, émigré geneticists, and wartime genetics research at Manzanar relocation center.

PubMed

Smocovitis, Vassiliki Betty

2011-02-01

This article explores the sociopolitical backdrop of genetics research during the politically turbulent decades of the mid-20th century that saw the persecution, displacement, and relocation of unpopular minorities in both the United States and Europe. It explores how geneticists in the United States accommodated these disruptions through formal and informal émigré networks and how the subsequent war affected their research programs and their lives. It does so by focusing on the career and life of geneticist Masuo Kodani, who, as a Japanese American, found himself conducting unexpected cytogenetics research in Manzanar, a "relocation center," or internment camp, located in the California desert, after the attack on Pearl Harbor. After the war, Kodani's subsequent career continued to be shaped by his experiences as a Japanese American and by the specific skills as a cytogeneticist that he demonstrated at a critical period in the history of 20th-century genetics. His many relocations in search of employment culminated in his work with the Atomic Bomb Casualty Commission on human chromosomes, for which he is best known.

Whole-exome analysis to detect congenital hemolytic anemia mimicking congenital dyserythropoietic anemia.

PubMed

Hamada, Motoharu; Doisaki, Sayoko; Okuno, Yusuke; Muramatsu, Hideki; Hama, Asahito; Kawashima, Nozomu; Narita, Atsushi; Nishio, Nobuhiro; Yoshida, Kenichi; Kanno, Hitoshi; Manabe, Atsushi; Taga, Takashi; Takahashi, Yoshiyuki; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji

2018-06-23

Congenital dyserythropoietic anemia (CDA) is a heterogeneous group of rare congenital disorders characterized by ineffective erythropoiesis and dysplastic changes in erythroblasts. Diagnosis of CDA is based primarily on the morphology of bone marrow erythroblasts; however, genetic tests have recently become more important. Here, we performed genetic analysis of 10 Japanese patients who had been diagnosed with CDA based on laboratory findings and morphological characteristics. We examined 10 CDA patients via central review of bone marrow morphology and genetic analysis for congenital bone marrow failure syndromes. Sanger sequencing for CDAN1, SEC23B, and KLF1 was performed for all patients. We performed whole-exome sequencing in patients without mutation in these genes. Three patients carried pathogenic CDAN1 mutations, whereas no SEC23B mutations were identified in our cohort. WES unexpectedly identified gene mutations known to cause congenital hemolytic anemia in two patients: canonical G6PD p.Val394Leu mutation and SPTA1 p.Arg28His mutation. Comprehensive genetic analysis is warranted for more effective diagnosis of patients with suspected CDA.

Unexpected Nongenetic Individual Heterogeneity and Trait Covariance in Daphnia and Its Consequences for Ecological and Evolutionary Dynamics.

PubMed

Cressler, Clayton E; Bengtson, Stefan; Nelson, William A

2017-07-01

Individual differences in genetics, age, or environment can cause tremendous differences in individual life-history traits. This individual heterogeneity generates demographic heterogeneity at the population level, which is predicted to have a strong impact on both ecological and evolutionary dynamics. However, we know surprisingly little about the sources of individual heterogeneity for particular taxa or how different sources scale up to impact ecological and evolutionary dynamics. Here we experimentally study the individual heterogeneity that emerges from both genetic and nongenetic sources in a species of freshwater zooplankton across a large gradient of food quality. Despite the tight control of environment, we still find that the variation from nongenetic sources is greater than that from genetic sources over a wide range of food quality and that this variation has strong positive covariance between growth and reproduction. We evaluate the general consequences of genetic and nongenetic covariance for ecological and evolutionary dynamics theoretically and find that increasing nongenetic variation slows evolution independent of the correlation in heritable life-history traits but that the impact on ecological dynamics depends on both nongenetic and genetic covariance. Our results demonstrate that variation in the relative magnitude of nongenetic versus genetic sources of variation impacts the predicted ecological and evolutionary dynamics.

Long-Distance Dispersal Shaped Patterns of Human Genetic Diversity in Eurasia.

PubMed

Alves, Isabel; Arenas, Miguel; Currat, Mathias; Sramkova Hanulova, Anna; Sousa, Vitor C; Ray, Nicolas; Excoffier, Laurent

2016-04-01

Most previous attempts at reconstructing the past history of human populations did not explicitly take geography into account or considered very simple scenarios of migration and ignored environmental information. However, it is likely that the last glacial maximum (LGM) affected the demography and the range of many species, including our own. Moreover, long-distance dispersal (LDD) may have been an important component of human migrations, allowing fast colonization of new territories and preserving high levels of genetic diversity. Here, we use a high-quality microsatellite data set genotyped in 22 populations to estimate the posterior probabilities of several scenarios for the settlement of the Old World by modern humans. We considered models ranging from a simple spatial expansion to others including LDD and a LGM-induced range contraction, as well as Neolithic demographic expansions. We find that scenarios with LDD are much better supported by data than models without LDD. Nevertheless, we show evidence that LDD events to empty habitats were strongly prevented during the settlement of Eurasia. This unexpected absence of LDD ahead of the colonization wave front could have been caused by an Allee effect, either due to intrinsic causes such as an inbreeding depression built during the expansion or due to extrinsic causes such as direct competition with archaic humans. Overall, our results suggest only a relatively limited effect of the LGM contraction on current patterns of human diversity. This is in clear contrast with the major role of LDD migrations, which have potentially contributed to the intermingled genetic structure of Eurasian populations. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Experimental evolution under hyper-promiscuity in Drosophila melanogaster.

PubMed

Perry, Jennifer C; Joag, Richa; Hosken, David J; Wedell, Nina; Radwan, Jacek; Wigby, Stuart

2016-06-16

The number of partners that individuals mate with over their lifetime is a defining feature of mating systems, and variation in mate number is thought to be a major driver of sexual evolution. Although previous research has investigated the evolutionary consequences of reductions in the number of mates, we know little about the costs and benefits of increased numbers of mates. Here, we use a genetic manipulation of mating frequency in Drosophila melanogaster to create a novel, highly promiscuous mating system. We generated D. melanogaster populations in which flies were deficient for the sex peptide receptor (SPR) gene - resulting in SPR- females that mated more frequently - and genetically-matched control populations, and allowed them to evolve for 55 generations. At several time-points during this experimental evolution, we assayed behavioural, morphological and transcriptional reproductive phenotypes expected to evolve in response to increased population mating frequencies. We found that males from the high mating frequency SPR- populations evolved decreased ability to inhibit the receptivity of their mates and decreased copulation duration, in line with predictions of decreased per-mating investment with increased sperm competition. Unexpectedly, SPR- population males also evolved weakly increased sex peptide (SP) gene expression. Males from SPR- populations initially (i.e., before experimental evolution) exhibited more frequent courtship and faster time until mating relative to controls, but over evolutionary time these differences diminished or reversed. In response to experimentally increased mating frequency, SPR- males evolved behavioural responses consistent with decreased male post-copulatory investment at each mating and decreased overall pre-copulatory performance. The trend towards increased SP gene expression might plausibly relate to functional differences in the two domains of the SP protein. Our study highlights the utility of genetic manipulations of animal social and sexual environments coupled with experimental evolution.

The need for interaction between assisted reproduction technology and genetics: recommendations of the European Societies of Human Genetics and Human Reproduction and Embryology.

PubMed

2006-08-01

Infertility and reproductive genetic risk are both increasing in our societies because of lifestyle changes and possibly environmental factors. Owing to the magnitude of the problem, they have implications not only at the individual and family levels but also at the community level. This leads to an increasing demand for access to assisted reproduction technology (ART) and genetic services, especially when the cause of infertility may be genetic in origin. The increasing application of genetics in reproductive medicine and vice versa requires closer collaboration between the two disciplines. ART and genetics are rapidly evolving fields where new technologies are currently introduced without sufficient knowledge of their potential long-term effects. As for any medical procedures, there are possible unexpected effects which need to be envisaged to make sure that the balance between benefits and risks is clearly on the benefit side. The development of ART and genetics as scientific activities is creating an opportunity to understand the early stages of human development, which is leading to new and challenging findings/knowledge. However, there are opinions against investigating the early stages of development in humans who deserve respect and attention. For all these reasons, these two societies, European Society of Human Genetics (ESHG) and European Society of Human Reproduction and Embryology (ESHRE), have joined efforts to explore the issues at stake and to set up recommendations to maximize the benefit for the couples in need and for the community.

Genetic genealogy: the Woodson family's experience.

PubMed

Williams, Sloan R

2005-06-01

In 1998, Foster and colleagues published the results of a genetic study intended to test whether Thomas Jefferson could have fathered any of Sally Hemings' children. They found that the Jefferson Y chromosome haplotype matched that of a descendant of Hemings' youngest child, but not that of the descendants of the eldest son, Thomas Woodson. The Woodson descendants were shocked by the study's finding, which disagreed with their family oral history. They were suspicious of the study conclusions because of the methods used in recruiting participants for the study and the manner in which they learned of the results. The Woodsons' experience as participants in one of the first examples of genetic genealogy illustrates several issues that both geneticists and amateur genetic genealogists will face in studies of this kind. Misperceptions about the relationship between biology and race, and group genetics in general, can make the interpretation of genetic data difficult. Continuing collaborations between the media and the scientific community will help the public to better understand the risks as well as the benefits of genetic genealogy. Researchers must decide prior to beginning their research what role the human subjects will play in the study and when they will be notified of the study's conclusions. Amateur genetic genealogists should anticipate unexpected outcomes, such as the identification of nonpaternity, to minimize any harmful effects to study participants. Although modern genetic methods provide a powerful new tool for genealogical study, they cannot resolve all genealogical issues, as this study shows, and can involve unanticipated risks to the participants.

Exploring chemical diversity of α-pyrone antibiotics: molecular basis of myxopyronin biosynthesis.

PubMed

Sucipto, Hilda; Wenzel, Silke C; Müller, Rolf

2013-09-02

Myxopyronins and corallopyronins are structurally related α-pyrone antibiotics from myxobacteria. They are thought to represent a highly promising compound class for the development of broad-spectrum antibacterial therapeutic agents, because of their ability to inhibit RNA polymerase through interaction with the "switch region", a recently identified novel drug target. Here we describe the identification and characterization of the myxopyronin biosynthetic pathway from Myxococcus fulvus Mx f50. A detailed comparison with the recently identified corallopyronin biosynthetic pathway revealed the genetic and biochemical basis, thus explaining the observed structural differences between the two natural product families. Directed mutagenesis procedures for M. fulvus Mx f50 were developed to enable functional studies and pathway modifications. Our work provided new insights into myxopyronin biosynthesis and led to the production of a novel and unexpected myxopyronin derivative. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system

PubMed Central

Desguin, Benoît; Goffin, Philippe; Viaene, Eric; Kleerebezem, Michiel; Martin-Diaconescu, Vlad; Maroney, Michael J; Declercq, Jean-Paul; Soumillion, Patrice; Hols, Pascal

2014-01-01

Racemases catalyze the inversion of stereochemistry in biological molecules, giving the organism the ability to use both isomers. Among them, lactate racemase remains unexplored due to its intrinsic instability and lack of molecular characterization. Here we determine the genetic basis of lactate racemization in Lactobacillus plantarum. We show that, unexpectedly, the racemase is a nickel-dependent enzyme with a novel α/β fold. In addition, we decipher the process leading to an active enzyme, which involves the activation of the apo-enzyme by a single nickel-containing maturation protein that requires preactivation by two other accessory proteins. Genomic investigations reveal the wide distribution of the lactate racemase system among prokaryotes, showing the high significance of both lactate enantiomers in carbon metabolism. The even broader distribution of the nickel-based maturation system suggests a function beyond activation of the lactate racemase and possibly linked with other undiscovered nickel-dependent enzymes. PMID:24710389

Recurrent astrocytoma in a child: a report of cytogenetics and TP53 gene mutation screening.

PubMed Central

Dam, A.; Fock, J. M.; Hayes, V. M.; Molenaar, W. M.; van den Berg, E.

2000-01-01

An 8-year-old girl presented with a cerebral tumor and 3 recurrences within 15 months. The primary tumor was a low-grade astrocytoma, but the recurrences showed progressively malignant phenotypes with increasing mitotic activity and MIB-1 labeling indices. Radiotherapy was given between the first and the second recurrences. Cytogenetic analysis of the first and the second recurrences showed abnormal karyotypes. There seemed to be 2 common breakpoints in these 2 recurrences. TP53 gene mutation screening, using comprehensive denaturing gradient gel electrophoresis, revealed among others a possibly causative mutation of exon 5 in 3 of 4 tumor samples. The meaning of TP53 mutations in low-grade astrocytomas is still unclear, but the highly abnormal karyotypes, which are unusual in these tumors, probably provide genetic evidence for the unexpected aggressive behavior of the tumor in this patient. PMID:11302339

Saccharomyces cerevisiae metabolism in ecological context.

PubMed

Jouhten, Paula; Ponomarova, Olga; Gonzalez, Ramon; Patil, Kiran R

2016-11-01

The architecture and regulation of Saccharomyces cerevisiae metabolic network are among the best studied owing to its widespread use in both basic research and industry. Yet, several recent studies have revealed notable limitations in explaining genotype-metabolic phenotype relations in this yeast, especially when concerning multiple genetic/environmental perturbations. Apparently unexpected genotype-phenotype relations may originate in the evolutionarily shaped cellular operating principles being hidden in common laboratory conditions. Predecessors of laboratory S. cerevisiae strains, the wild and the domesticated yeasts, have been evolutionarily shaped by highly variable environments, very distinct from laboratory conditions, and most interestingly by social life within microbial communities. Here we present a brief review of the genotypic and phenotypic peculiarities of S. cerevisiae in the context of its social lifestyle beyond laboratory environments. Accounting for this ecological context and the origin of the laboratory strains in experimental design and data analysis would be essential in improving the understanding of genotype-environment-phenotype relationships. © FEMS 2016.

How global extinctions impact regional biodiversity in mammals.

PubMed

Huang, Shan; Davies, T Jonathan; Gittleman, John L

2012-04-23

Phylogenetic diversity (PD) represents the evolutionary history of a species assemblage and is a valuable measure of biodiversity because it captures not only species richness but potentially also genetic and functional diversity. Preserving PD could be critical for maintaining the functional integrity of the world's ecosystems, and species extinction will have a large impact on ecosystems in areas where the ecosystem cost per species extinction is high. Here, we show that impacts from global extinctions are linked to spatial location. Using a phylogeny of all mammals, we compare regional losses of PD against a model of random extinction. At regional scales, losses differ dramatically: several biodiversity hotspots in southern Asia and Amazonia will lose an unexpectedly large proportion of PD. Global analyses may therefore underestimate the impacts of extinction on ecosystem processes and function because they occur at finer spatial scales within the context of natural biogeography.

Distinct human antibody response to the biological warfare agent Burkholderia mallei.

PubMed

Varga, John J; Vigil, Adam; DeShazer, David; Waag, David M; Felgner, Philip; Goldberg, Joanna B

2012-10-01

The genetic similarity between Burkholderia mallei (glanders) and Burkholderia pseudomallei (melioidosis) had led to the general assumption that pathogenesis of each bacterium would be similar. In 2000, the first human case of glanders in North America since 1945 was reported in a microbiology laboratory worker. Leveraging the availability of pre-exposure sera for this individual and employing the same well-characterized protein array platform that has been previously used to study a large cohort of melioidosis patients in southeast Asia, we describe the antibody response in a human with glanders. Analysis of 156 peptides present on the array revealed antibodies against 17 peptides with a > 2-fold increase in this infection. Unexpectedly, when the glanders data were compared with a previous data set from B. pseudomallei infections, there were only two highly increased antibodies shared between these two infections. These findings have implications in the diagnosis and treatment of B. mallei and B. pseudomallei infections.

Saccharomyces cerevisiae metabolism in ecological context

PubMed Central

Jouhten, Paula; Ponomarova, Olga; Gonzalez, Ramon

2016-01-01

The architecture and regulation of Saccharomyces cerevisiae metabolic network are among the best studied owing to its widespread use in both basic research and industry. Yet, several recent studies have revealed notable limitations in explaining genotype–metabolic phenotype relations in this yeast, especially when concerning multiple genetic/environmental perturbations. Apparently unexpected genotype–phenotype relations may originate in the evolutionarily shaped cellular operating principles being hidden in common laboratory conditions. Predecessors of laboratory S. cerevisiae strains, the wild and the domesticated yeasts, have been evolutionarily shaped by highly variable environments, very distinct from laboratory conditions, and most interestingly by social life within microbial communities. Here we present a brief review of the genotypic and phenotypic peculiarities of S. cerevisiae in the context of its social lifestyle beyond laboratory environments. Accounting for this ecological context and the origin of the laboratory strains in experimental design and data analysis would be essential in improving the understanding of genotype–environment–phenotype relationships. PMID:27634775

Diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A clinical and genetic study.

PubMed Central

Nagi, N. A.

1979-01-01

Two Iraqi sisters and a female cousin developed diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and deafness (D), (the 'DIDMOAD' syndrome) before the age of 12 years. One girl exhibited all the features of this disease complex only 3 months after an unusually late onset of recognizable symptoms at 11 years 9 months. Another girl died suddenly and unexpectedly. This family study illustrates the recessive inheritance pattern of the syndrome. Images Fig. 2 Fig. 3 PMID:482181

Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series.

PubMed

Partemi, Sara; Vidal, Monica Coll; Striano, Pasquale; Campuzano, Oscar; Allegue, Catarina; Pezzella, Marianna; Elia, Maurizio; Parisi, Pasquale; Belcastro, Vincenzo; Casellato, Susanna; Giordano, Lucio; Mastrangelo, Massimo; Pietrafusa, Nicola; Striano, Salvatore; Zara, Federico; Bianchi, Amedeo; Buti, Daniela; La Neve, Angela; Tassinari, Carlo Alberto; Oliva, Antonio; Brugada, Ramon

2015-05-01

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

A test of genetic models for the evolutionary maintenance of same-sex sexual behaviour.

PubMed

Hoskins, Jessica L; Ritchie, Michael G; Bailey, Nathan W

2015-06-22

The evolutionary maintenance of same-sex sexual behaviour (SSB) has received increasing attention because it is perceived to be an evolutionary paradox. The genetic basis of SSB is almost wholly unknown in non-human animals, though this is key to understanding its persistence. Recent theoretical work has yielded broadly applicable predictions centred on two genetic models for SSB: overdominance and sexual antagonism. Using Drosophila melanogaster, we assayed natural genetic variation for male SSB and empirically tested predictions about the mode of inheritance and fitness consequences of alleles influencing its expression. We screened 50 inbred lines derived from a wild population for male-male courtship and copulation behaviour, and examined crosses between the lines for evidence of overdominance and antagonistic fecundity selection. Consistent variation among lines revealed heritable genetic variation for SSB, but the nature of the genetic variation was complex. Phenotypic and fitness variation was consistent with expectations under overdominance, although predictions of the sexual antagonism model were also supported. We found an unexpected and strong paternal effect on the expression of SSB, suggesting possible Y-linkage of the trait. Our results inform evolutionary genetic mechanisms that might maintain low but persistently observed levels of male SSB in D. melanogaster, but highlight a need for broader taxonomic representation in studies of its evolutionary causes. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Genomic data reveal a loss of diversity in two species of tuco-tucos (genus Ctenomys) following a volcanic eruption.

PubMed

Hsu, Jeremy L; Crawford, Jeremy Chase; Tammone, Mauro N; Ramakrishnan, Uma; Lacey, Eileen A; Hadly, Elizabeth A

2017-11-24

Marked reductions in population size can trigger corresponding declines in genetic variation. Understanding the precise genetic consequences of such reductions, however, is often challenging due to the absence of robust pre- and post-reduction datasets. Here, we use heterochronous genomic data from samples obtained before and immediately after the 2011 eruption of the Puyehue-Cordón Caulle volcanic complex in Patagonia to explore the genetic impacts of this event on two parapatric species of rodents, the colonial tuco-tuco (Ctenomys sociabilis) and the Patagonian tuco-tuco (C. haigi). Previous analyses using microsatellites revealed no post-eruption changes in genetic variation in C. haigi, but an unexpected increase in variation in C. sociabilis. To explore this outcome further, we used targeted gene capture to sequence over 2,000 putatively neutral regions for both species. Our data revealed that, contrary to the microsatellite analyses, the eruption was associated with a small but significant decrease in genetic variation in both species. We suggest that genome-level analyses provide greater power than traditional molecular markers to detect the genetic consequences of population size changes, particularly changes that are recent, short-term, or modest in size. Consequently, genomic analyses promise to generate important new insights into the effects of specific environmental events on demography and genetic variation.

Patterns of ecological specialization among microbial populations in the Red Sea and diverse oligotrophic marine environments

PubMed Central

Thompson, Luke R; Field, Chris; Romanuk, Tamara; Ngugi, David; Siam, Rania; El Dorry, Hamza; Stingl, Ulrich

2013-01-01

Large swaths of the nutrient-poor surface ocean are dominated numerically by cyanobacteria (Prochlorococcus), cyanobacterial viruses (cyanophage), and alphaproteobacteria (SAR11). How these groups thrive in the diverse physicochemical environments of different oceanic regions remains poorly understood. Comparative metagenomics can reveal adaptive responses linked to ecosystem-specific selective pressures. The Red Sea is well-suited for studying adaptation of pelagic-microbes, with salinities, temperatures, and light levels at the extreme end for the surface ocean, and low nutrient concentrations, yet no metagenomic studies have been done there. The Red Sea (high salinity, high light, low N and P) compares favorably with the Mediterranean Sea (high salinity, low P), Sargasso Sea (low P), and North Pacific Subtropical Gyre (high light, low N). We quantified the relative abundance of genetic functions among Prochlorococcus, cyanophage, and SAR11 from these four regions. Gene frequencies indicate selection for phosphorus acquisition (Mediterranean/Sargasso), DNA repair and high-light responses (Red Sea/Pacific Prochlorococcus), and osmolyte C1 oxidation (Red Sea/Mediterranean SAR11). The unexpected connection between salinity-dependent osmolyte production and SAR11 C1 metabolism represents a potentially major coevolutionary adaptation and biogeochemical flux. Among Prochlorococcus and cyanophage, genes enriched in specific environments had ecotype distributions similar to nonenriched genes, suggesting that inter-ecotype gene transfer is not a major source of environment-specific adaptation. Clustering of metagenomes using gene frequencies shows similarities in populations (Red Sea with Pacific, Mediterranean with Sargasso) that belie their geographic distances. Taken together, the genetic functions enriched in specific environments indicate competitive strategies for maintaining carrying capacity in the face of physical stressors and low nutrient availability. PMID:23789085

Patterns of ecological specialization among microbial populations in the Red Sea and diverse oligotrophic marine environments.

PubMed

Thompson, Luke R; Field, Chris; Romanuk, Tamara; Ngugi, David; Siam, Rania; El Dorry, Hamza; Stingl, Ulrich

2013-06-01

Large swaths of the nutrient-poor surface ocean are dominated numerically by cyanobacteria (Prochlorococcus), cyanobacterial viruses (cyanophage), and alphaproteobacteria (SAR11). How these groups thrive in the diverse physicochemical environments of different oceanic regions remains poorly understood. Comparative metagenomics can reveal adaptive responses linked to ecosystem-specific selective pressures. The Red Sea is well-suited for studying adaptation of pelagic-microbes, with salinities, temperatures, and light levels at the extreme end for the surface ocean, and low nutrient concentrations, yet no metagenomic studies have been done there. The Red Sea (high salinity, high light, low N and P) compares favorably with the Mediterranean Sea (high salinity, low P), Sargasso Sea (low P), and North Pacific Subtropical Gyre (high light, low N). We quantified the relative abundance of genetic functions among Prochlorococcus, cyanophage, and SAR11 from these four regions. Gene frequencies indicate selection for phosphorus acquisition (Mediterranean/Sargasso), DNA repair and high-light responses (Red Sea/Pacific Prochlorococcus), and osmolyte C1 oxidation (Red Sea/Mediterranean SAR11). The unexpected connection between salinity-dependent osmolyte production and SAR11 C1 metabolism represents a potentially major coevolutionary adaptation and biogeochemical flux. Among Prochlorococcus and cyanophage, genes enriched in specific environments had ecotype distributions similar to nonenriched genes, suggesting that inter-ecotype gene transfer is not a major source of environment-specific adaptation. Clustering of metagenomes using gene frequencies shows similarities in populations (Red Sea with Pacific, Mediterranean with Sargasso) that belie their geographic distances. Taken together, the genetic functions enriched in specific environments indicate competitive strategies for maintaining carrying capacity in the face of physical stressors and low nutrient availability.

Precision medicine in heritable cancer: when somatic tumour testing and germline mutations meet.

PubMed

Ngeow, Joanne; Eng, Charis

2016-01-01

Cancer is among the leading causes of death and disfigurement worldwide with an estimated global incidence of 14 million and ~8.2 million cancer-related deaths per annum. An estimated 5-10% of all cancers are hereditary, meaning a single gene mutation contributed to development of the cancer. In other words, inherited cancer has a worldwide incidence of ~1.4 million new cases per annum and a global prevalence of 300 million, and are often poorly recognised. The increase in genetic sequencing capability combined with the decrease in the cost of testing has altered both regulatory policy and clinical oncology practice Well-known examples of clinically important cancer susceptibility syndromes such as those caused by genetic mutations in highly penetrant genes such as BRCA1/2 hereditary breast-ovarian cancer syndrome genes have provided the framework for the practice of clinical cancer genetics. There is no question that these tests have provided clinical benefit to the patient and her/his family. However, with the expanding role of next generation sequencing in tumour profiling as well as in germline testing, clinicians are now faced with significant new challenges and potentially unexpected opportunities. Issues such as determining how best to deal with gene variants of uncertain clinical significance and the issue of incidental findings of hereditary cancer risk may be encountered during tumour genomic testing will require a concerted effort and dialogue on the part of the broad genomic community.

The costs (or benefits) associated with attended objects do little to influence inattentional blindness.

PubMed

Stothart, Cary R; Wright, Timothy J; Simons, Daniel J; Boot, Walter R

2017-02-01

We sometimes fail to notice unexpected objects or events when our attention is directed elsewhere, a phenomenon called inattentional blindness. We explored whether unexpected objects that shared the color of consequential objects would be noticed more often. In three pre-registered experiments, participants played a custom video game in which they avoided both low- and high-cost missiles (Experiment 1 and 2) or tried to hit rewarding missiles while avoiding costly ones (Experiment 3). After participants had played the game for about 8min, an unexpected object moved across the screen. Although participants selectively avoided more costly missiles when playing, they were no more likely to notice an unexpected object when its color was associated with greater costs. Apparently, people are no more likely to notice unexpected objects that are associated with negative consequences. Future research should examine whether objects that are themselves consequential are noticed more frequently. Copyright © 2016 Elsevier B.V. All rights reserved.

Unraveling the molecular genetics of head and neck cancer through genome-wide approaches

PubMed Central

Riaz, Nadeem; Morris, Luc G.; Lee, William; Chan, Timothy A.

2014-01-01

The past decade has seen an unprecedented increase in our understanding of the biology and etiology of head and neck squamous cell carcinomas (HNSCC). Genome-wide sequencing projects have identified a number of recurrently mutated genes, including unexpected alterations in the NOTCH pathway and chromatin related genes. Gene-expression profiling has identified 4 distinct genetic subtypes which show some parallels to lung squamous cell carcinoma biology. The identification of the human papilloma virus as one causative agent in a subset of oropharyngeal cancers and their association with a favorable prognosis has opened up avenues for new therapeutic strategies. The expanding knowledge of the underlying molecular abnormalities in this once very poorly understood cancer should allow for increasingly rational clinical trial design and improved patient outcomes. PMID:25642447

Behavioral neuroscience of psychological pain.

PubMed

Papini, Mauricio R; Fuchs, Perry N; Torres, Carmen

2015-01-01

Pain is a common word used to refer to a wide range of physical and mental states sharing hedonic aversive value. Three types of pain are distinguished in this article: Physical pain, an aversive state related to actual or potential injury and disease; social pain, an aversive emotion associated to social exclusion; and psychological pain, a negative emotion induced by incentive loss. This review centers on psychological pain as studied in nonhuman animals. After covering issues of terminology, the article briefly discusses the daily-life significance of psychological pain and then centers on a discussion of the results originating from two procedures involving incentive loss: successive negative contrast-the unexpected devaluation of a reward-and appetitive extinction-the unexpected omission of a reward. The evidence reviewed points to substantial commonalities, but also some differences and interactions between physical and psychological pains. This evidence is discussed in relation to behavioral, pharmacological, neurobiological, and genetic factors that contribute to the multidimensional experience of psychological pain. Copyright © 2014 Elsevier Ltd. All rights reserved.

The event-related potential effects of cognitive conflict in a Chinese character-generation task.

PubMed

Qiu, Jiang; Zhang, Qinglin; Li, Hong; Luo, Yuejia; Yin, Qinging; Chen, Antao; Yuan, Hong

2007-06-11

High-density event-related potentials were recorded to examine the electrophysiologic correlates of the evaluation of possible answers provided during a Chinese character-generation task. We examined three conditions: the character given was what participants initially generated (Consistent answer), the character given was correct (Unexpected Correct answer), or it was incorrect (Unexpected Incorrect answer). Results showed that Unexpected Correct and Incorrect answers elicited a more negative event-related potential deflection (N320) than did Consistent answers between 300 and 400 ms. Dipole source analysis of difference waves (Unexpected Correct or Incorrect minus Consistent answers) localized the generator of the N320 in the anterior cingulate cortex. The N320 therefore likely reflects the cognitive change or conflict between old and new ways of thinking while identifying and judging characters.

Identification of a Classical Mutant in the Industrial Host Aspergillus niger by Systems Genetics: LaeA Is Required for Citric Acid Production and Regulates the Formation of Some Secondary Metabolites

PubMed Central

Niu, Jing; Arentshorst, Mark; Nair, P. Deepa S.; Dai, Ziyu; Baker, Scott E.; Frisvad, Jens C.; Nielsen, Kristian F.; Punt, Peter J.; Ram, Arthur F.J.

2015-01-01

The asexual filamentous fungus Aspergillus niger is an important industrial cell factory for citric acid production. In this study, we genetically characterized a UV-generated A. niger mutant that was originally isolated as a nonacidifying mutant, which is a desirable trait for industrial enzyme production. Physiological analysis showed that this mutant did not secrete large amounts of citric acid and oxalic acid, thus explaining the nonacidifying phenotype. As traditional complementation approaches to characterize the mutant genotype were unsuccessful, we used bulk segregant analysis in combination with high-throughput genome sequencing to identify the mutation responsible for the nonacidifying phenotype. Since A. niger has no sexual cycle, parasexual genetics was used to generate haploid segregants derived from diploids by loss of whole chromosomes. We found that the nonacidifying phenotype was caused by a point mutation in the laeA gene. LaeA encodes a putative methyltransferase-domain protein, which we show here to be required for citric acid production in an A. niger lab strain (N402) and in other citric acid production strains. The unexpected link between LaeA and citric acid production could provide new insights into the transcriptional control mechanisms related to citric acid production in A. niger. Interestingly, the secondary metabolite profile of a ΔlaeA strain differed from the wild-type strain, showing both decreased and increased metabolite levels, indicating that LaeA is also involved in regulating the production of secondary metabolites. Finally, we show that our systems genetics approach is a powerful tool to identify trait mutations. PMID:26566947

Identification of a Classical Mutant in the Industrial Host Aspergillus niger by Systems Genetics: LaeA Is Required for Citric Acid Production and Regulates the Formation of Some Secondary Metabolites.

PubMed

Niu, Jing; Arentshorst, Mark; Nair, P Deepa S; Dai, Ziyu; Baker, Scott E; Frisvad, Jens C; Nielsen, Kristian F; Punt, Peter J; Ram, Arthur F J

2015-11-13

The asexual filamentous fungus Aspergillus niger is an important industrial cell factory for citric acid production. In this study, we genetically characterized a UV-generated A. niger mutant that was originally isolated as a nonacidifying mutant, which is a desirable trait for industrial enzyme production. Physiological analysis showed that this mutant did not secrete large amounts of citric acid and oxalic acid, thus explaining the nonacidifying phenotype. As traditional complementation approaches to characterize the mutant genotype were unsuccessful, we used bulk segregant analysis in combination with high-throughput genome sequencing to identify the mutation responsible for the nonacidifying phenotype. Since A. niger has no sexual cycle, parasexual genetics was used to generate haploid segregants derived from diploids by loss of whole chromosomes. We found that the nonacidifying phenotype was caused by a point mutation in the laeA gene. LaeA encodes a putative methyltransferase-domain protein, which we show here to be required for citric acid production in an A. niger lab strain (N402) and in other citric acid production strains. The unexpected link between LaeA and citric acid production could provide new insights into the transcriptional control mechanisms related to citric acid production in A. niger. Interestingly, the secondary metabolite profile of a ΔlaeA strain differed from the wild-type strain, showing both decreased and increased metabolite levels, indicating that LaeA is also involved in regulating the production of secondary metabolites. Finally, we show that our systems genetics approach is a powerful tool to identify trait mutations. Copyright © 2016 Niu et al.

Identification of a classical mutant in the industrial host Aspergillus niger by systems genetics: LaeA is required for citric acid production and regulates the formation of some secondary metabolites

DOE PAGES

Niu, Jing; Arentshorst, Mark; Nair, P. Deepa S.; ...

2015-11-13

The asexual filamentous fungus Aspergillus niger is an important industrial cell factory for citric acid production. In this study, we genetically characterized a UV-generated A. niger mutant that was originally isolated as a nonacidifying mutant, which is a desirable trait for industrial enzyme production. Physiological analysis showed that this mutant did not secrete large amounts of citric acid and oxalic acid, thus explaining the nonacidifying phenotype. As traditional complementation approaches to characterize the mutant genotype were unsuccessful, we used bulk segregant analysis in combination with high-throughput genome sequencing to identify the mutation responsible for the nonacidifying phenotype. Since A. nigermore » has no sexual cycle, parasexual genetics was used to generate haploid segregants derived from diploids by loss of whole chromosomes. We found that the nonacidifying phenotype was caused by a point mutation in the laeA gene. LaeA encodes a putative methyltransferase-domain protein, which we show here to be required for citric acid production in an A. niger lab strain (N402) and in other citric acid production strains. The unexpected link between LaeA and citric acid production could provide new insights into the transcriptional control mechanisms related to citric acid production in A. niger. Interestingly, the secondary metabolite profile of a Δ laeA strain differed from the wild-type strain, showing both decreased and increased metabolite levels, indicating that LaeA is also involved in regulating the production of secondary metabolites. As a result, we show that our systems genetics approach is a powerful tool to identify trait mutations.« less

Implications of discoveries from genome-wide association studies in current cardiovascular practice

PubMed Central

Jeemon, Panniyammakal; Pettigrew, Kerry; Sainsbury, Christopher; Prabhakaran, Dorairaj; Padmanabhan, Sandosh

2011-01-01

Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to CDKN2A/CDKN2B/ANRIL, MTHFD1L, CELSR2, PSRC1 and SORT1 genes have been associated with CHD, and TMEM57, DOCK7, CELSR2, APOB, ABCG5, HMGCR, TRIB1, FADS2/S3, LDLR, NCAN and TOMM40-APOE with total cholesterol. Similarly, CELSR2-PSRC1-SORT1, PCSK9, APOB, HMGCR, NCAN-CILP2-PBX4, LDLR, TOMM40-APOE, and APOC1-APOE are associated with variations in low-density lipoprotein cholesterol levels. Altogether, forty, forty three and twenty loci have been associated with high-density lipoprotein cholesterol, triglycerides and BP phenotypes, respectively. Some of these identified loci are common for all the traits, some do not map to functional genes, and some are located in genes that encode for proteins not previously known to be involved in the biological pathway of the trait. GWAS have been successful at identifying new and unexpected genetic loci common to diseases and traits, thus rapidly providing key novel insights into disease biology. Since genotype information is fixed, with minimum biological variability, it is useful in early life risk prediction. However, these variants explain only a small proportion of the observed variance of these traits. Therefore, the utility of genetic determinants in assessing risk at later stages of life has limited immediate clinical impact. The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures. PMID:21860704

Identification of a classical mutant in the industrial host Aspergillus niger by systems genetics: LaeA is required for citric acid production and regulates the formation of some secondary metabolites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niu, Jing; Arentshorst, Mark; Nair, P. Deepa S.

The asexual filamentous fungus Aspergillus niger is an important industrial cell factory for citric acid production. In this study, we genetically characterized a UV-generated A. niger mutant that was originally isolated as a nonacidifying mutant, which is a desirable trait for industrial enzyme production. Physiological analysis showed that this mutant did not secrete large amounts of citric acid and oxalic acid, thus explaining the nonacidifying phenotype. As traditional complementation approaches to characterize the mutant genotype were unsuccessful, we used bulk segregant analysis in combination with high-throughput genome sequencing to identify the mutation responsible for the nonacidifying phenotype. Since A. nigermore » has no sexual cycle, parasexual genetics was used to generate haploid segregants derived from diploids by loss of whole chromosomes. We found that the nonacidifying phenotype was caused by a point mutation in the laeA gene. LaeA encodes a putative methyltransferase-domain protein, which we show here to be required for citric acid production in an A. niger lab strain (N402) and in other citric acid production strains. The unexpected link between LaeA and citric acid production could provide new insights into the transcriptional control mechanisms related to citric acid production in A. niger. Interestingly, the secondary metabolite profile of a Δ laeA strain differed from the wild-type strain, showing both decreased and increased metabolite levels, indicating that LaeA is also involved in regulating the production of secondary metabolites. As a result, we show that our systems genetics approach is a powerful tool to identify trait mutations.« less

Genetic Dosage Compensation in a Family with Velo-cardio-facial/DiGeorge/22q11.2 Deletion Syndrome

PubMed Central

Alkalay, Avishai A.; Guo, Tingwei; Montagna, Cristina; Digilio, M. Cristina; Marino, Bruno; Dallapiccola, Bruno; Morrow, Bernice

2014-01-01

Cytogenetic studies of a male child carrying the 22q11.2 deletion common in patients with velo-cardio-facial/DiGeorge syndrome revealed an unexpected rearrangement of the 22q11.2 region in his normal appearing mother. The mother carries a 3 Mb deletion on one copy and a reciprocal, similar sized duplication on the other copy of chromosome 22q11.2 as revealed by fluorescence in situ hybridization and array comparative genome hybridization analysis. The most parsimonious mechanism for the rearrangement is a mitotic non-allelic homologous recombination event in a cell in the early embryo soon after fertilization. The normal phenotype of the mother can be explained by the theory of genetic dosage compensation. This is the second documented case of such an event for this or any genomic disorder. This finding helps to reinforce this phenomenon in a human model, and has significant implications for genetic counseling of future children. PMID:21337693

Interdependence between transcription and mRNP processing and export, and its impact on genetic stability.

PubMed

Luna, Rosa; Jimeno, Sonia; Marín, Mercedes; Huertas, Pablo; García-Rubio, María; Aguilera, Andrés

2005-06-10

The conserved eukaryotic THO-TREX complex acts at the interface between transcription and mRNA export and affects transcription-associated recombination. To investigate the interdependence of nuclear mRNA processes and their impact on genomic integrity, we analyzed transcript accumulation and recombination of 40 selected mutants covering representative steps of the biogenesis and export of the messenger ribonucleoprotein particle (mRNP). None of the mutants analyzed shared the strong transcript-accumulation defect and hyperrecombination of THO mutants. Nevertheless, mutants in 3' end cleavage/polyadenylation, nuclear exosome, and mRNA export showed a weak but significant effect on recombination and transcript accumulation. Mutants of the nuclear exosome (rrp6) and 3' end processing factors (rna14 and rna15) showed inefficient transcription elongation and genetic interactions with THO. The results suggest a tight interdependence among mRNP biogenesis steps and transcription and an unexpected effect of the nuclear exosome and the cleavage/polyadenylation factors on transcription elongation and genetic integrity.

Immune modulation by genetic modification of dendritic cells with lentiviral vectors.

PubMed

Liechtenstein, Therese; Perez-Janices, Noemi; Bricogne, Christopher; Lanna, Alessio; Dufait, Inès; Goyvaerts, Cleo; Laranga, Roberta; Padella, Antonella; Arce, Frederick; Baratchian, Mehdi; Ramirez, Natalia; Lopez, Natalia; Kochan, Grazyna; Blanco-Luquin, Idoia; Guerrero-Setas, David; Breckpot, Karine; Escors, David

2013-09-01

Our work over the past eight years has focused on the use of HIV-1 lentiviral vectors (lentivectors) for the genetic modification of dendritic cells (DCs) to control their functions in immune modulation. DCs are key professional antigen presenting cells which regulate the activity of most effector immune cells, including T, B and NK cells. Their genetic modification provides the means for the development of targeted therapies towards cancer and autoimmune disease. We have been modulating with lentivectors the activity of intracellular signalling pathways and co-stimulation during antigen presentation to T cells, to fine-tune the type and strength of the immune response. In the course of our research, we have found unexpected results such as the surprising immunosuppressive role of anti-viral signalling pathways, and the close link between negative co-stimulation in the immunological synapse and T cell receptor trafficking. Here we review our major findings and put them into context with other published work. Copyright © 2013 Elsevier B.V. All rights reserved.

Specification of Drosophila Corpora Cardiaca Neuroendocrine Cells from Mesoderm Is Regulated by Notch Signaling

PubMed Central

Park, Sangbin; Bustamante, Erika L.; Antonova, Julie; McLean, Graeme W.; Kim, Seung K.

2011-01-01

Drosophila neuroendocrine cells comprising the corpora cardiaca (CC) are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism. PMID:21901108

Nickel-catalyzed hydrocarboxylation of ynamides with CO2 and H2O: observation of unexpected regioselectivity.

PubMed

Doi, Ryohei; Abdullah, Iman; Taniguchi, Takahisa; Saito, Nozomi; Sato, Yoshihiro

2017-07-06

We describe the nickel-catalyzed hydrocarboxylation of ynamides with CO 2 and H 2 O to afford a variety of α-amino-α,β-unsaturated esters with high regioselectivities. The selective α-carboxylation of ynamides with this catalytic protocol is unexpected in view of the electronic bias of ynamides and is in sharp contrast to our previous study in which a stoichiometric amount of Ni(0) was used to form a β-carboxylated product exclusively. We revealed that this unexpected C-C bond formation was induced by the combination of Zn and MgBr 2 .

Mating competitiveness of male Anopheles arabiensis mosquitoes irradiated with a partially or fully sterilizing dose in small and large laboratory cages.

PubMed

Helinski, M E H; Knols, B G J

2008-07-01

Male mating competitiveness is a crucial parameter in many genetic control programs including the sterile insect technique (SIT). We evaluated competitiveness of male Anopheles arabiensis Patton as a function of three experimental variables: (1) small or large cages for mating, (2) the effects of either a partially sterilizing (70 Gy) or fully sterilizing (120 Gy) dose, and (3) pupal or adult irradiation. Irradiated males competed for females with an equal number of unirradiated males. Competitiveness was determined by measuring hatch rates of individually laid egg batches. In small cages, pupal irradiation with the high dose resulted in the lowest competitiveness, whereas adult irradiation with the low dose gave the highest, with the latter males being equal in competitiveness to unirradiated males. In the large cage, reduced competitiveness of males irradiated in the pupal stage was more pronounced compared with the small cage; the males irradiated as adults at both doses performed similarly to unirradiated males. Unexpectedly, males irradiated with the high dose performed better in a large cage than in a small one. A high proportion of intermediate hatch rates was observed for eggs collected in the large cage experiments with males irradiated at the pupal stage. It is concluded that irradiation of adult An. arabiensis with the partially sterilizing dose results in the highest competitiveness for both cage designs. Cage size affected competitiveness for some treatments; therefore, competitiveness determined in laboratory experiments must be confirmed by releases into simulated field conditions. The protocols described are readily transferable to evaluate male competitiveness for other genetic control techniques.

Long-lived mitochondrial (Mit) mutants of Caenorhabditis elegans utilize a novel metabolism.

PubMed

Butler, Jeffrey A; Ventura, Natascia; Johnson, Thomas E; Rea, Shane L

2010-12-01

The Caenorhabditis elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain (ETC) functionality, yet, surprisingly, they are long lived. We have previously proposed that Mit mutants supplement their energy needs by exploiting alternate energy production pathways normally used by wild-type animals only when exposed to hypoxic conditions. We have also proposed that longevity in the Mit mutants arises as a property of their new metabolic state. If longevity does arise as a function of metabolic state, we would expect to find a common metabolic signature among these animals. To test these predictions, we established a novel approach monitoring the C. elegans exometabolism as a surrogate marker for internal metabolic events. Using HPLC-ultraviolet-based metabolomics and multivariate analyses, we show that long-lived clk-1(qm30) and isp-1(qm150) Mit mutants have a common metabolic profile that is distinct from that of aerobically cultured wild-type animals and, unexpectedly, wild-type animals cultured under severe oxygen deprivation. Moreover, we show that 2 short-lived mitochondrial ETC mutants, mev-1(kn1) and ucr-2.3(pk732), also share a common metabolic signature that is unique. We show that removal of soluble fumarate reductase unexpectedly increases health span in several genetically defined Mit mutants, identifying at least 1 alternate energy production pathway, malate dismutation, that is operative in these animals. Our study suggests long-lived, genetically specified Mit mutants employ a novel metabolism and that life span may well arise as a function of metabolic state.

Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization.

PubMed

Alger, Heather M; Brown, J Mark; Sawyer, Janet K; Kelley, Kathryn L; Shah, Ramesh; Wilson, Martha D; Willingham, Mark C; Rudel, Lawrence L

2010-05-07

Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease.

Identification of Small Molecule and Genetic Modulators of AON-Induced Dystrophin Exon Skipping by High-Throughput Screening

PubMed Central

O'Leary, Debra A.; Sharif, Orzala; Anderson, Paul; Tu, Buu; Welch, Genevieve; Zhou, Yingyao; Caldwell, Jeremy S.; Engels, Ingo H.; Brinker, Achim

2009-01-01

One therapeutic approach to Duchenne Muscular Dystrophy (DMD) recently entering clinical trials aims to convert DMD phenotypes to that of a milder disease variant, Becker Muscular Dystrophy (BMD), by employing antisense oligonucleotides (AONs) targeting splice sites, to induce exon skipping and restore partial dystrophin function. In order to search for small molecule and genetic modulators of AON-dependent and independent exon skipping, we screened ∼10,000 known small molecule drugs, >17,000 cDNA clones, and >2,000 kinase- targeted siRNAs against a 5.6 kb luciferase minigene construct, encompassing exon 71 to exon 73 of human dystrophin. As a result, we identified several enhancers of exon skipping, acting on both the reporter construct as well as endogenous dystrophin in mdx cells. Multiple mechanisms of action were identified, including histone deacetylase inhibition, tubulin modulation and pre-mRNA processing. Among others, the nucleolar protein NOL8 and staufen RNA binding protein homolog 2 (Stau2) were found to induce endogenous exon skipping in mdx cells in an AON-dependent fashion. An unexpected but recurrent theme observed in our screening efforts was the apparent link between the inhibition of cell cycle progression and the induction of exon skipping. PMID:20020055

Identification of small molecule and genetic modulators of AON-induced dystrophin exon skipping by high-throughput screening.

PubMed

O'Leary, Debra A; Sharif, Orzala; Anderson, Paul; Tu, Buu; Welch, Genevieve; Zhou, Yingyao; Caldwell, Jeremy S; Engels, Ingo H; Brinker, Achim

2009-12-17

One therapeutic approach to Duchenne Muscular Dystrophy (DMD) recently entering clinical trials aims to convert DMD phenotypes to that of a milder disease variant, Becker Muscular Dystrophy (BMD), by employing antisense oligonucleotides (AONs) targeting splice sites, to induce exon skipping and restore partial dystrophin function. In order to search for small molecule and genetic modulators of AON-dependent and independent exon skipping, we screened approximately 10,000 known small molecule drugs, >17,000 cDNA clones, and >2,000 kinase- targeted siRNAs against a 5.6 kb luciferase minigene construct, encompassing exon 71 to exon 73 of human dystrophin. As a result, we identified several enhancers of exon skipping, acting on both the reporter construct as well as endogenous dystrophin in mdx cells. Multiple mechanisms of action were identified, including histone deacetylase inhibition, tubulin modulation and pre-mRNA processing. Among others, the nucleolar protein NOL8 and staufen RNA binding protein homolog 2 (Stau2) were found to induce endogenous exon skipping in mdx cells in an AON-dependent fashion. An unexpected but recurrent theme observed in our screening efforts was the apparent link between the inhibition of cell cycle progression and the induction of exon skipping.

Integrating mRNA and Protein Sequencing Enables the Detection and Quantitative Profiling of Natural Protein Sequence Variants of Populus trichocarpa.

PubMed

Abraham, Paul E; Wang, Xiaojing; Ranjan, Priya; Nookaew, Intawat; Zhang, Bing; Tuskan, Gerald A; Hettich, Robert L

2015-12-04

Next-generation sequencing has transformed the ability to link genotypes to phenotypes and facilitates the dissection of genetic contribution to complex traits. However, it is challenging to link genetic variants with the perturbed functional effects on proteins encoded by such genes. Here we show how RNA sequencing can be exploited to construct genotype-specific protein sequence databases to assess natural variation in proteins, providing information about the molecular toolbox driving cellular processes. For this study, we used two natural genotypes selected from a recent genome-wide association study of Populus trichocarpa, an obligate outcrosser with tremendous phenotypic variation across the natural population. This strategy allowed us to comprehensively catalogue proteins containing single amino acid polymorphisms (SAAPs), as well as insertions and deletions. We profiled the frequency of 128 types of naturally occurring amino acid substitutions, including both expected (neutral) and unexpected (non-neutral) SAAPs, with a subset occurring in regions of the genome having strong polymorphism patterns consistent with recent positive and/or divergent selection. By zeroing in on the molecular signatures of these important regions that might have previously been uncharacterized, we now provide a high-resolution molecular inventory that should improve accessibility and subsequent identification of natural protein variants in future genotype-to-phenotype studies.

PCR on yeast colonies: an improved method for glyco-engineered Saccharomyces cerevisiae

PubMed Central

2013-01-01

Background Saccharomyces cerevisiae is extensively used in bio-industries. However, its genetic engineering to introduce new metabolism pathways can cause unexpected phenotypic alterations. For example, humanisation of the glycosylation pathways is a high priority pharmaceutical industry goal for production of therapeutic glycoproteins in yeast. Genomic modifications can lead to several described physiological changes: biomass yields decrease, temperature sensitivity or cell wall structure modifications. We have observed that deletion of several N-mannosyltransferases in Saccharomyces cerevisiae, results in strains that can no longer be analyzed by classical PCR on yeast colonies. Findings In order to validate our glyco-engineered Saccharomyces cerevisiae strains, we developed a new protocol to carry out PCR directly on genetically modified yeast colonies. A liquid culture phase, combined with the use of a Hot Start DNA polymerase, allows a 3-fold improvement of PCR efficiency. The results obtained are repeatable and independent of the targeted sequence; as such the protocol is well adapted for intensive screening applications. Conclusions The developed protocol enables by-passing of many of the difficulties associated with PCR caused by phenotypic modifications brought about by humanisation of the glycosylation in yeast and allows rapid validation of glyco-engineered Saccharomyces cerevisiae cells. It has the potential to be extended to other yeast strains presenting cell wall structure modifications. PMID:23688076

Investigating the origin of vagrant dusky groupers, Epinephelus marginatus (Lowe, 1834), in coastal waters of Réunion Island.

PubMed

Reid, Kerry; Crochelet, Estelle; Bloomer, Paulette; Hoareau, Thierry B

2016-10-01

Due to their geographic isolation, biotas of oceanic islands are likely influenced by episodic long distance dispersal events, but such observations are scarce. In June 2012, fishermen from Réunion Island caught an unknown specimen of grouper, identified as dusky grouper Epinephelus marginatus (Lowe, 1834). This was highly unexpected considering the large distance of its closest verified occurrence (South Africa, ∼2500km). To identify the origin of this specimen and the mechanisms driving this potential long distance colonization, we combined genetic analyses and hydrodynamic connectivity modeling approaches. Molecular markers and samples from various locations across the distribution range resulted in the identification of three putative source populations. The Réunion specimen clustered genetically with South Africa. The estimated spawning period in relation to the connectivity modeling of larvae showed no possible direct connection between South Africa and Réunion. However, connectivity was predicted through intermediate stepping stone populations likely located around the southern tip of Madagascar, where the occurrence of the species has yet to be verified. The results further highlight the potential role of the cyclone Bingiza (February 2011) in the connection between Madagascar and Réunion. This shows that cyclones may be an important driver in long distance colonization of oceanic islands. Copyright © 2016 Elsevier Inc. All rights reserved.

Females Choose Mates Based on Genetic Relatedness in a Small Dasyurid Marsupial, the Agile Antechinus (Antechinus agilis)

PubMed Central

Parrott, Marissa L.; Ward, Simon J.; Temple-Smith, Peter D.; Selwood, Lynne

2015-01-01

Females in a variety of taxa mate with more than one male during a single oestrus and exhibit mate preferences for genetically compatible males, but the influence of female mate choice on siring success is not clearly understood. Whether females choose to mate with more than one male or endure forced copulations is also often unknown. Here, we examined the effects of genetic relatedness on female mate choice and siring success in a small semelparous carnivorous marsupial, the agile antechinus (Antechinus agilis), during two consecutive breeding seasons. Experimental trials were conducted in captivity over periods of 72 hours using interconnected enclosures in which female antechinus could choose to access any of four separated males, but males were only able to access females that entered their quarters. Females had access to two genetically similar and two genetically dissimilar males simultaneously and all behavioural interactions were observed and scored from continuous video recordings. Genetic similarity between mates and paternity of young was determined by microsatellite analyses. Some females chose to enter and mate with more than one male during a single oestrus period. Although females investigated all males, they spent significantly more time visiting, and mated more times with, genetically dissimilar males. Males that were genetically dissimilar to the female sired 88% of subsequent offspring. Whilst males mated readily with most females, they rejected the advances of some receptive females, indicating a previously unexpected level of male mate choice. The results show that genetic relatedness between mates has a significant influence on mate choice, breeding and siring success in the agile antechinus. PMID:25923325

Females Choose Mates Based on Genetic Relatedness in a Small Dasyurid Marsupial, the Agile Antechinus (Antechinus agilis).

PubMed

Parrott, Marissa L; Ward, Simon J; Temple-Smith, Peter D; Selwood, Lynne

2015-01-01

Females in a variety of taxa mate with more than one male during a single oestrus and exhibit mate preferences for genetically compatible males, but the influence of female mate choice on siring success is not clearly understood. Whether females choose to mate with more than one male or endure forced copulations is also often unknown. Here, we examined the effects of genetic relatedness on female mate choice and siring success in a small semelparous carnivorous marsupial, the agile antechinus (Antechinus agilis), during two consecutive breeding seasons. Experimental trials were conducted in captivity over periods of 72 hours using interconnected enclosures in which female antechinus could choose to access any of four separated males, but males were only able to access females that entered their quarters. Females had access to two genetically similar and two genetically dissimilar males simultaneously and all behavioural interactions were observed and scored from continuous video recordings. Genetic similarity between mates and paternity of young was determined by microsatellite analyses. Some females chose to enter and mate with more than one male during a single oestrus period. Although females investigated all males, they spent significantly more time visiting, and mated more times with, genetically dissimilar males. Males that were genetically dissimilar to the female sired 88% of subsequent offspring. Whilst males mated readily with most females, they rejected the advances of some receptive females, indicating a previously unexpected level of male mate choice. The results show that genetic relatedness between mates has a significant influence on mate choice, breeding and siring success in the agile antechinus.

High levels of variation in Salix lignocellulose genes revealed using poplar genomic resources

PubMed Central

2013-01-01

Background Little is known about the levels of variation in lignin or other wood related genes in Salix, a genus that is being increasingly used for biomass and biofuel production. The lignin biosynthesis pathway is well characterized in a number of species, including the model tree Populus. We aimed to transfer the genomic resources already available in Populus to its sister genus Salix to assess levels of variation within genes involved in wood formation. Results Amplification trials for 27 gene regions were undertaken in 40 Salix taxa. Twelve of these regions were sequenced. Alignment searches of the resulting sequences against reference databases, combined with phylogenetic analyses, showed the close similarity of these Salix sequences to Populus, confirming homology of the primer regions and indicating a high level of conservation within the wood formation genes. However, all sequences were found to vary considerably among Salix species, mainly as SNPs with a smaller number of insertions-deletions. Between 25 and 176 SNPs per kbp per gene region (in predicted exons) were discovered within Salix. Conclusions The variation found is sizeable but not unexpected as it is based on interspecific and not intraspecific comparison; it is comparable to interspecific variation in Populus. The characterisation of genetic variation is a key process in pre-breeding and for the conservation and exploitation of genetic resources in Salix. This study characterises the variation in several lignocellulose gene markers for such purposes. PMID:23924375

Vsx2 Controls Eye Organogenesis and Retinal Progenitor Identity Via Homeodomain and Non-Homeodomain Residues Required for High Affinity DNA Binding

PubMed Central

Zou, Changjiang; Levine, Edward M.

2012-01-01

The homeodomain and adjacent CVC domain in the visual system homeobox (VSX) proteins are conserved from nematodes to humans. Humans with missense mutations in these regions of VSX2 have microphthalmia, suggesting both regions are critical for function. To assess this, we generated the corresponding mutations in mouse Vsx2. The homeodomain mutant protein lacked DNA binding activity and the knock-in mutant phenocopied the null mutant, ocular retardation J. The CVC mutant protein exhibited weakened DNA binding; and, although the corresponding knock-in allele was recessive, it unexpectedly caused the strongest phenotype, as indicated by severe microphthalmia and hyperpigmentation of the neural retina. This occurred through a cryptic transcriptional feedback loop involving the transcription factors Mitf and Otx1 and the Cdk inhibitor p27Kip1. Our data suggest that the phenotypic severity of the CVC mutant depends on the weakened DNA binding activity elicited by the CVC mutation and a previously unknown protein interaction between Vsx2 and its regulatory target Mitf. Our data also suggest that an essential function of the CVC domain is to assist the homeodomain in high-affinity DNA binding, which is required for eye organogenesis and unhindered execution of the retinal progenitor program in mammals. Finally, the genetic and phenotypic behaviors of the CVC mutation suggest it has the characteristics of a recessive neomorph, a rare type of genetic allele. PMID:23028343

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

PubMed Central

McDermott-Roe, Chris; Ye, Junmei; Ahmed, Rizwan; Sun, Xi-Ming; Serafín, Anna; Ware, James; Bottolo, Leonardo; Muckett, Phil; Cañas, Xavier; Zhang, Jisheng; Rowe, Glenn C.; Buchan, Rachel; Lu, Han; Braithwaite, Adam; Mancini, Massimiliano; Hauton, David; Martí, Ramon; García-Arumí, Elena; Hubner, Norbert; Jacob, Howard; Serikawa, Tadao; Zidek, Vaclav; Papousek, Frantisek; Kolar, Frantisek; Cardona, Maria; Ruiz-Meana, Marisol; García-Dorado, David; Comella, Joan X; Felkin, Leanne E; Barton, Paul JR; Arany, Zoltan; Pravenec, Michal; Petretto, Enrico; Sanchis, Daniel; Cook, Stuart A.

2011-01-01

Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation3 and the regulatory mechanisms for blood pressure (BP)-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems-genetics approaches in the rat6,7 now provide a powerful complementary tool to GWAS and we applied integrative genomics to dissect a highly replicated, BP-independent LVM locus on rat chromosome 3p. We identified endonuclease G (Endog), previously implicated in apoptosis8 but not hypertrophy, as the gene at the locus and demonstrated loss-of-function mutation in Endog associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly inferred ENDOG in fundamental mitochondrial processes unrelated to apoptosis. We showed direct regulation of ENDOG by ERRα and PGC1α, master regulators of mitochondrial and cardiac function9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, Endog deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated reactive oxygen species (ROS), which was associated with enlarged and steatotic cardiomyocytes. Our studies establish further the link between mitochondrial dysfunction, ROS and heart disease and demonstrate a new role for Endog in maladaptive cardiac hypertrophy. PMID:21979051

One species for one island? Unexpected diversity and weak connectivity in a widely distributed tropical hydrozoan.

PubMed

Postaire, B; Gélin, P; Bruggemann, J H; Magalon, H

2017-04-01

Isolation by distance (IBD) is one of the main modes of differentiation in marine species, above all in species presenting low dispersal capacities. This study reports the genetic structuring in the tropical hydrozoan Lytocarpia brevirostris α (sensu Postaire et al, 2016b), a brooding species, from 13 populations in the Western Indian Ocean (WIO) and one from New Caledonia (Tropical Southwestern Pacific). At the local scale, populations rely on asexual propagation at short distance, which was not found at larger scales; identical genotypes were restricted to single populations. After the removal of repeated genotypes, all populations presented significant positive F IS values (between 0.094*** and 0.335***). Gene flow was extremely low at all spatial scales, between sites within islands (<10 km distance) and among islands (100 to>11 000 km distance), with significant pairwise F ST values (between 0.012*** and 0.560***). A general pattern of IBD was found at the Indo-Pacific scale, but also within sampled ecoregions of the WIO province. Clustering analyses identified each sampled island as an independent population, whereas analysis of molecular variance indicated that population genetic differentiation was significant at small (within island) and intermediate (among islands within province) spatial scales. The high population differentiation might reflect the life cycle of this brooding hydrozoan, possibly preventing regular dispersal at distances more than a few kilometres and probably leading to high cryptic diversity, each island housing an independent evolutionary lineage.

doublesex alters aggressiveness as a function of social context and sex in the polyphenic beetle Onthophagus taurus.

PubMed

Beckers, Oliver M; Kijimoto, Teiya; Moczek, Armin P

2017-10-01

Despite sharing nearly the same genome, individuals within the same species can vary drastically in both morphology and behaviour as a function of developmental stage, sex or developmental plasticity. Thus, regulatory processes must exist that enable the stage-, sex- or environment-specific expression of traits and their integration during ontogeny, yet exactly how trait complexes are co-regulated and integrated is poorly understood. In this study, we explore the developmental genetic basis of the regulation and integration of environment-dependent sexual dimorphism in behaviour and morphology in the horn-polyphenic dung beetle Onthophagus taurus through the experimental manipulation of the transcription factor doublesex (dsx). The gene dsx plays a profound role in the developmental regulation of morphological differences between sexes as well as alternative male morphs by inhibiting horn formation in females but enabling nutrition-responsive horn growth in males. Specifically, we investigated whether experimental downregulation of dsx expression affects male and female aggressive and courtship behaviours in two social contexts: interactions between individuals of the same sex and interactions between males and females. We find that dsx downregulation significantly alters aggressiveness in both males and females, yet does so differently for both sexes as a function of social context: dsx RNAi males exhibited elevated aggression towards males but showed reduced aggression towards females, whereas dsx RNAi females became more aggressive towards males, while their aggressiveness towards other females was unaffected. Moreover, we document unexpectedly high levels of female aggression independent of dsx treatment in both wild-type and control-injected individuals. Lastly, we found no effects of dsx RNAi on courtship and mating behaviours. We discuss the role of dsx in the regulation of sex-specific and plastic behaviours, the unexpectedly high levels of aggression of hornless dsx RNAi males in relation to the well-established description of the hornless sneaker phenotype and the potential ecological function of high female aggression.

Considering the Influence of Nonadaptive Evolution on Primate Color Vision.

PubMed

Jacobs, Rachel L; Bradley, Brenda J

2016-01-01

Color vision in primates is variable across species, and it represents a rare trait in which the genetic mechanisms underlying phenotypic variation are fairly well-understood. Research on primate color vision has largely focused on adaptive explanations for observed variation, but it remains unclear why some species have trichromatic or polymorphic color vision while others are red-green color blind. Lemurs, in particular, are highly variable. While some species are polymorphic, many closely-related species are strictly dichromatic. We provide the first characterization of color vision in a wild population of red-bellied lemurs (Eulemur rubriventer, Ranomafana National Park, Madagascar) with a sample size (87 individuals; NX chromosomes = 134) large enough to detect even rare variants (0.95 probability of detection at ≥ 3% frequency). By sequencing exon 5 of the X-linked opsin gene we identified opsin spectral sensitivity based on known diagnostic sites and found this population to be dichromatic and monomorphic for a long wavelength allele. Apparent fixation of this long allele is in contrast to previously published accounts of Eulemur species, which exhibit either polymorphic color vision or only the medium wavelength opsin. This unexpected result may represent loss of color vision variation, which could occur through selective processes and/or genetic drift (e.g., genetic bottleneck). To indirectly assess the latter scenario, we genotyped 55 adult red-bellied lemurs at seven variable microsatellite loci and used heterozygosity excess and M-ratio tests to assess if this population may have experienced a recent genetic bottleneck. Results of heterozygosity excess but not M-ratio tests suggest a bottleneck might have occurred in this red-bellied lemur population. Therefore, while selection may also play a role, the unique color vision observed in this population might have been influenced by a recent genetic bottleneck. These results emphasize the need to consider adaptive and nonadaptive mechanisms of color vision evolution in primates.

Considering the Influence of Nonadaptive Evolution on Primate Color Vision

PubMed Central

Jacobs, Rachel L.; Bradley, Brenda J.

2016-01-01

Color vision in primates is variable across species, and it represents a rare trait in which the genetic mechanisms underlying phenotypic variation are fairly well-understood. Research on primate color vision has largely focused on adaptive explanations for observed variation, but it remains unclear why some species have trichromatic or polymorphic color vision while others are red-green color blind. Lemurs, in particular, are highly variable. While some species are polymorphic, many closely-related species are strictly dichromatic. We provide the first characterization of color vision in a wild population of red-bellied lemurs (Eulemur rubriventer, Ranomafana National Park, Madagascar) with a sample size (87 individuals; NX chromosomes = 134) large enough to detect even rare variants (0.95 probability of detection at ≥ 3% frequency). By sequencing exon 5 of the X-linked opsin gene we identified opsin spectral sensitivity based on known diagnostic sites and found this population to be dichromatic and monomorphic for a long wavelength allele. Apparent fixation of this long allele is in contrast to previously published accounts of Eulemur species, which exhibit either polymorphic color vision or only the medium wavelength opsin. This unexpected result may represent loss of color vision variation, which could occur through selective processes and/or genetic drift (e.g., genetic bottleneck). To indirectly assess the latter scenario, we genotyped 55 adult red-bellied lemurs at seven variable microsatellite loci and used heterozygosity excess and M-ratio tests to assess if this population may have experienced a recent genetic bottleneck. Results of heterozygosity excess but not M-ratio tests suggest a bottleneck might have occurred in this red-bellied lemur population. Therefore, while selection may also play a role, the unique color vision observed in this population might have been influenced by a recent genetic bottleneck. These results emphasize the need to consider adaptive and nonadaptive mechanisms of color vision evolution in primates. PMID:26959829

Biogenetic models of psychopathology, implicit guilt, and mental illness stigma.

PubMed

Rüsch, Nicolas; Todd, Andrew R; Bodenhausen, Galen V; Corrigan, Patrick W

2010-10-30

Whereas some research suggests that acknowledgment of the role of biogenetic factors in mental illness could reduce mental illness stigma by diminishing perceived responsibility, other research has cautioned that emphasizing biogenetic aspects of mental illness could produce the impression that mental illness is a stable, intrinsic aspect of a person ("genetic essentialism"), increasing the desire for social distance. We assessed genetic and neurobiological causal attributions about mental illness among 85 people with serious mental illness and 50 members of the public. The perceived responsibility of persons with mental illness for their condition, as well as fear and social distance, was assessed by self-report. Automatic associations between Mental Illness and Guilt and between Self and Guilt were measured by the Brief Implicit Association Test. Among the general public, endorsement of biogenetic models was associated with not only less perceived responsibility, but also greater social distance. Among people with mental illness, endorsement of genetic models had only negative correlates: greater explicit fear and stronger implicit self-guilt associations. Genetic models may have unexpected negative consequences for implicit self-concept and explicit attitudes of people with serious mental illness. An exclusive focus on genetic models may therefore be problematic for clinical practice and anti-stigma initiatives. Copyright © 2009 Elsevier Ltd. All rights reserved.

Genetics of the Pig Tapeworm in Madagascar Reveal a History of Human Dispersal and Colonization

PubMed Central

Yanagida, Tetsuya; Carod, Jean-François; Sako, Yasuhito; Nakao, Minoru; Hoberg, Eric P.; Ito, Akira

2014-01-01

An intricate history of human dispersal and geographic colonization has strongly affected the distribution of human pathogens. The pig tapeworm Taenia solium occurs throughout the world as the causative agent of cysticercosis, one of the most serious neglected tropical diseases. Discrete genetic lineages of T. solium in Asia and Africa/Latin America are geographically disjunct; only in Madagascar are they sympatric. Linguistic, archaeological and genetic evidence has indicated that the people in Madagascar have mixed ancestry from Island Southeast Asia and East Africa. Hence, anthropogenic introduction of the tapeworm from Southeast Asia and Africa had been postulated. This study shows that the major mitochondrial haplotype of T. solium in Madagascar is closely related to those from the Indian Subcontinent. Parasitological evidence presented here, and human genetics previously reported, support the hypothesis of an Indian influence on Malagasy culture coinciding with periods of early human migration onto the island. We also found evidence of nuclear-mitochondrial discordance in single tapeworms, indicating unexpected cross-fertilization between the two lineages of T. solium. Analyses of genetic and geographic populations of T. solium in Madagascar will shed light on apparently rapid evolution of this organism driven by recent (<2,000 yr) human migrations, following tens of thousands of years of geographic isolation. PMID:25329310

Do Gametes Woo? Evidence for Their Nonrandom Union at Fertilization.

PubMed

Nadeau, Joseph H

2017-10-01

A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that gametes combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel's First Law. But exceptions are known. With transmission ratio distortion, particular alleles are preferentially transmitted to offspring. Preferential transmission usually occurs in one sex but not both, and is not known to require interactions between gametes at fertilization. A reanalysis of our published work in mice and of data in other published reports revealed instances where any of 12 mutant genes biases fertilization, with either too many or too few heterozygotes and homozygotes, depending on the mutant gene and on dietary conditions. Although such deviations are usually attributed to embryonic lethality of the underrepresented genotypes, the evidence is more consistent with genetically-determined preferences for specific combinations of egg and sperm at fertilization that result in genotype bias without embryo loss. This unexpected discovery of genetically-biased fertilization could yield insights about the molecular and cellular interactions between sperm and egg at fertilization, with implications for our understanding of inheritance, reproduction, population genetics, and medical genetics. Copyright © 2017 by the Genetics Society of America.

Diversity amongst trigeminal neurons revealed by high throughput single cell sequencing

PubMed Central

Nguyen, Minh Q.; Wu, Youmei; Bonilla, Lauren S.; von Buchholtz, Lars J.

2017-01-01

The trigeminal ganglion contains somatosensory neurons that detect a range of thermal, mechanical and chemical cues and innervate unique sensory compartments in the head and neck including the eyes, nose, mouth, meninges and vibrissae. We used single-cell sequencing and in situ hybridization to examine the cellular diversity of the trigeminal ganglion in mice, defining thirteen clusters of neurons. We show that clusters are well conserved in dorsal root ganglia suggesting they represent distinct functional classes of somatosensory neurons and not specialization associated with their sensory targets. Notably, functionally important genes (e.g. the mechanosensory channel Piezo2 and the capsaicin gated ion channel Trpv1) segregate into multiple clusters and often are expressed in subsets of cells within a cluster. Therefore, the 13 genetically-defined classes are likely to be physiologically heterogeneous rather than highly parallel (i.e., redundant) lines of sensory input. Our analysis harnesses the power of single-cell sequencing to provide a unique platform for in silico expression profiling that complements other approaches linking gene-expression with function and exposes unexpected diversity in the somatosensory system. PMID:28957441

The clinical maze of mitochondrial neurology

PubMed Central

DiMauro, Salvatore; Schon, Eric A.; Carelli, Valerio; Hirano, Michio

2014-01-01

Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. PMID:23835535

Genetics Behind Barbed Wire: Masuo Kodani, Émigré Geneticists, and Wartime Genetics Research at Manzanar Relocation Center

PubMed Central

Smocovitis, Vassiliki Betty

2011-01-01

This article explores the sociopolitical backdrop of genetics research during the politically turbulent decades of the mid-20th century that saw the persecution, displacement, and relocation of unpopular minorities in both the United States and Europe. It explores how geneticists in the United States accommodated these disruptions through formal and informal émigré networks and how the subsequent war affected their research programs and their lives. It does so by focusing on the career and life of geneticist Masuo Kodani, who, as a Japanese American, found himself conducting unexpected cytogenetics research in Manzanar, a “relocation center,” or internment camp, located in the California desert, after the attack on Pearl Harbor. After the war, Kodani's subsequent career continued to be shaped by his experiences as a Japanese American and by the specific skills as a cytogeneticist that he demonstrated at a critical period in the history of 20th-century genetics. His many relocations in search of employment culminated in his work with the Atomic Bomb Casualty Commission on human chromosomes, for which he is best known. PMID:21307394

Arabidopsis research requires a critical re-evaluation of genetic tools.

PubMed

Nikonorova, Natalia; Yue, Kun; Beeckman, Tom; De Smet, Ive

2018-06-27

An increasing number of reports question conclusions based on loss-of-function lines that have unexpected genetic backgrounds. In this opinion paper, we urge researchers to meticulously (re)investigate phenotypes retrieved from various genetic backgrounds and be critical regarding some previously drawn conclusions. As an example, we provide new evidence that acr4-2 mutant phenotypes with respect to columella stem cells are due to the lack of ACR4 and not - at least not as a major contributor - to a mutation in QRT1. In addition, we take the opportunity to alert the scientific community about the qrt1-2 background of a large number of Syngenta Arabidopsis Insertion Library (SAIL) T-DNA lines, a feature that is not commonly recognized by Arabidopsis researchers. This qrt1-2 background might have an important impact on the interpretation of the results obtained using these research tools, now and in the past. In conclusion, as a community, we should continuously assess and - if necessary - correct our conclusions based on the large number of (genetic) tools our work is built on. In addition, the positive or negative results of this self-criticism should be made available to the scientific community.

Isocost Lines Describe the Cellular Economy of Genetic Circuits.

PubMed

Gyorgy, Andras; Jiménez, José I; Yazbek, John; Huang, Hsin-Ho; Chung, Hattie; Weiss, Ron; Del Vecchio, Domitilla

2015-08-04

Genetic circuits in living cells share transcriptional and translational resources that are available in limited amounts. This leads to unexpected couplings among seemingly unconnected modules, which result in poorly predictable circuit behavior. In this study, we determine these interdependencies between products of different genes by characterizing the economy of how transcriptional and translational resources are allocated to the production of proteins in genetic circuits. We discover that, when expressed from the same plasmid, the combinations of attainable protein concentrations are constrained by a linear relationship, which can be interpreted as an isocost line, a concept used in microeconomics. We created a library of circuits with two reporter genes, one constitutive and the other inducible in the same plasmid, without a regulatory path between them. In agreement with the model predictions, experiments reveal that the isocost line rotates when changing the ribosome binding site strength of the inducible gene and shifts when modifying the plasmid copy number. These results demonstrate that isocost lines can be employed to predict how genetic circuits become coupled when sharing resources and provide design guidelines for minimizing the effects of such couplings. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

PubMed

Thompson, Paul M; Stein, Jason L; Medland, Sarah E; Hibar, Derrek P; Vasquez, Alejandro Arias; Renteria, Miguel E; Toro, Roberto; Jahanshad, Neda; Schumann, Gunter; Franke, Barbara; Wright, Margaret J; Martin, Nicholas G; Agartz, Ingrid; Alda, Martin; Alhusaini, Saud; Almasy, Laura; Almeida, Jorge; Alpert, Kathryn; Andreasen, Nancy C; Andreassen, Ole A; Apostolova, Liana G; Appel, Katja; Armstrong, Nicola J; Aribisala, Benjamin; Bastin, Mark E; Bauer, Michael; Bearden, Carrie E; Bergmann, Orjan; Binder, Elisabeth B; Blangero, John; Bockholt, Henry J; Bøen, Erlend; Bois, Catherine; Boomsma, Dorret I; Booth, Tom; Bowman, Ian J; Bralten, Janita; Brouwer, Rachel M; Brunner, Han G; Brohawn, David G; Buckner, Randy L; Buitelaar, Jan; Bulayeva, Kazima; Bustillo, Juan R; Calhoun, Vince D; Cannon, Dara M; Cantor, Rita M; Carless, Melanie A; Caseras, Xavier; Cavalleri, Gianpiero L; Chakravarty, M Mallar; Chang, Kiki D; Ching, Christopher R K; Christoforou, Andrea; Cichon, Sven; Clark, Vincent P; Conrod, Patricia; Coppola, Giovanni; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Deary, Ian J; de Geus, Eco J C; den Braber, Anouk; Delvecchio, Giuseppe; Depondt, Chantal; de Haan, Lieuwe; de Zubicaray, Greig I; Dima, Danai; Dimitrova, Rali; Djurovic, Srdjan; Dong, Hongwei; Donohoe, Gary; Duggirala, Ravindranath; Dyer, Thomas D; Ehrlich, Stefan; Ekman, Carl Johan; Elvsåshagen, Torbjørn; Emsell, Louise; Erk, Susanne; Espeseth, Thomas; Fagerness, Jesen; Fears, Scott; Fedko, Iryna; Fernández, Guillén; Fisher, Simon E; Foroud, Tatiana; Fox, Peter T; Francks, Clyde; Frangou, Sophia; Frey, Eva Maria; Frodl, Thomas; Frouin, Vincent; Garavan, Hugh; Giddaluru, Sudheer; Glahn, David C; Godlewska, Beata; Goldstein, Rita Z; Gollub, Randy L; Grabe, Hans J; Grimm, Oliver; Gruber, Oliver; Guadalupe, Tulio; Gur, Raquel E; Gur, Ruben C; Göring, Harald H H; Hagenaars, Saskia; Hajek, Tomas; Hall, Geoffrey B; Hall, Jeremy; Hardy, John; Hartman, Catharina A; Hass, Johanna; Hatton, Sean N; Haukvik, Unn K; Hegenscheid, Katrin; Heinz, Andreas; Hickie, Ian B; Ho, Beng-Choon; Hoehn, David; Hoekstra, Pieter J; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hoogman, Martine; Hong, L Elliot; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Hwang, Kristy S; Jack, Clifford R; Jenkinson, Mark; Johnston, Caroline; Jönsson, Erik G; Kahn, René S; Kasperaviciute, Dalia; Kelly, Sinead; Kim, Sungeun; Kochunov, Peter; Koenders, Laura; Krämer, Bernd; Kwok, John B J; Lagopoulos, Jim; Laje, Gonzalo; Landen, Mikael; Landman, Bennett A; Lauriello, John; Lawrie, Stephen M; Lee, Phil H; Le Hellard, Stephanie; Lemaître, Herve; Leonardo, Cassandra D; Li, Chiang-Shan; Liberg, Benny; Liewald, David C; Liu, Xinmin; Lopez, Lorna M; Loth, Eva; Lourdusamy, Anbarasu; Luciano, Michelle; Macciardi, Fabio; Machielsen, Marise W J; Macqueen, Glenda M; Malt, Ulrik F; Mandl, René; Manoach, Dara S; Martinot, Jean-Luc; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mattingsdal, Morten; Meyer-Lindenberg, Andreas; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Milaneschi, Yuri; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Moses, Eric K; Mueller, Bryon A; Muñoz Maniega, Susana; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Mwangi, Benson; Nauck, Matthias; Nho, Kwangsik; Nichols, Thomas E; Nilsson, Lars-Göran; Nugent, Allison C; Nyberg, Lars; Olvera, Rene L; Oosterlaan, Jaap; Ophoff, Roel A; Pandolfo, Massimo; Papalampropoulou-Tsiridou, Melina; Papmeyer, Martina; Paus, Tomas; Pausova, Zdenka; Pearlson, Godfrey D; Penninx, Brenda W; Peterson, Charles P; Pfennig, Andrea; Phillips, Mary; Pike, G Bruce; Poline, Jean-Baptiste; Potkin, Steven G; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rietschel, Marcella; Rijpkema, Mark; Risacher, Shannon L; Roffman, Joshua L; Roiz-Santiañez, Roberto; Romanczuk-Seiferth, Nina; Rose, Emma J; Royle, Natalie A; Rujescu, Dan; Ryten, Mina; Sachdev, Perminder S; Salami, Alireza; Satterthwaite, Theodore D; Savitz, Jonathan; Saykin, Andrew J; Scanlon, Cathy; Schmaal, Lianne; Schnack, Hugo G; Schork, Andrew J; Schulz, S Charles; Schür, Remmelt; Seidman, Larry; Shen, Li; Shoemaker, Jody M; Simmons, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soares, Jair C; Sponheim, Scott R; Sprooten, Emma; Starr, John M; Steen, Vidar M; Strakowski, Stephen; Strike, Lachlan; Sussmann, Jessika; Sämann, Philipp G; Teumer, Alexander; Toga, Arthur W; Tordesillas-Gutierrez, Diana; Trabzuni, Daniah; Trost, Sarah; Turner, Jessica; Van den Heuvel, Martijn; van der Wee, Nic J; van Eijk, Kristel; van Erp, Theo G M; van Haren, Neeltje E M; van 't Ent, Dennis; van Tol, Marie-Jose; Valdés Hernández, Maria C; Veltman, Dick J; Versace, Amelia; Völzke, Henry; Walker, Robert; Walter, Henrik; Wang, Lei; Wardlaw, Joanna M; Weale, Michael E; Weiner, Michael W; Wen, Wei; Westlye, Lars T; Whalley, Heather C; Whelan, Christopher D; White, Tonya; Winkler, Anderson M; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Zilles, David; Zwiers, Marcel P; Thalamuthu, Anbupalam; Schofield, Peter R; Freimer, Nelson B; Lawrence, Natalia S; Drevets, Wayne

2014-06-01

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Genetic characterization of local Criollo pig breeds from the Americas using microsatellite markers.

PubMed

Revidatti, M A; Delgado Bermejo, J V; Gama, L T; Landi Periati, V; Ginja, C; Alvarez, L A; Vega-Pla, J L; Martínez, A M

2014-11-01

Little is known about local Criollo pig genetic resources and relationships among the various populations. In this paper, genetic diversity and relationships among 17 Criollo pig populations from 11 American countries were assessed with 24 microsatellite markers. Heterozygosities, F-statistics, and genetic distances were estimated, and multivariate, genetic structure and admixture analyses were performed. The overall means for genetic variability parameters based on the 24 microsatellite markers were the following: mean number of alleles per locus of 6.25 ± 2.3; effective number of alleles per locus of 3.33 ± 1.56; allelic richness per locus of 4.61 ± 1.37; expected and observed heterozygosity of 0.62 ± 0.04 and 0.57 ± 0.02, respectively; within-population inbreeding coefficient of 0.089; and proportion of genetic variability accounted for by differences among breeds of 0.11 ± 0.01. Genetic differences were not significantly associated with the geographical location to which breeds were assigned or their country of origin. Still, the NeighborNet dendrogram depicted the clustering by geographic origin of several South American breeds (Criollo Boliviano, Criollo of northeastern Argentina wet, and Criollo of northeastern Argentina dry), but some unexpected results were also observed, such as the grouping of breeds from countries as distant as El Salvador, Mexico, Ecuador, and Cuba. The results of genetic structure and admixture analyses indicated that the most likely number of ancestral populations was 11, and most breeds clustered separately when this was the number of predefined populations, with the exception of some closely related breeds that shared the same cluster and others that were admixed. These results indicate that Criollo pigs represent important reservoirs of pig genetic diversity useful for local development as well as for the pig industry.

High Frequency and Diversity of Antimicrobial Activities Produced by Nasal Staphylococcus Strains against Bacterial Competitors

PubMed Central

Janek, Daniela; Zipperer, Alexander; Kulik, Andreas; Krismer, Bernhard; Peschel, Andreas

2016-01-01

The human nasal microbiota is highly variable and dynamic often enclosing major pathogens such as Staphylococcus aureus. The potential roles of bacteriocins or other mechanisms allowing certain bacterial clones to prevail in this nutrient-poor habitat have hardly been studied. Of 89 nasal Staphylococcus isolates, unexpectedly, the vast majority (84%) was found to produce antimicrobial substances in particular under habitat-specific stress conditions, such as iron limitation or exposure to hydrogen peroxide. Activity spectra were generally narrow but highly variable with activities against certain nasal members of the Actinobacteria, Proteobacteria, Firmicutes, or several groups of bacteria. Staphylococcus species and many other Firmicutes were insusceptible to most of the compounds. A representative bacteriocin was identified as a nukacin-related peptide whose inactivation reduced the capacity of the producer Staphylococcus epidermidis IVK45 to limit growth of other nasal bacteria. Of note, the bacteriocin genes were found on mobile genetic elements exhibiting signs of extensive horizontal gene transfer and rearrangements. Thus, continuously evolving bacteriocins appear to govern bacterial competition in the human nose and specific bacteriocins may become important agents for eradication of notorious opportunistic pathogens from human microbiota. PMID:27490492

Identification and removal of low-complexity sites in allele-specific analysis of ChIP-seq data.

PubMed

Waszak, Sebastian M; Kilpinen, Helena; Gschwind, Andreas R; Orioli, Andrea; Raghav, Sunil K; Witwicki, Robert M; Migliavacca, Eugenia; Yurovsky, Alisa; Lappalainen, Tuuli; Hernandez, Nouria; Reymond, Alexandre; Dermitzakis, Emmanouil T; Deplancke, Bart

2014-01-15

High-throughput sequencing technologies enable the genome-wide analysis of the impact of genetic variation on molecular phenotypes at unprecedented resolution. However, although powerful, these technologies can also introduce unexpected artifacts. We investigated the impact of library amplification bias on the identification of allele-specific (AS) molecular events from high-throughput sequencing data derived from chromatin immunoprecipitation assays (ChIP-seq). Putative AS DNA binding activity for RNA polymerase II was determined using ChIP-seq data derived from lymphoblastoid cell lines of two parent-daughter trios. We found that, at high-sequencing depth, many significant AS binding sites suffered from an amplification bias, as evidenced by a larger number of clonal reads representing one of the two alleles. To alleviate this bias, we devised an amplification bias detection strategy, which filters out sites with low read complexity and sites featuring a significant excess of clonal reads. This method will be useful for AS analyses involving ChIP-seq and other functional sequencing assays. The R package abs filter for library clonality simulations and detection of amplification-biased sites is available from http://updepla1srv1.epfl.ch/waszaks/absfilter

What we can learn about hereditary dystonia from HSDI of the glottis

NASA Astrophysics Data System (ADS)

Pedersen, Mette; Eeg, Martin

2012-02-01

This study examined efficacy of the innate immune defence via the mannose binding lectin (MBL) in a cohort of 55 dystonic patients prospectively referred to the clinic with laryngeal mucosal complaints, who were placed on local steroids (budesonid inhaler, 400 μg 2 times daily) and antihistamines (fexofenadin 180 mg mostly 3 times daily) with adjuvant lifestyle corrections. Treatment efficacy of the larynx was assessed based on mucosal findings of the vocal folds examined with High speed mucosa studies comprising simultaneous high speed digital imagines (HSDI), kymography, electroglottography (EGG) and voice acoustics combined with a visual score of arytenoids oedema, as these measures are indicative of the magnitude of laryngitis. Lactose and gluten intolerance and immunological analyses of the innate system were made systematically. Results showed that the genetic aspects of immunology did not reveal a role for the innate immune system, represented by the mannose binding lectin (MBL). An unexpected positive effect of the larynx treatment on dystonia symptoms was found evidenced by reduction of dystonic complaints and more normative results of High speed mucosa, and a reduction of oedema of the inter arytenoids region. Symptoms relieve and better quality of life was observed on follow up for the dystonia complaints.

The role of domain expertise and judgment in dealing with unexpected events

NASA Astrophysics Data System (ADS)

Kochan, Janeen Adrion

Unexpected events, particularly those creating surprise, interrupt ongoing mental and behavioral processes, creating an increased potential for unwanted outcomes to the situation. Human reactions to unexpected events vary. One can hypothesize a number of reasons for this variation, including level of domain expertise, previous experience with similar events, emotional connotation, and the contextual surround of the event. Whereas interrupting ongoing activities and focusing attention temporarily on a surprising event may be a useful evolutionary response to a threatening situation, the same process may be maladaptive in today's highly dynamic world. The purpose of this study was to investigate how different aspects of expertise affected one's ability to detect and react to an unexpected event. It was hypothesized that there were two general types of expertise, domain expertise and judgment (Hammond, 2000), which influenced one's performance on dealing with an unexpected event. The goal of the research was to parse out the relative contribution of domain expertise, so the role of judgment could be revealed. The research questions for this study were: (a) Can we identify specific knowledges and skills which enhance one's ability to deal with unexpected events? (b) Are these skills "automatically" included in domain expertise? (c) How does domain expertise improve or deter one's reaction and response to unexpected events? (d) What role does judgment play in responding to surprise? The general hypothesis was that good judgment would influence the process of surprise at different stages and in different ways than would domain expertise. The conclusions from this research indicated that good judgment had a significant positive effect in helping pilots deal with unexpected events. This was most pronounced when domain expertise was low.

Pruning the Pearlsides: Reconciling morphology and molecules in mesopelagic fishes (Maurolicus: Sternoptychidae)

NASA Astrophysics Data System (ADS)

Rees, D. J.; Byrkjedal, I.; Sutton, T. T.

2017-03-01

The genus Maurolicus comprises extremely abundant vertically-migrating fishes that have considerable biomass in a number of regions worldwide. The genus was generally considered monotypic, with a single species, M. muelleri (Gmelin, 1789), inhabiting all world oceans. Based on differences in combinations of a limited number of morphometric characters, 15 separate species have been proposed, mostly associated with different ocean basins and seamounts. However, due to similarities in external morphology and overlap in ranges of morphometric characteristics, there remains a need for further validation of these species. Here, we present results of a multi-gene analysis, together with morphological data, for five putative Maurolicus species from multiple locations in the northern and southern hemispheres. Sampling encompasses described species from the North and South Atlantic, Mediterranean Sea, south-east Indian Ocean and the western South Pacific. Mitochondrial (16S and COI) and nuclear (ITS-2) gene sequences for 120 specimens were used in Maximum Parsimony and Bayesian Inference analyses as well as creation of haplotype networks. Morphological character analyses were based on data from 279 adult individuals. Several clear groupings emerge, conflicting with previously recognised species: (1) a 'northern' clade comprising Maurolicus muelleri and M. amethystinopunctatus, (2) a 'southern' clade comprising M. australis, M. walvisensis (also M. japonicus) and (3) eastern Equatorial and western North Atlantic M. weitzmani. The southern clade taxa are genetically indistinguishable and not well defined morphologically and present a clear case for synonymisation as M. australis. Synonymisation is also proposed for M. muelleri and M. amethystinopunctatus, with limited morphological variation likely to reflect physical and biological differences experienced north / south of the sub-polar front. Maurolicus weitzmani is clearly differentiated from all other Maurolicus species on both a molecular and morphological basis. Studies of genetic and morphological diversity in Maurolicus will further contribute to the question of 'what constitutes a species in the open ocean?', where a complex picture is emerging of both unexpected variation, as well as the unexpectantly absent genetic variation, in cosmopolitan taxa.

Anti-P1: the most common unexpected antibodies in northeastern-Thais.

PubMed

Romphruk, A V; Wanhagij, C; Akahat, J; Tantanapornkul, P; Anuphan, T; Pattayaso, P; Puapairoj, C

1999-08-01

The prevalence of unexpected antibodies in the Northeastern-Thai population was studied. Sera were collected from 25,673 blood donors including 18,209 males and 7,464 females. The sera were screened for unexpected antibodies by saline and enzyme techniques. The sera which gave a positive antibody screening test were identified for specificity of antibody. The result demonstrated that 3,928 from 25,673 samples (15.30%) were positive for the antibody screening test and only 3,883 samples could be identified for specificity of antibody. The most common unexpected antibodies were anti-P1, anti-lewis and anti-P1 + anti-lewis with the frequency of 70.8, 18.6 and 10.1 per cent, respectively. The prevalence of anti-P1 in this study was higher than that reported in Central Thailand and Southeast Asia which may due to the high prevalence of liver fluke infection in the Northeastern-Thai population.

A Validated Methodology for Genetic Identification of Tuna Species (Genus Thunnus)

PubMed Central

Viñas, Jordi; Tudela, Sergi

2009-01-01

Background Tuna species of the genus Thunnus, such as the bluefin tunas, are some of the most important and yet most endangered trade fish in the world. Identification of these species in traded forms, however, may be difficult depending on the presentation of the products, which may hamper conservation efforts on trade control. In this paper, we validated a genetic methodology that can fully distinguish between the eight Thunnus species from any kind of processed tissue. Methodology After testing several genetic markers, a complete discrimination of the eight tuna species was achieved using Forensically Informative Nucleotide Sequencing based primarily on the sequence variability of the hypervariable genetic marker mitochondrial DNA control region (mtDNA CR), followed, in some specific cases, by a second validation by a nuclear marker rDNA first internal transcribed spacer (ITS1). This methodology was able to distinguish all tuna species, including those belonging to the subgenus Neothunnus that are very closely related, and in consequence can not be differentiated with other genetic markers of lower variability. This methodology also took into consideration the presence of introgression that has been reported in past studies between T. thynnus, T. orientalis and T. alalunga. Finally, we applied the methodology to cross-check the species identity of 26 processed tuna samples. Conclusions Using the combination of two genetic markers, one mitochondrial and another nuclear, allows a full discrimination between all eight tuna species. Unexpectedly, the genetic marker traditionally used for DNA barcoding, cytochrome oxidase 1, could not differentiate all species, thus its use as a genetic marker for tuna species identification is questioned. PMID:19898615

A validated methodology for genetic identification of tuna species (genus Thunnus).

PubMed

Viñas, Jordi; Tudela, Sergi

2009-10-27

Tuna species of the genus Thunnus, such as the bluefin tunas, are some of the most important and yet most endangered trade fish in the world. Identification of these species in traded forms, however, may be difficult depending on the presentation of the products, which may hamper conservation efforts on trade control. In this paper, we validated a genetic methodology that can fully distinguish between the eight Thunnus species from any kind of processed tissue. After testing several genetic markers, a complete discrimination of the eight tuna species was achieved using Forensically Informative Nucleotide Sequencing based primarily on the sequence variability of the hypervariable genetic marker mitochondrial DNA control region (mtDNA CR), followed, in some specific cases, by a second validation by a nuclear marker rDNA first internal transcribed spacer (ITS1). This methodology was able to distinguish all tuna species, including those belonging to the subgenus Neothunnus that are very closely related, and in consequence can not be differentiated with other genetic markers of lower variability. This methodology also took into consideration the presence of introgression that has been reported in past studies between T. thynnus, T. orientalis and T. alalunga. Finally, we applied the methodology to cross-check the species identity of 26 processed tuna samples. Using the combination of two genetic markers, one mitochondrial and another nuclear, allows a full discrimination between all eight tuna species. Unexpectedly, the genetic marker traditionally used for DNA barcoding, cytochrome oxidase 1, could not differentiate all species, thus its use as a genetic marker for tuna species identification is questioned.

The role of high-frequency oscillatory activity in reward processing and learning.

PubMed

Marco-Pallarés, Josep; Münte, Thomas F; Rodríguez-Fornells, Antoni

2015-02-01

Oscillatory activity has been proposed as a key mechanism in the integration of brain activity of distant structures. Particularly, high frequency brain oscillatory activity in the beta and gamma range has received increasing interest in the domains of attention and memory. In addition, a number of recent studies have revealed an increase of beta-gamma activity (20-35 Hz) after unexpected or relevant positive reward outcomes. In the present manuscript we review the literature on this phenomenon and we propose that this activity is a brain signature elicited by unexpected positive outcomes in order to transmit a fast motivational value signal to the reward network. In addition, we hypothesize that beta-gamma oscillatory activity indexes the interaction between attentional and emotional systems, and that it directly reflects the appearance of unexpected positive rewards in learning-related contexts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mitochondrial DNA Analyses Indicate High Diversity, Expansive Population Growth and High Genetic Connectivity of Vent Copepods (Dirivultidae) across Different Oceans

PubMed Central

Kihara, Terue C.; Laurent, Stefan; Kodami, Sahar; Martinez Arbizu, Pedro

2016-01-01

Communities in spatially fragmented deep-sea hydrothermal vents rich in polymetallic sulfides could soon face major disturbance events due to deep-sea mineral mining, such that unraveling patterns of gene flow between hydrothermal vent populations will be an important step in the development of conservation policies. Indeed, the time required by deep-sea populations to recover following habitat perturbations depends both on the direction of gene flow and the number of migrants available for re-colonization after disturbance. In this study we compare nine dirivultid copepod species across various geological settings. We analyze partial nucleotide sequences of the mtCOI gene and use divergence estimates (FST) and haplotype networks to infer intraspecific population connectivity between vent sites. Furthermore, we evaluate contrasting scenarios of demographic population expansion/decline versus constant population size (using, for example, Tajima’s D). Our results indicate high diversity, population expansion and high connectivity of all copepod populations in all oceans. For example, haplotype diversity values range from 0.89 to 1 and FST values range from 0.001 to 0.11 for Stygiopontius species from the Central Indian Ridge, Mid Atlantic Ridge, East Pacific Rise, and Eastern Lau Spreading Center. We suggest that great abundance and high site occupancy by these species favor high genetic diversity. Two scenarios both showed similarly high connectivity: fast spreading centers with little distance between vent fields and slow spreading centers with greater distance between fields. This unexpected result may be due to some distinct frequency of natural disturbance events, or to aspects of individual life histories that affect realized rates of dispersal. However, our statistical performance analyses showed that at least 100 genomic regions should be sequenced to ensure accurate estimates of migration rate. Our demography parameters demonstrate that dirivultid populations are generally large and continuously undergoing population growth. Benthic and pelagic species abundance data support these findings. PMID:27732624

Mitochondrial DNA Analyses Indicate High Diversity, Expansive Population Growth and High Genetic Connectivity of Vent Copepods (Dirivultidae) across Different Oceans.

PubMed

Gollner, Sabine; Stuckas, Heiko; Kihara, Terue C; Laurent, Stefan; Kodami, Sahar; Martinez Arbizu, Pedro

2016-01-01

Communities in spatially fragmented deep-sea hydrothermal vents rich in polymetallic sulfides could soon face major disturbance events due to deep-sea mineral mining, such that unraveling patterns of gene flow between hydrothermal vent populations will be an important step in the development of conservation policies. Indeed, the time required by deep-sea populations to recover following habitat perturbations depends both on the direction of gene flow and the number of migrants available for re-colonization after disturbance. In this study we compare nine dirivultid copepod species across various geological settings. We analyze partial nucleotide sequences of the mtCOI gene and use divergence estimates (FST) and haplotype networks to infer intraspecific population connectivity between vent sites. Furthermore, we evaluate contrasting scenarios of demographic population expansion/decline versus constant population size (using, for example, Tajima's D). Our results indicate high diversity, population expansion and high connectivity of all copepod populations in all oceans. For example, haplotype diversity values range from 0.89 to 1 and FST values range from 0.001 to 0.11 for Stygiopontius species from the Central Indian Ridge, Mid Atlantic Ridge, East Pacific Rise, and Eastern Lau Spreading Center. We suggest that great abundance and high site occupancy by these species favor high genetic diversity. Two scenarios both showed similarly high connectivity: fast spreading centers with little distance between vent fields and slow spreading centers with greater distance between fields. This unexpected result may be due to some distinct frequency of natural disturbance events, or to aspects of individual life histories that affect realized rates of dispersal. However, our statistical performance analyses showed that at least 100 genomic regions should be sequenced to ensure accurate estimates of migration rate. Our demography parameters demonstrate that dirivultid populations are generally large and continuously undergoing population growth. Benthic and pelagic species abundance data support these findings.

Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research.

PubMed

Talkowski, Michael E; Ernst, Carl; Heilbut, Adrian; Chiang, Colby; Hanscom, Carrie; Lindgren, Amelia; Kirby, Andrew; Liu, Shangtao; Muddukrishna, Bhavana; Ohsumi, Toshiro K; Shen, Yiping; Borowsky, Mark; Daly, Mark J; Morton, Cynthia C; Gusella, James F

2011-04-08

The contribution of balanced chromosomal rearrangements to complex disorders remains unclear because they are not detected routinely by genome-wide microarrays and clinical localization is imprecise. Failure to consider these events bypasses a potentially powerful complement to single nucleotide polymorphism and copy-number association approaches to complex disorders, where much of the heritability remains unexplained. To capitalize on this genetic resource, we have applied optimized sequencing and analysis strategies to test whether these potentially high-impact variants can be mapped at reasonable cost and throughput. By using a whole-genome multiplexing strategy, rearrangement breakpoints could be delineated at a fraction of the cost of standard sequencing. For rearrangements already mapped regionally by karyotyping and fluorescence in situ hybridization, a targeted approach enabled capture and sequencing of multiple breakpoints simultaneously. Importantly, this strategy permitted capture and unique alignment of up to 97% of repeat-masked sequences in the targeted regions. Genome-wide analyses estimate that only 3.7% of bases should be routinely omitted from genomic DNA capture experiments. Illustrating the power of these approaches, the rearrangement breakpoints were rapidly defined to base pair resolution and revealed unexpected sequence complexity, such as co-occurrence of inversion and translocation as an underlying feature of karyotypically balanced alterations. These findings have implications ranging from genome annotation to de novo assemblies and could enable sequencing screens for structural variations at a cost comparable to that of microarrays in standard clinical practice. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A study of lactose metabolism in Lactococcus garvieae reveals a genetic marker for distinguishing between dairy and fish biotypes.

PubMed

Fortina, Maria Grazia; Ricci, Giovanni; Borgo, Francesca

2009-06-01

Dairy and fish isolates of Lactococcus garvieae were tested for their ability to utilize lactose and to grow in milk. Fish isolates were unable to assimilate lactose, but unexpectedly, they possessed the ability to grow in milk. Genetic studies, carried out constructing different vectorette libraries, provided evidence that in fish isolates, no genes involved in lactose utilization were present. For L. garvieae dairy isolates, a single system for the catabolism of lactose was found. It consists of a lactose transport and hydrolysis depending on a phosphoenolpyruvate-dependent phosphotransferase system combined with a phospho-beta-galactosidase. The genes involved were highly similar at the nucleotide sequence level to their counterparts in Lactococcus lactis; however, while in many L. lactis strains these genes are plasmid encoded, in L. garvieae they are chromosomally located. Thus, in the species L. garvieae, the phospho-beta-galactosidase gene, detectable in all strains of dairy origin but lacking in fish isolates, can be considered a reliable genetic marker for distinguishing biotypes in the two diverse ecological niches. Moreover, we obtained information regarding the complete nucleotide sequence of the gal operon in L. garvieae, consisting of a galactose permease and the Leloir pathway enzymes. This is one of the first reports concerning the determination of the nucleotide sequences of genes (other than the 16S rDNA gene) in L. garvieae and should be considered a step in a continuous effort to explore the genome of this species, with the aim of determining the real relationship between the presence of L. garvieae in dairy products and food safety.

Implications of genome wide association studies for addiction: are our a priori assumptions all wrong?

PubMed

Hall, F Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R

2013-12-01

Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS. © 2013.

Genomic and Physiological Characterization of the Chromate-Reducing, Aquifer-Derived Firmicute Pelosinus sp. Strain HCF1

NASA Astrophysics Data System (ADS)

Beller, H. R.; Han, R.; Karaoz, U.; Lim, H.; Brodie, E. L.

2012-12-01

Pelosinus species are fermentative firmicutes that were recently reported to be prominent members of microbial communities at contaminated subsurface sites in multiple locations. Here we report metabolic characteristics and their putative genetic basis in Pelosinus sp. strain HCF1, an isolate that predominated anaerobic, Cr(VI)-reducing columns constructed with Hanford 100H aquifer sediment (constituting 80% of the total bacterial population in the columns). Strain HCF1 ferments lactate to propionate and acetate (a complete fermentation pathway was identified in the genome) and its genome encodes both [NiFe]- and [FeFe]-hydrogenases for H2 cycling. This bacterium has unexpected capabilities and gene content associated with reduction of nitrogen oxides. In this strain, either H2 or lactate can act as a sole electron donor for nitrate, Cr(VI), and Fe(III) reduction. Transcriptional studies demonstrated differential expression of nitrate reductases and hydrogenases. Overall, the unexpected metabolic capabilities and gene content reported here broaden our perspective on what biogeochemical and ecological roles this species might play as a prominent member of microbial communities in subsurface environments.

Transcriptome map of plant mitochondria reveals islands of unexpected transcribed regions.

PubMed

Fujii, Sota; Toda, Takushi; Kikuchi, Shunsuke; Suzuki, Ryutaro; Yokoyama, Koji; Tsuchida, Hiroko; Yano, Kentaro; Toriyama, Kinya

2011-06-01

Plant mitochondria contain a relatively large amount of genetic information, suggesting that their functional regulation may not be as straightforward as that of metazoans. We used a genomic tiling array to draw a transcriptomic atlas of Oryza sativa japonica (rice) mitochondria, which was predicted to be approximately 490-kb long. Whereas statistical analysis verified the transcription of all previously known functional genes such as the ones related to oxidative phosphorylation, a similar extent of RNA expression was frequently observed in the inter-genic regions where none of the previously annotated genes are located. The newly identified open reading frames (ORFs) predicted in these transcribed inter-genic regions were generally not conserved among flowering plant species, suggesting that these ORFs did not play a role in mitochondrial principal functions. We also identified two partial fragments of retrotransposon sequences as being transcribed in rice mitochondria. The present study indicated the previously unexpected complexity of plant mitochondrial RNA metabolism. Our transcriptomic data (Oryza sativa Mitochondrial rna Expression Server: OsMES) is publicly accessible at [http://bioinf.mind.meiji.ac.jp/cgi-bin/gbrowse/OsMes/#search].

Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

PubMed Central

Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

2017-01-01

Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations. PMID:28076437

Sockeye salmon (Oncorhynchus nerka) return after an absence of nearly 90 years: A case of reversion to anadromy

USGS Publications Warehouse

Godbout, L.; Wood, C.C.; Withler, R.E.; Latham, S.; Nelson, R.J.; Wetzel, L.; Barnett-Johnson, R.; Grove, M.J.; Schmitt, A.K.; McKeegan, K.D.

2011-01-01

We document the recent reappearance of anadromous sockeye salmon (Oncorhynchus nerka) that were thought to have been extirpated by the construction of hydroelectric dams on the Coquitlam and Alouette rivers in British Columbia, Canada, in 1914 and 1927, respectively. Unexpected downstream migrations of juveniles during experimental water releases into both rivers in 2005 and 2006 preceded upstream return migrations of adults in 2007 and 2008. Genetic (microsatellite and mitochondrial DNA) markers and stable isotope (??34S and 87Sr/86Sr) patterns in otoliths confirm that both the juvenile downstream migrants and adult upstream migrants were progeny of nonanadromous sockeye salmon (kokanee) that inhabit Coquitlam and Alouette reservoirs. Low genetic diversity and evidence of genetic bottlenecks suggest that the kokanee populations in both reservoirs originated from relatively few anadromous individuals that residualized after downstream migration was largely prevented by the construction of dams. Once given an opportunity for upstream and downstream migration, both populations appear capable of reverting to a successful anadromous form, even after 25 generations.

A novel Sarcocystis neurona genotype XIII is associated with severe encephalitis in an unexpectedly broad range of marine mammals from the northeastern Pacific Ocean.

PubMed

Barbosa, Lorraine; Johnson, Christine K; Lambourn, Dyanna M; Gibson, Amanda K; Haman, Katherine H; Huggins, Jessica L; Sweeny, Amy R; Sundar, Natarajan; Raverty, Stephen A; Grigg, Michael E

2015-08-01

Sarcocystis neurona is an important cause of protozoal encephalitis among marine mammals in the northeastern Pacific Ocean. To characterise the genetic type of S. neurona in this region, samples from 227 stranded marine mammals, most with clinical or pathological evidence of protozoal disease, were tested for the presence of coccidian parasites using a nested PCR assay. The frequency of S. neurona infection was 60% (136/227) among pinnipeds and cetaceans, including seven marine mammal species not previously known to be susceptible to infection by this parasite. Eight S. neurona fetal infections identified this coccidian parasite as capable of being transmitted transplacentally. Thirty-seven S. neurona-positive samples were multilocus sequence genotyped using three genetic markers: SnSAG1-5-6, SnSAG3 and SnSAG4. A novel genotype, referred to as Type XIII within the S. neurona population genetic structure, has emerged recently in the northeastern Pacific Ocean and is significantly associated with an increased severity of protozoal encephalitis and mortality among multiple stranded marine mammal species. Published by Elsevier Ltd.

A novel Sarcocystis neurona genotype XIII is associated with severe encephalitis in an unexpectedly broad range of marine mammals from the northeastern Pacific Ocean

PubMed Central

Barbosa, Lorraine; Johnson, Christine K.; Lambourn, Dyanna M.; Gibson, Amanda K.; Haman, Katherine H.; Huggins, Jessica L.; Sweeny, Amy R.; Sundar, Natarajan; Raverty, Stephen A.; Grigg, Michael E.

2015-01-01

Sarcocystis neurona is an important cause of protozoal encephalitis among marine mammals in the northeastern Pacific Ocean. To characterize the genetic type of S. neurona in this region, samples from 227 stranded marine mammals, most with clinical or pathological evidence of protozoal disease, were tested for the presence of coccidian parasites using a nested PCR assay. The frequency of S. neurona infection was 60% (136/227) among pinnipeds and cetaceans, including seven marine mammal species not previously known to be susceptible to infection by this parasite. Eight S. neurona fetal infections identified this coccidian parasite as capable of being transmitted transplacentally. Thirty-seven S. neurona-positive samples were multilocus sequence genotyped using three genetic markers: SnSAG1-5-6, SnSAG3 and SnSAG4. A novel genotype, referred to as Type XIII within the S. neurona population genetic structure, has emerged recently in the northeastern Pacific Ocean and is significantly associated with an increased severity of protozoal encephalitis and mortality among multiple stranded marine mammal species. PMID:25997588

Long QT syndrome and sudden unexpected infant death.

PubMed

Van Niekerk, Chantal; Van Deventer, Barbara Ströh; du Toit-Prinsloo, Lorraine

2017-09-01

Long QT syndrome (LQTS) is an inheritable primary electric disease of the heart characterised by abnormally long QT intervals and a propensity to develop atrial and ventricular tachyarrhythmias. It is caused by an inherited channelopathy responsible for sudden cardiac death in individuals with structurally normal hearts. Long QT syndrome can present early in life, and some studies suggest that it may be associated with up to 20% of sudden unexplained infant death (SUID), particularly when associated with external stressors such as asphyxia, which is commonly seen in many infant death scenes. With an understanding of the genetic defects, it has now been possible to retrospectively analyse samples from infants who have presented to forensic pathology services with a history of unexplained sudden death, which may, in turn, enable the implementation of preventative treatment for siblings previously not known to have pathogenic genetic variations. In this viewpoint article, we will discuss SUID, LQTS and postmortem genetic analysis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Genes versus environment: geography and phylogenetic relationships shape the chemical profiles of stingless bees on a global scale

PubMed Central

Leonhardt, Sara D.; Rasmussen, Claus; Schmitt, Thomas

2013-01-01

Chemical compounds are highly important in the ecology of animals. In social insects, compounds on the body surface represent a particularly interesting trait, because they comprise different compound classes that are involved in different functions, such as communication, recognition and protection, all of which can be differentially affected by evolutionary processes. Here, we investigate the widely unknown and possibly antagonistic influence of phylogenetic and environmental factors on the composition of the cuticular chemistry of tropical stingless bees. We chose stingless bees because some species are unique in expressing not only self-produced compounds, but also compounds that are taken up from the environment. By relating the cuticular chemistry of 40 bee species from all over the world to their molecular phylogeny and geographical occurrence, we found that distribution patterns of different groups of compounds were differentially affected by genetic relatedness and biogeography. The ability to acquire environmental compounds was, for example, highly correlated with the bees' phylogeny and predominated in evolutionarily derived species. Owing to the presence of environmentally derived compounds, those species further expressed a higher chemical and thus functional diversity. In Old World species, chemical similarity of both environmentally derived and self-produced compounds was particularly high among sympatric species, even when they were less related to each other than to allopatric species, revealing a strong environmental effect even on largely genetically determined compounds. Thus, our findings do not only reveal an unexpectedly strong influence of the environment on the cuticular chemistry of stingless bees, but also demonstrate that even within one morphological trait (an insect's cuticular profile), different components (compound classes) can be differentially affected by different drivers (relatedness and biogeography), depending on the functional context. PMID:23658202

Attentional gain and processing capacity limits predict the propensity to neglect unexpected visual stimuli.

PubMed

Papera, Massimiliano; Richards, Anne

2016-05-01

Exogenous allocation of attentional resources allows the visual system to encode and maintain representations of stimuli in visual working memory (VWM). However, limits in the processing capacity to allocate resources can prevent unexpected visual stimuli from gaining access to VWM and thereby to consciousness. Using a novel approach to create unbiased stimuli of increasing saliency, we investigated visual processing during a visual search task in individuals who show a high or low propensity to neglect unexpected stimuli. When propensity to inattention is high, ERP recordings show a diminished amplification concomitantly with a decrease in theta band power during the N1 latency, followed by a poor target enhancement during the N2 latency. Furthermore, a later modulation in the P3 latency was also found in individuals showing propensity to visual neglect, suggesting that more effort is required for conscious maintenance of visual information in VWM. Effects during early stages of processing (N80 and P1) were also observed suggesting that sensitivity to contrasts and medium-to-high spatial frequencies may be modulated by low-level saliency (albeit no statistical group differences were found). In accordance with the Global Workplace Model, our data indicate that a lack of resources in low-level processors and visual attention may be responsible for the failure to "ignite" a state of high-level activity spread across several brain areas that is necessary for stimuli to access awareness. These findings may aid in the development of diagnostic tests and intervention to detect/reduce inattention propensity to visual neglect of unexpected stimuli. © 2016 Society for Psychophysiological Research.

[Investigation of the causes of infant sudden unexpected death in children younger than one year in Bariloche city and surrounding areas].

PubMed

Gil, Leonardo; Herbón, Fabiana; Little, Andrés; López, Mónica; Martínez, Lucía; Cancilliere, María del Carmen

2008-12-01

In the beginning of 2002 there were an unusually high number of sudden unexpected infant deaths. A prospective study was started to determine the cause of unexpected deaths in infants younger than 1 year. Investigate the possible causes of sudden and unexpected death in infants of Bariloche and surrounding areas, using a protocol created for that purpose. All infants under 1 year of age who died unexpectedly between May 2002 and April 2007 were studied. A complete physical examination, a thorough interrogation to the parents and an autopsy were performed. According to the findings a definitive diagnosis was made on each case. During the study period 10 infants younger than 1 year died. One case was excluded because the autopsy could not be done. The mean age was 74 days, 6 were males. All died while sleeping and no sign of disease were noticed in any case. In 6 cases, the autopsy findings explained the death. In the 3 others no cause for the death was found. The implementation of this protocol allowed to find out the cause of death in 6 cases, that could not have been achieved without the autopsy.

[Development of the unexpected reality scale for childcare training].

PubMed

Matsuda, Yuko; Shitara, Saeko; Hamada, Shoko

2016-10-01

This study aimed to develop a scale for unexpected reality for childcare training (Study 1) and examine the change and influence it exerts on the efficacy of preschool teachers (Study 2). In Study 1, the sample consisted of 571 university and junior college students enrolled in a childcare course. After exploratory factor analysis, four factors were extracted: “actual feelings for childcare as a field of study,” “difficulties faced during involvement with children,” “negative aspects of the childcare worker,” and “severity of work.” The study’s scale was shown to be internally consistent and valid. In Study 2, the sample consisted of 122 junior college students enrolled in a childcare course. The results showed that the high-scoring groups of each unexpected reality subscales experienced less unexpected reality in the subsequent training session. Moreover, the results of multiple regression showed that preschool teacher efficacy was predicted positively by “actual feelings for childcare as a field of study” and negatively by “difficulties faced during involvement with children.” Thus, we suggest that for effective pre- and post-guidance of childcare training, unexpected realities should be considered.

Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania.

PubMed

Puffenberger, E G

2003-08-15

The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th-century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50-year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites and the Old Order Amish demonstrates the unique genetic heritage of each group despite a common religious and geographic history. Unexpectedly, several diseases in both groups demonstrate allelic and/or locus heterogeneity. The population genetics of the 1312T --> A BCKDHA gene mutation, which causes classical MSUD, are presented in detail. The incidence of MSUD in the Old Order Mennonites is estimated to be 1/358 births, yielding a corrected carrier frequency of 7.96% and a mutation allele frequency of 4.15%. Analysis of the population demonstrates that repeated cycles of sampling effects, population bottlenecks, and subsequent genetic drift were important in shaping the current allele frequencies. A linkage disequilibrium analysis of 1312T --> A mutation haplotypes is provided and discussed in the context of the known genealogical history of the population. Finally, data from microsatellite marker genotyping within the Old Order Mennonite population are provided that show a significant but modest decrease in genetic diversity and elevated levels of background linkage disequilibrium. Copyright 2003 Wiley-Liss, Inc.

Integration of Proteomic, Transcriptional, and Interactome Data Reveals Hidden Signaling Components

PubMed Central

Huang, Shao-shan Carol; Fraenkel, Ernest

2009-01-01

Cellular signaling and regulatory networks underlie fundamental biological processes such as growth, differentiation, and response to the environment. Although there are now various high-throughput methods for studying these processes, knowledge of them remains fragmentary. Typically, the vast majority of hits identified by transcriptional, proteomic, and genetic assays lie outside of the expected pathways. These unexpected components of the cellular response are often the most interesting, because they can provide new insights into biological processes and potentially reveal new therapeutic approaches. However, they are also the most difficult to interpret. We present a technique, based on the Steiner tree problem, that uses previously reported protein-protein and protein-DNA interactions to determine how these hits are organized into functionally coherent pathways, revealing many components of the cellular response that are not readily apparent in the original data. Applied simultaneously to phosphoproteomic and transcriptional data for the yeast pheromone response, it identifies changes in diverse cellular processes that extend far beyond the expected pathways. PMID:19638617

Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex.

PubMed

Zhang, Wei; Neo, Suat Peng; Gunaratne, Jayantha; Poulsen, Anders; Boping, Liu; Ong, Esther Hongqian; Sangthongpitag, Kanda; Pendharkar, Vishal; Hill, Jeffrey; Cohen, Stephen M

2015-03-01

The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents. Copyright © 2014. Published by Elsevier Inc.

Human body epigenome maps reveal noncanonical DNA methylation variation.

PubMed

Schultz, Matthew D; He, Yupeng; Whitaker, John W; Hariharan, Manoj; Mukamel, Eran A; Leung, Danny; Rajagopal, Nisha; Nery, Joseph R; Urich, Mark A; Chen, Huaming; Lin, Shin; Lin, Yiing; Jung, Inkyung; Schmitt, Anthony D; Selvaraj, Siddarth; Ren, Bing; Sejnowski, Terrence J; Wang, Wei; Ecker, Joseph R

2015-07-09

Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.

Psychiatric Genocide: Nazi Attempts to Eradicate Schizophrenia

PubMed Central

Torrey, E. Fuller; Yolken, Robert H.

2010-01-01

Although the Nazi genocide of Jews during World War II is well known, the concurrent Nazi genocide of psychiatric patients is much less widely known. An attempt was made to estimate the number of individuals with schizophrenia who were sterilized and murdered by the Nazis and to assess the effect on the subsequent prevalence and incidence of this disease. It is estimated that between 220 000 and 269 500 individuals with schizophrenia were sterilized or killed. This total represents between 73% and 100% of all individuals with schizophrenia living in Germany between 1939 and 1945. Postwar studies of the prevalence of schizophrenia in Germany reported low rates, as expected. However, postwar rates of the incidence of schizophrenia in Germany were unexpectedly high. The Nazi genocide of psychiatric patients was the greatest criminal act in the history of psychiatry. It was also based on what are now known to be erroneous genetic theories and had no apparent long-term effect on the subsequent incidence of schizophrenia. PMID:19759092

The Ebola virus glycoprotein mediates entry via a non-classical dynamin-dependent macropinocytic pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulherkar, Nirupama; Raaben, Matthijs; Torre, Juan Carlos de la

2011-10-25

Ebola virus (EBOV) has been reported to enter cultured cell lines via a dynamin-2-independent macropinocytic pathway or clathrin-mediated endocytosis. The route(s) of productive EBOV internalization into physiologically relevant cell types remain unexplored, and viral-host requirements for this process are incompletely understood. Here, we use electron microscopy and complementary chemical and genetic approaches to demonstrate that the viral glycoprotein, GP, induces macropinocytic uptake of viral particles into cells. GP's highly-glycosylated mucin domain is dispensable for virus-induced macropinocytosis, arguing that interactions between other sequences in GP and the host cell surface are responsible. Unexpectedly, we also found a requirement for the largemore » GTPase dynamin-2, which is proposed to be dispensable for several types of macropinocytosis. Our results provide evidence that EBOV uses an atypical dynamin-dependent macropinocytosis-like entry pathway to enter Vero cells, adherent human peripheral blood-derived monocytes, and a mouse dendritic cell line.« less

The tumor suppressor cybL, a component of the respiratory chain, mediates apoptosis induction.

PubMed

Albayrak, Timur; Scherhammer, Volker; Schoenfeld, Nicole; Braziulis, Erik; Mund, Thomas; Bauer, Manuel K A; Scheffler, Immo E; Grimm, Stefan

2003-08-01

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome bL (cybL also known as SDHC, CII-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors.

The Tumor Suppressor cybL, a Component of the Respiratory Chain, Mediates Apoptosis Induction

PubMed Central

Albayrak, Timur; Scherhammer, Volker; Schoenfeld, Nicole; Braziulis, Erik; Mund, Thomas; Bauer, Manuel K.A.; Scheffler, Immo E.; Grimm, Stefan

2003-01-01

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome bL (cybL also known as SDHC, CII-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors. PMID:12925748

Genetic dissection of cardiac growth control pathways

NASA Technical Reports Server (NTRS)

MacLellan, W. R.; Schneider, M. D.

2000-01-01

Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud

PubMed Central

Packard, Adam; Georgas, Kylie; Michos, Odyssé; Riccio, Paul; Cebrian, Cristina; Combes, Alexander N.; Ju, Adler; Ferrer-Vaquer, Anna; Hadjantonakis, Anna-Katerina; Zong, Hui; Little, Melissa H.; Costantini, Frank

2013-01-01

Summary The ureteric bud is an epithelial tube that undergoes branching morphogenesis to form the renal collecting system. Though development of a normal kidney depends on proper ureteric bud morphogenesis, the cellular events underlying this process remain obscure. Here, we used time-lapse microscopy together with several genetic labeling methods to observe ureteric bud cell behaviors in developing mouse kidneys. We observed an unexpected cell behavior in the branching tips of the ureteric bud, which we term “mitosis-associated cell dispersal”. Pre-mitotic ureteric tip cells delaminate from the epithelium and divide within the lumen; while one daughter cell retains a basal process, allowing it to reinsert into the epithelium at the site of origin, the other daughter cell reinserts at a position one to three cell diameters away. Given the high rate of cell division in ureteric tips, this cellular behavior causes extensive epithelial cell rearrangements that may contribute to renal branching morphogenesis. PMID:24183650

Distinct human antibody response to the biological warfare agent Burkholderia mallei

PubMed Central

Varga, John J.; Vigil, Adam; DeShazer, David; Waag, David M.; Felgner, Philip; Goldberg, Joanna B.

2012-01-01

The genetic similarity between Burkholderia mallei (glanders) and Burkholderia pseudomallei (melioidosis) had led to the general assumption that pathogenesis of each bacterium would be similar. In 2000, the first human case of glanders in North America since 1945 was reported in a microbiology laboratory worker. Leveraging the availability of pre-exposure sera for this individual and employing the same well-characterized protein array platform that has been previously used to study a large cohort of melioidosis patients in southeast Asia, we describe the antibody response in a human with glanders. Analysis of 156 peptides present on the array revealed antibodies against 17 peptides with a > 2-fold increase in this infection. Unexpectedly, when the glanders data were compared with a previous data set from B. pseudomallei infections, there were only two highly increased antibodies shared between these two infections. These findings have implications in the diagnosis and treatment of B. mallei and B. pseudomallei infections. PMID:23076276

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.

PubMed

Gadd, Samantha; Huff, Vicki; Walz, Amy L; Ooms, Ariadne H A G; Armstrong, Amy E; Gerhard, Daniela S; Smith, Malcolm A; Auvil, Jaime M Guidry; Meerzaman, Daoud; Chen, Qing-Rong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying; Hermida, Leandro C; Davidsen, Tanja; Gesuwan, Patee; Ma, Yussanne; Zong, Zusheng; Mungall, Andrew J; Moore, Richard A; Marra, Marco A; Dome, Jeffrey S; Mullighan, Charles G; Ma, Jing; Wheeler, David A; Hampton, Oliver A; Ross, Nicole; Gastier-Foster, Julie M; Arold, Stefan T; Perlman, Elizabeth J

2017-10-01

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

A Children's Oncology Group and TARGET Initiative Exploring the Genetic Landscape of Wilms Tumor

PubMed Central

Gadd, Samantha; Huff, Vicki; Walz, Amy L.; Ooms, Ariadne H.A.G.; Armstrong, Amy E.; Gerhard, Daniela S.; Smith, Malcolm A.; Guidry Auvil, Jaime M.; Meerzaman, Daoud; Chen, Qing-Rong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying; Hermida, Leandro C.; Davidsen, Tanja; Gesuwan, Patee; Ma, Yussanne; Zong, Zusheng; Mungall, Andrew J.; Moore, Richard A.; Marra, Marco A.; Dome, Jeffrey S.; Mullighan, Charles G.; Ma, Jing; Wheeler, David A.; Hampton, Oliver A.; Ross, Nicole; Gastier-Foster, Julie M.; Arold, Stefan T.; Perlman, Elizabeth J.

2017-01-01

Genome-wide sequencing, mRNA and miRNA expression, DNA copy number and methylation analyses were performed on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, FAM123B, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), mutations were identified in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and let-7a loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development. PMID:28825729

Increased microtubule assembly rates mediate chromosomal instability in colorectal cancer cells

PubMed Central

Ertych, Norman; Stolz, Ailine; Stenzinger, Albrecht; Weichert, Wilko; Kaulfuß, Silke; Burfeind, Peter; Aigner, Achim; Wordeman, Linda

2015-01-01

Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms causing CIN and its consequences on tumor growth are largely unknown. We identify an increase in microtubule plus end assembly rates as a fundamental trigger for CIN in CRC cells. This trigger is mediated by overexpression of the oncogene AURKA or by loss of the tumor suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and resulting in CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumor growth in vitro and in vivo. Thus, we identify a fundamental mechanism triggering CIN in cancer cells and reveal its adverse consequence on tumor growth. PMID:24976383

Plant comparative genetics after 10 years.

PubMed

Gale, M D; Devos, K M

1998-10-23

The past 10 years have seen the discovery of unexpected levels of conservation of gene content and gene orders over millions of years of evolution within grasses, crucifers, legumes, some trees, and Solanaceae crops. Within the grasses, which include the three 500-million-ton-plus-per-year crops (wheat, maize, and rice), and the crucifers, which include all the Brassica crops, colinearity looks good enough to do most map-based cloning only in the small genome model species, rice and Arabidopsis. Elsewhere, knowledge gained in a few major crops is being pooled and applied across the board. The extrapolation of information from the well-studied species to orphan crops, which include many tropical species, is providing a solid base for their improvement. Genome rearrangements are giving new insights into evolution. In fact, comparative genetics is the key that will unlock the secrets of crop plants with genomes larger than that of humans.

DNA synthesis security.

PubMed

Nouri, Ali; Chyba, Christopher F

2012-01-01

It is generally assumed that genetic engineering advances will, inevitably, facilitate the misapplication of biotechnology toward the production of biological weapons. Unexpectedly, however, some of these very advances in the areas of DNA synthesis and sequencing may enable the implementation of automated and nonintrusive safeguards to avert the illicit applications of biotechnology. In the case of DNA synthesis, automated DNA screening tools could be built into DNA synthesizers in order to block the synthesis of hazardous agents. In addition, a comprehensive safety and security regime for dual-use genetic engineering research could include nonintrusive monitoring of DNA sequencing. This is increasingly feasible as laboratories outsource this service to just a few centralized sequencing factories. The adoption of automated, nonintrusive monitoring and surveillance of the DNA synthesis and sequencing pipelines may avert many risks associated with dual-use biotechnology. Here, we describe the historical background and current challenges associated with dual-use biotechnologies and propose strategies to address these challenges.

Giraffe genome sequence reveals clues to its unique morphology and physiology

PubMed Central

Agaba, Morris; Ishengoma, Edson; Miller, Webb C.; McGrath, Barbara C.; Hudson, Chelsea N.; Bedoya Reina, Oscar C.; Ratan, Aakrosh; Burhans, Rico; Chikhi, Rayan; Medvedev, Paul; Praul, Craig A.; Wu-Cavener, Lan; Wood, Brendan; Robertson, Heather; Penfold, Linda; Cavener, Douglas R.

2016-01-01

The origins of giraffe's imposing stature and associated cardiovascular adaptations are unknown. Okapi, which lacks these unique features, is giraffe's closest relative and provides a useful comparison, to identify genetic variation underlying giraffe's long neck and cardiovascular system. The genomes of giraffe and okapi were sequenced, and through comparative analyses genes and pathways were identified that exhibit unique genetic changes and likely contribute to giraffe's unique features. Some of these genes are in the HOX, NOTCH and FGF signalling pathways, which regulate both skeletal and cardiovascular development, suggesting that giraffe's stature and cardiovascular adaptations evolved in parallel through changes in a small number of genes. Mitochondrial metabolism and volatile fatty acids transport genes are also evolutionarily diverged in giraffe and may be related to its unusual diet that includes toxic plants. Unexpectedly, substantial evolutionary changes have occurred in giraffe and okapi in double-strand break repair and centrosome functions. PMID:27187213

A Step Toward High Reliability: Implementation of a Daily Safety Brief in a Children's Hospital.

PubMed

Saysana, Michele; McCaskey, Marjorie; Cox, Elaine; Thompson, Rachel; Tuttle, Lora K; Haut, Paul R

2017-09-01

Health care is a high-risk industry. To improve communication about daily events and begin the journey toward a high reliability organization, the Riley Hospital for Children at Indiana University Health implemented a daily safety brief. Various departments in our children's hospital were asked to participate in a daily safety brief, reporting daily events and unexpected outcomes within their scope of responsibility. Participants were surveyed before and after implementation of the safety brief about communication and awareness of events in the hospital. The length of the brief and percentage of departments reporting unexpected outcomes were measured. The analysis of the presurvey and the postsurvey showed a statistically significant improvement in the questions related to the awareness of daily events as well as communication and relationships between departments. The monthly mean length of time for the brief was 15 minutes or less. Unexpected outcomes were reported by 50% of the departments for 8 months. A daily safety brief can be successfully implemented in a children's hospital. Communication between departments and awareness of daily events were improved. Implementation of a daily safety brief is a step toward becoming a high reliability organization.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

PubMed

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

PubMed Central

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype–phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines. PMID:29176389

The ecological risks of transgenic plants.

PubMed

Giovannetti, Manuela

2003-01-01

Biotechnologies have been utilized "ante litteram" for thousands of years to produce food and drink and genetic engineering techniques have been widely applied to produce many compounds for human use, from insulin to other medicines. The debate on genetically modified (GM) organisms broke out all over the world only when GM crops were released into the field. Plant ecologists, microbiologists and population geneticists carried out experiments aimed at evaluating the environmental impact of GM crops. The most significant findings concern: the spread of transgenes through GM pollen diffusion and its environmental impact after hybridisation with closely related wild species or subspecies; horizontal gene transfer from transgenic plants to soil microbes; the impact of insecticide proteins released into the soil by transformed plants on non-target microbial soil communities. Recent developments in genetic engineering produced a technology, dubbed "Terminator", which protects patented genes introduced in transgenic plants by killing the seeds in the second generation. This genetic construct, which interferes so heavily with fundamental life processes, is considered dangerous and should be ex-ante evaluated taking into account the data on "unexpected events", as here discussed, instead of relying on the "safe until proven otherwise" claim. Awareness that scientists, biotechnologists and genetic engineers cannot answer the fundamental question "how likely is that transgenes will be transferred from cultivated plants into the natural environment?" should foster long-term studies on the ecological risks and benefits of transgenic crops.

Breeding and Genetics Symposium: really big data: processing and analysis of very large data sets.

PubMed

Cole, J B; Newman, S; Foertter, F; Aguilar, I; Coffey, M

2012-03-01

Modern animal breeding data sets are large and getting larger, due in part to recent availability of high-density SNP arrays and cheap sequencing technology. High-performance computing methods for efficient data warehousing and analysis are under development. Financial and security considerations are important when using shared clusters. Sound software engineering practices are needed, and it is better to use existing solutions when possible. Storage requirements for genotypes are modest, although full-sequence data will require greater storage capacity. Storage requirements for intermediate and results files for genetic evaluations are much greater, particularly when multiple runs must be stored for research and validation studies. The greatest gains in accuracy from genomic selection have been realized for traits of low heritability, and there is increasing interest in new health and management traits. The collection of sufficient phenotypes to produce accurate evaluations may take many years, and high-reliability proofs for older bulls are needed to estimate marker effects. Data mining algorithms applied to large data sets may help identify unexpected relationships in the data, and improved visualization tools will provide insights. Genomic selection using large data requires a lot of computing power, particularly when large fractions of the population are genotyped. Theoretical improvements have made possible the inversion of large numerator relationship matrices, permitted the solving of large systems of equations, and produced fast algorithms for variance component estimation. Recent work shows that single-step approaches combining BLUP with a genomic relationship (G) matrix have similar computational requirements to traditional BLUP, and the limiting factor is the construction and inversion of G for many genotypes. A naïve algorithm for creating G for 14,000 individuals required almost 24 h to run, but custom libraries and parallel computing reduced that to 15 m. Large data sets also create challenges for the delivery of genetic evaluations that must be overcome in a way that does not disrupt the transition from conventional to genomic evaluations. Processing time is important, especially as real-time systems for on-farm decisions are developed. The ultimate value of these systems is to decrease time-to-results in research, increase accuracy in genomic evaluations, and accelerate rates of genetic improvement.

Deep genetic divergences among Indo-Pacific populations of the coral reef sponge Leucetta chagosensis (Leucettidae): Founder effects, vicariance, or both?

PubMed Central

2008-01-01

Background An increasing number of studies demonstrate that genetic differentiation and speciation in the sea occur over much smaller spatial scales than previously appreciated given the wide distribution range of many morphologically defined coral reef invertebrate species and the presumed dispersal-enhancing qualities of ocean currents. However, knowledge about the processes that lead to population divergence and speciation is often lacking despite being essential for the understanding, conservation, and management of marine biodiversity. Sponges, a highly diverse, ecologically and economically important reef-invertebrate taxon, exhibit spatial trends in the Indo-West Pacific that are not universally reflected in other marine phyla. So far, however, processes generating those unexpected patterns are not understood. Results We unraveled the phylogeographic structure of the widespread Indo-Pacific coral reef sponge Leucetta chagosensis across its known geographic range using two nuclear markers: the rDNA internal transcribed spacers (ITS 1&2) and a fragment of the 28S gene, as well as the second intron of the ATP synthetase beta subunit-gene (ATPSb-iII). This enabled the detection of several deeply divergent clades congruent over both loci, one containing specimens from the Indian Ocean (Red Sea and Maldives), another one from the Philippines, and two other large and substructured NW Pacific and SW Pacific clades with an area of overlap in the Great Barrier Reef/Coral Sea. Reciprocally monophyletic populations were observed from the Philippines, Red Sea, Maldives, Japan, Samoa, and Polynesia, demonstrating long-standing isolation. Populations along the South Equatorial Current in the south-western Pacific showed isolation-by-distance effects. Overall, the results pointed towards stepping-stone dispersal with some putative long-distance exchange, consistent with expectations from low dispersal capabilities. Conclusion We argue that both founder and vicariance events during the late Pliocene and Pleistocene were responsible to varying degrees for generating the deep phylogeographic structure. This structure was perpetuated largely as a result of the life history of L. chagosensis, resulting in high levels of regional isolation. Reciprocally monophyletic populations constitute putative sibling (cryptic) species, while population para- and polyphyly may indicate incipient speciation processes. The genetic diversity and biodiversity of tropical Indo-Pacific sponges appears to be substantially underestimated since the high level of genetic divergence is not necessarily manifested at the morphological level. PMID:18221552

Deep genetic divergences among Indo-Pacific populations of the coral reef sponge Leucetta chagosensis (Leucettidae): founder effects, vicariance, or both?

PubMed

Wörheide, Gert; Epp, Laura S; Macis, Luciana

2008-01-26

An increasing number of studies demonstrate that genetic differentiation and speciation in the sea occur over much smaller spatial scales than previously appreciated given the wide distribution range of many morphologically defined coral reef invertebrate species and the presumed dispersal-enhancing qualities of ocean currents. However, knowledge about the processes that lead to population divergence and speciation is often lacking despite being essential for the understanding, conservation, and management of marine biodiversity. Sponges, a highly diverse, ecologically and economically important reef-invertebrate taxon, exhibit spatial trends in the Indo-West Pacific that are not universally reflected in other marine phyla. So far, however, processes generating those unexpected patterns are not understood. We unraveled the phylogeographic structure of the widespread Indo-Pacific coral reef sponge Leucetta chagosensis across its known geographic range using two nuclear markers: the rDNA internal transcribed spacers (ITS 1&2) and a fragment of the 28S gene, as well as the second intron of the ATP synthetase beta subunit-gene (ATPSb-iII). This enabled the detection of several deeply divergent clades congruent over both loci, one containing specimens from the Indian Ocean (Red Sea and Maldives), another one from the Philippines, and two other large and substructured NW Pacific and SW Pacific clades with an area of overlap in the Great Barrier Reef/Coral Sea. Reciprocally monophyletic populations were observed from the Philippines, Red Sea, Maldives, Japan, Samoa, and Polynesia, demonstrating long-standing isolation. Populations along the South Equatorial Current in the south-western Pacific showed isolation-by-distance effects. Overall, the results pointed towards stepping-stone dispersal with some putative long-distance exchange, consistent with expectations from low dispersal capabilities. We argue that both founder and vicariance events during the late Pliocene and Pleistocene were responsible to varying degrees for generating the deep phylogeographic structure. This structure was perpetuated largely as a result of the life history of L. chagosensis, resulting in high levels of regional isolation. Reciprocally monophyletic populations constitute putative sibling (cryptic) species, while population para- and polyphyly may indicate incipient speciation processes. The genetic diversity and biodiversity of tropical Indo-Pacific sponges appears to be substantially underestimated since the high level of genetic divergence is not necessarily manifested at the morphological level.

The contribution of animal models to the study of obesity.

PubMed

Speakman, John; Hambly, Catherine; Mitchell, Sharon; Król, Elzbieta

2008-10-01

Obesity results from prolonged imbalance of energy intake and energy expenditure. Animal models have provided a fundamental contribution to the historical development of understanding the basic parameters that regulate the components of our energy balance. Five different types of animal model have been employed in the study of the physiological and genetic basis of obesity. The first models reflect single gene mutations that have arisen spontaneously in rodent colonies and have subsequently been characterized. The second approach is to speed up the random mutation rate artificially by treating rodents with mutagens or exposing them to radiation. The third type of models are mice and rats where a specific gene has been disrupted or over-expressed as a deliberate act. Such genetically-engineered disruptions may be generated through the entire body for the entire life (global transgenic manipulations) or restricted in both time and to certain tissue or cell types. In all these genetically-engineered scenarios, there are two types of situation that lead to insights: where a specific gene hypothesized to play a role in the regulation of energy balance is targeted, and where a gene is disrupted for a different purpose, but the consequence is an unexpected obese or lean phenotype. A fourth group of animal models concern experiments where selective breeding has been utilized to derive strains of rodents that differ in their degree of fatness. Finally, studies have been made of other species including non-human primates and dogs. In addition to studies of the physiological and genetic basis of obesity, studies of animal models have also informed us about the environmental aspects of the condition. Studies in this context include exploring the responses of animals to high fat or high fat/high sugar (Cafeteria) diets, investigations of the effects of dietary restriction on body mass and fat loss, and studies of the impact of candidate pharmaceuticals on components of energy balance. Despite all this work, there are many gaps in our understanding of how body composition and energy storage are regulated, and a continuing need for the development of pharmaceuticals to treat obesity. Accordingly, reductions in the use of animal models, while ethically desirable, will not be feasible in the short to medium term, and indeed an expansion in activity using animal models is anticipated as the epidemic continues and spreads geographically.

Development of Fluorescent Reverse Transcription Loop-mediated Isothermal Amplification (RT-LAMP) using Quenching Probes for the Detection of the Middle East Respiratory Syndrome Coronavirus.

PubMed

Shirato, Kazuya; Semba, Shohei; El-Kafrawy, Sherif A; Hassan, Ahmed M; Tolah, Ahmed M; Takayama, Ikuyo; Kageyama, Tsutomu; Notomi, Tsugunori; Kamitani, Wataru; Matsuyama, Shutoku; Azhar, Esam Ibraheem

2018-05-12

Clinical detection of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) in patients is achieved using genetic diagnostic methods, such as real-time RT-PCR assay. Previously, we developed a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for the detection of MERS-CoV [Virol J. 2014. 11:139]. Generally, amplification of RT-LAMP is monitored by the turbidity induced by precipitation of magnesium pyrophosphate with newly synthesized DNA. However, this mechanism cannot completely exclude the possibility of unexpected reactions. Therefore, in this study, fluorescent RT-LAMP assays using quenching probes (QProbes) were developed specifically to monitor only primer-derived signals. Two primer sets (targeting nucleocapsid and ORF1a sequences) were constructed to confirm MERS cases by RT-LAMP assay only. Our data indicate that both primer sets were capable of detecting MERS-CoV RNA to the same level as existing genetic diagnostic methods, and that both were highly specific with no cross-reactivity observed with other respiratory viruses. These primer sets were highly efficient in amplifying target sequences derived from different MERS-CoV strains, including camel MERS-CoV. In addition, the detection efficacy of QProbe RT-LAMP was comparable to that of real-time RT-PCR assay using clinical specimens from patients in Saudi Arabia. Altogether, these results indicate that QProbe RT-LAMP assays described here can be used as powerful diagnostic tools for rapid detection and surveillance of MERS-CoV infections. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Go West: A One Way Stepping-Stone Dispersion Model for the Cavefish Lucifuga dentata in Western Cuba.

PubMed

Hernández, Damir; Casane, Didier; Chevalier-Monteagudo, Pedro; Bernatchez, Louis; García-Machado, Erik

2016-01-01

Consistent with the limited dispersal capacity of most troglobitic animals, almost all Lucifuga cavefish species have very narrow geographic distribution in Cuba. However, one species, L. dentata, has a wide but disjointed distribution over 300 km in the west of the island. In order to estimate the relative role of vicariance and dispersal in the unexpected L. dentata distribution, we obtained partial sequences of the mitochondrial DNA (mtDNA) cytochrome b (cytb) gene and control region (CR), and then applied Approximate Bayesian Computation (ABC), based on the identification of five genetic and geographic congruent groups of populations. The process that best explains the distribution of genetic diversity in this species is sequential range expansion from east Matanzas to the western Pinar del Río provinces, followed by isolation of groups of populations. We found relative high haplotype diversity and low nucleotide diversity in all but the Havana group, which has high values for both diversity parameters, suggesting that this group has been demographically stable over time. For two groups of populations (Cayuco and Bolondrón), the mismatch distribution analyses suggests past demographic expansion. In the case of the Cayuco region, the star like relationships of haplotypes in the network suggests a recent founding event, congruent with other evidence indicating that this is the most recently colonized region. Over all, the results suggest that a combination of habitat availability, temporal interconnections, and possibly the biological properties of this species, may have enabled its dispersal and range expansion compared to other species of the genus, which are more geographically restricted.

A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations.

PubMed

Munford, V; Castro, L P; Souto, R; Lerner, L K; Vilar, J B; Quayle, C; Asif, H; Schuch, A P; de Souza, T A; Ienne, S; Alves, F I A; Moura, L M S; Galante, P A F; Camargo, A A; Liboredo, R; Pena, S D J; Sarasin, A; Chaibub, S C; Menck, C F M

2017-05-01

Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants). To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe. © 2016 British Association of Dermatologists.

Shedding genomic light on Aristotle's lantern.

PubMed

Sodergren, Erica; Shen, Yufeng; Song, Xingzhi; Zhang, Lan; Gibbs, Richard A; Weinstock, George M

2006-12-01

Sea urchins have proved fascinating to biologists since the time of Aristotle who compared the appearance of their bony mouth structure to a lantern in The History of Animals. Throughout modern times it has been a model system for research in developmental biology. Now, the genome of the sea urchin Strongylocentrotus purpuratus is the first echinoderm genome to be sequenced. A high quality draft sequence assembly was produced using the Atlas assembler to combine whole genome shotgun sequences with sequences from a collection of BACs selected to form a minimal tiling path along the genome. A formidable challenge was presented by the high degree of heterozygosity between the two haplotypes of the selected male representative of this marine organism. This was overcome by use of the BAC tiling path backbone, in which each BAC represents a single haplotype, as well as by improvements in the Atlas software. Another innovation introduced in this project was the sequencing of pools of tiling path BACs rather than individual BAC sequencing. The Clone-Array Pooled Shotgun Strategy greatly reduced the cost and time devoted to preparing shotgun libraries from BAC clones. The genome sequence was analyzed with several gene prediction methods to produce a comprehensive gene list that was then manually refined and annotated by a volunteer team of sea urchin experts. This latter annotation community edited over 9000 gene models and uncovered many unexpected aspects of the sea urchin genetic content impacting transcriptional regulation, immunology, sensory perception, and an organism's development. Analysis of the basic deuterostome genetic complement supports the sea urchin's role as a model system for deuterostome and, by extension, chordate development.

The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles.

PubMed

Nguyen, Albert T; Feasley, Christa L; Jackson, Ken W; Nitz, Theodore J; Salzwedel, Karl; Air, Gillian M; Sakalian, Michael

2011-12-07

Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1. In this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly. This is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors.

AKAP200 promotes Notch stability by protecting it from Cbl/lysosome-mediated degradation in Drosophila melanogaster.

PubMed

Bala Tannan, Neeta; Collu, Giovanna; Humphries, Ashley C; Serysheva, Ekatherina; Weber, Ursula; Mlodzik, Marek

2018-01-01

AKAP200 is a Drosophila melanogaster member of the "A Kinase Associated Protein" family of scaffolding proteins, known for their role in the spatial and temporal regulation of Protein Kinase A (PKA) in multiple signaling contexts. Here, we demonstrate an unexpected function of AKAP200 in promoting Notch protein stability. In Drosophila, AKAP200 loss-of-function (LOF) mutants show phenotypes that resemble Notch LOF defects, including eye patterning and sensory organ specification defects. Through genetic interactions, we demonstrate that AKAP200 interacts positively with Notch in both the eye and the thorax. We further show that AKAP200 is part of a physical complex with Notch. Biochemical studies reveal that AKAP200 stabilizes endogenous Notch protein, and that it limits ubiquitination of Notch. Specifically, our genetic and biochemical evidence indicates that AKAP200 protects Notch from the E3-ubiquitin ligase Cbl, which targets Notch to the lysosomal pathway. Indeed, we demonstrate that the effect of AKAP200 on Notch levels depends on the lysosome. Interestingly, this function of AKAP200 is fully independent of its role in PKA signaling and independent of its ability to bind PKA. Taken together, our data indicate that AKAP200 is a novel tissue specific posttranslational regulator of Notch, maintaining high Notch protein levels and thus promoting Notch signaling.

Patterns of expression of position-dependent integrated transgenes in mouse embryo.

PubMed Central

Bonnerot, C; Grimber, G; Briand, P; Nicolas, J F

1990-01-01

The abilities to introduce foreign DNA into the genome of mice and to visualize gene expression at the single-cell level underlie a method for defining individual elements of a genetic program. We describe the use of an Escherichia coli lacZ reporter gene fused to the promoter of the gene for hypoxanthine phosphoribosyl transferase that is expressed in all tissues. Most transgenic mice (six of seven) obtained with this construct express the lacZ gene from the hypoxanthine phosphoribosyltransferase promoter. Unexpectedly, however, the expression is temporally and spatially regulated. Each transgenic line is characterized by a specific, highly reproducible pattern of lacZ expression. These results show that, for expression, the integrated construct must be complemented by elements of the genome. These elements exert dominant developmental control on the hypoxanthine phosphoribosyltransferase promoter. The expression patterns in some transgenic mice conform to a typological marker and in others to a subtle combination of typology and topography. These observations define discrete heterogeneities of cell types and of certain structures, particularly in the nervous system and in the mesoderm. This system opens opportunities for developmental studies by providing cellular, molecular, and genetic markers of cell types, cell states, and cells from developmental compartments. Finally this method illustrates that genes transduced or transposed to a different position in the genome acquire different spatiotemporal specificities, a result that has implications for evolution. Images PMID:1696727

New Insights from Drosophila into the Regulation of EGFR Signaling.

PubMed

Harden, Nicholas

2017-01-01

Genetic analysis of Egfr signaling in Drosophila has a long-standing track record of making important contributions to our understanding of the Egfr pathway. While the central Ras/MAPK pathway has long been well defined, there is much to learn with regard to its cross talk with other pathways and how it is regulated. A better understanding of the regulation of Egfr signaling is of particular interest with regard to the participation of misregulated Egfr signaling in tumorigenesis. Recent studies in the fly have led to some surprising results, identifying regulators of Egfr acting in unexpected ways.

Melanosomes – dark organelles enlighten endosomal membrane transport

PubMed Central

Raposo, Graça; Marks, Michael S.

2009-01-01

Melanosomes are tissue-specific “lysosome-related” organelles of pigment cells in which melanins are synthesized and stored. Analyses of the trafficking and fate of melanosomal components are beginning to reveal how melanosomes are formed through novel pathways from early endosomal intermediates. These studies unveil generalized structural and functional modifications of the endosomal system in specialized cells, and provide unexpected insights into the biogenesis of multivesicular bodies and how compartmentalization regulates protein refolding. Moreover, genetic disorders that affect the biogenesis of melanosomes and other lysosome-related organelles have shed light into the molecular machinery that controls specialized endosomal sorting events. PMID:17878918

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

PubMed

Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R; Bowles, Karla R; Judkins, Thaddeus; Kaushik, Praveen; Roa, Benjamin B; Wenstrup, Richard J; Hartman, Anne-Renee; Syngal, Sapna

2015-09-01

Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

A novel (A)γδβ(0)-thalassemia caused by DNA deletion-inversion-insertion of the β-globin gene cluster and five olfactory receptor genes: Genetic interactions, hematological phenotypes and molecular characterization.

PubMed

Singha, Kritsada; Fucharoen, Goonnapa; Hama, Abdulloh; Fucharoen, Supan

2015-07-01

To report the phenotypes and genetic basis of a novel (A)γδβ(0)-thalassemia found in Thai individuals with several forms of thalassemia. An initial study was done in an adult Thai woman who had hypochromic microcytic red cells with unusually 100% Hb F. Extended study was carried out on her parents and another 17 unrelated individuals with elevated Hb F. Hb analysis was performed by capillary electrophoresis and DNA analysis was done using PCR. A novel diagnostic method based on multiplex PCR assays was developed. DNA analysis of the proband revealed the homozygosity for a novel deletion of 118.3 kb, removing the entire (A)γ, ψβ, δ-, β-globin and five olfactory receptor (OR) genes with an insertion of a 179 bp inverted DNA sequence located behind the OR52A5 gene located downstream and an insertion of 7 orphan nucleotides. Her parents were both carriers of this mutation. Further screening in suspected cases in our series unexpectedly led to identification of an additional 17 cases with this mutation in different genotypes including plain heterozygote, homozygote, compound heterozygote with Hb E, and double heterozygote with several forms of α-thalassemia. Hematological features associated with these genetic interactions are presented. Haplotype analysis indicated a single origin of this novel deletion-inversion-insertion (A)γδβ(0)-thalassemia in the Thai population. Differentiation of this mutation and other high Hb F determinants documented previously could be done by using a developed multiplex PCR assay. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Population genetics of the Schistosoma snail host Bulinus truncatus in Egypt.

PubMed

Zein-Eddine, Rima; Djuikwo-Teukeng, Félicité F; Dar, Yasser; Dreyfuss, Gilles; Van den Broeck, Frederik

2017-08-01

The tropical freshwater snail Bulinus truncatus serves as an important intermediate host of several human and cattle Schistosoma species in many African regions. Despite some ecological and malacological studies, there is no information on the genetic diversity of B. truncatus in Egypt. Here, we sampled 70-100 snails in ten localities in Upper Egypt and the Nile Delta. Per locality, we sequenced 10 snails at a partial fragment of the cytochrome c oxidase subunit 1 gene (cox1) and we genotyped 25-30 snails at six microsatellite markers. A total of nine mitochondrial haplotypes were detected, of which five were unique to the Nile Delta and three were unique to Upper Egypt, indicating that snail populations may have evolved independently in both regions. Bayesian clustering and hierarchical F-statistics using microsatellite markers further revealed strong population genetic structure at the level of locality. Observed heterozygosity was much lower compared to what is expected under random mating, which could be explained by high selfing rates, population size reductions and to a lesser extent by the Wahlund effect. Despite these observations, we found signatures of gene flow and cross-fertilization, even between snails from the Nile Delta and Upper Egypt, indicating that B. truncatus can travel across large distances in Egypt. These observations could have serious consequences for disease epidemiology, as it means that infected snails from one region could rapidly and unexpectedly spark a new epidemic in another distant region. This could be one of the factors explaining the rebound of human Schistosoma infections in the Nile Delta, despite decades of sustained schistosomiasis control. Copyright © 2017 Elsevier B.V. All rights reserved.

High protists diversity in the plankton of sulfurous lakes and lagoons examined by 18s rRNA gene sequence analyses.

PubMed

Triadó-Margarit, Xavier; Casamayor, Emilio O

2015-12-01

Diversity of small protists was studied in sulfidic and anoxic (euxinic) stratified karstic lakes and coastal lagoons by 18S rRNA gene analyses. We hypothesized a major sulfide effect, reducing protist diversity and richness with only a few specialized populations adapted to deal with low-redox conditions and high-sulfide concentrations. However, genetic fingerprinting suggested similar ecological diversity in anoxic and sulfurous than in upper oxygen rich water compartments with specific populations inhabiting euxinic waters. Many of them agreed with genera previously identified by microscopic observations, but also new and unexpected groups were detected. Most of the sequences matched a rich assemblage of Ciliophora (i.e., Coleps, Prorodon, Plagiopyla, Strombidium, Metopus, Vorticella and Caenomorpha, among others) and algae (mainly Cryptomonadales). Unidentified Cercozoa, Fungi, Stramenopiles and Discoba were recurrently found. The lack of GenBank counterparts was higher in deep hypolimnetic waters and appeared differentially allocated in the different taxa, being higher within Discoba and lower in Cryptophyceae. A larger number of populations than expected were specifically detected in the deep sulfurous waters, with unknown ecological interactions and metabolic capabilities. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.

Resistance of virus to extinction on bottleneck passages: study of a decaying and fluctuating pattern of fitness loss

NASA Technical Reports Server (NTRS)

Lazaro, Ester; Escarmis, Cristina; Perez-Mercader, Juan; Manrubia, Susanna C.; Domingo, Esteban

2003-01-01

RNA viruses display high mutation rates and their populations replicate as dynamic and complex mutant distributions, termed viral quasispecies. Repeated genetic bottlenecks, which experimentally are carried out through serial plaque-to-plaque transfers of the virus, lead to fitness decrease (measured here as diminished capacity to produce infectious progeny). Here we report an analysis of fitness evolution of several low fitness foot-and-mouth disease virus clones subjected to 50 plaque-to-plaque transfers. Unexpectedly, fitness decrease, rather than being continuous and monotonic, displayed a fluctuating pattern, which was influenced by both the virus and the state of the host cell as shown by effects of recent cell passage history. The amplitude of the fluctuations increased as fitness decreased, resulting in a remarkable resistance of virus to extinction. Whereas the frequency distribution of fitness in control (independent) experiments follows a log-normal distribution, the probability of fitness values in the evolving bottlenecked populations fitted a Weibull distribution. We suggest that multiple functions of viral genomic RNA and its encoded proteins, subjected to high mutational pressure, interact with cellular components to produce this nontrivial, fluctuating pattern.

High Diversity of Genes for Nonhost Resistance of Barley to Heterologous Rust Fungi

PubMed Central

Jafary, Hossein; Albertazzi, Giorgia; Marcel, Thierry C.; Niks, Rients E.

2008-01-01

Inheritance studies on the nonhost resistance of plants would normally require interspecific crosses that suffer from sterility and abnormal segregation. Therefore, we developed the barley–Puccinia rust model system to study, using forward genetics, the specificity, number, and diversity of genes involved in nonhost resistance. We developed two mapping populations by crossing the line SusPtrit, with exceptional susceptibility to heterologous rust species, with the immune barley cultivars Vada and Cebada Capa. These two mapping populations along with the Oregon Wolfe Barley population, which showed unexpected segregation for resistance to heterologous rusts, were phenotyped with four heterologous rust fungal species. Positions of QTL conferring nonhost resistance in the three mapping populations were compared using an integrated consensus map. The results confirmed that nonhost resistance in barley to heterologous rust species is controlled by QTL with different and overlapping specificities and by an occasional contribution of an R-gene for hypersensitivity. In each population, different sets of loci were implicated in resistance. Few genes were common between the populations, suggesting a high diversity of genes conferring nonhost resistance to heterologous pathogens. These loci were significantly associated with QTL for partial resistance to the pathogen Puccinia hordei and with defense-related genes. PMID:18430953

Dendrites are dispensable for basic motoneuron function but essential for fine tuning of behavior.

PubMed

Ryglewski, Stefanie; Kadas, Dimitrios; Hutchinson, Katie; Schuetzler, Natalie; Vonhoff, Fernando; Duch, Carsten

2014-12-16

Dendrites are highly complex 3D structures that define neuronal morphology and connectivity and are the predominant sites for synaptic input. Defects in dendritic structure are highly consistent correlates of brain diseases. However, the precise consequences of dendritic structure defects for neuronal function and behavioral performance remain unknown. Here we probe dendritic function by using genetic tools to selectively abolish dendrites in identified Drosophila wing motoneurons without affecting other neuronal properties. We find that these motoneuron dendrites are unexpectedly dispensable for synaptic targeting, qualitatively normal neuronal activity patterns during behavior, and basic behavioral performance. However, significant performance deficits in sophisticated motor behaviors, such as flight altitude control and switching between discrete courtship song elements, scale with the degree of dendritic defect. To our knowledge, our observations provide the first direct evidence that complex dendrite architecture is critically required for fine-tuning and adaptability within robust, evolutionarily constrained behavioral programs that are vital for mating success and survival. We speculate that the observed scaling of performance deficits with the degree of structural defect is consistent with gradual increases in intellectual disability during continuously advancing structural deficiencies in progressive neurological disorders.

Genomic Diversification in Strains of Rickettsia felis Isolated from Different Arthropods

PubMed Central

Gillespie, Joseph J.; Driscoll, Timothy P.; Verhoeve, Victoria I.; Utsuki, Tadanobu; Husseneder, Claudia; Chouljenko, Vladimir N.; Azad, Abdu F.; Macaluso, Kevin R.

2015-01-01

Rickettsia felis (Alphaproteobacteria: Rickettsiales) is the causative agent of an emerging flea-borne rickettsiosis with worldwide occurrence. Originally described from the cat flea, Ctenocephalides felis, recent reports have identified R. felis from other flea species, as well as other insects and ticks. This diverse host range for R. felis may indicate an underlying genetic variability associated with host-specific strains. Accordingly, to determine a potential genetic basis for host specialization, we sequenced the genome of R. felis str. LSU-Lb, which is an obligate mutualist of the parthenogenic booklouse Liposcelis bostrychophila (Insecta: Psocoptera). We also sequenced the genome of R. felis str. LSU, the second genome sequence for cat flea-associated strains (cf. R. felis str. URRWXCal2), which are presumably facultative parasites of fleas. Phylogenomics analysis revealed R. felis str. LSU-Lb diverged from the flea-associated strains. Unexpectedly, R. felis str. LSU was found to be divergent from R. felis str. URRWXCal2, despite sharing similar hosts. Although all three R. felis genomes contain the pRF plasmid, R. felis str. LSU-Lb carries an additional unique plasmid, pLbaR (plasmid of L. bostrychophila associated Rickettsia), nearly half of which encodes a unique 23-gene integrative conjugative element. Remarkably, pLbaR also encodes a repeats-in-toxin-like type I secretion system and associated toxin, heretofore unknown from other Rickettsiales genomes, which likely originated from lateral gene transfer with another obligate intracellular parasite of arthropods, Cardinium (Bacteroidetes). Collectively, our study reveals unexpected genomic diversity across three R. felis strains and identifies several diversifying factors that differentiate facultative parasites of fleas from obligate mutualists of booklice. PMID:25477419

The unique and cooperative roles of the Grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity.

PubMed

Boglev, Yeliz; Wilanowski, Tomasz; Caddy, Jacinta; Parekh, Vishwas; Auden, Alana; Darido, Charbel; Hislop, Nikki R; Cangkrama, Michael; Ting, Stephen B; Jane, Stephen M

2011-01-15

The Grainy head-like 3 (Grhl3) gene encodes a transcription factor that plays essential roles in epidermal morphogenesis during embryonic development, with deficient mice exhibiting failed skin barrier formation, defective wound repair, and loss of eyelid fusion. Despite sharing significant sequence homology, overlapping expression patterns, and an identical core consensus DNA binding site, the other members of the Grhl family (Grhl1 and -2) fail to compensate for the loss of Grhl3 in these processes. Here, we have employed diverse genetic models, coupled with biochemical studies, to define the inter-relationships of the Grhl factors in epidermal development. We show that Grhl1 and Grhl3 have evolved complete functional independence, as evidenced by a lack of genetic interactions in embryos carrying combinations of targeted alleles of these genes. In contrast, compound heterozygous Grhl2/Grhl3 embryos displayed failed wound repair, and loss of a single Grhl2 allele in Grhl3-null embryos results in fully penetrant eyes open at birth. Expression of Grhl2 from the Grhl3 locus in homozygous knock-in mice corrects the wound repair defect, but these embryos still display a complete failure of skin barrier formation. This functional dissociation is due to unexpected differences in target gene specificity, as both GRHL2 and GRHL3 bind to and regulate expression of the wound repair gene Rho GEF 19, but regulation of the barrier forming gene, Transglutaminase 1 (TGase1), is unique to GRHL3. Our findings define the mechanisms underpinning the unique and cooperative roles of the Grhl genes in epidermal development. Copyright © 2010 Elsevier Inc. All rights reserved.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

PubMed

Bagnall, Richard D; Crompton, Douglas E; Petrovski, Slavé; Lam, Lien; Cutmore, Carina; Garry, Sarah I; Sadleir, Lynette G; Dibbens, Leanne M; Cairns, Anita; Kivity, Sara; Afawi, Zaid; Regan, Brigid M; Duflou, Johan; Berkovic, Samuel F; Scheffer, Ingrid E; Semsarian, Christopher

2016-04-01

The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members. © 2016 American Neurological Association.

Formulating autism systemically: Part 1 - A review of the published literature and case assessments.

PubMed

Crittenden, Patricia M

2017-07-01

Autism is a psychiatric disorder of unknown aetiology. In this article, the literature on genetic, neurological, psychological, relational and cultural causes of autism is reviewed, beginning with the 2014 review of Crittenden, Dallos, Landini et al. (pp. 64-70) up to and including recent publications in 2017. Some of the findings were unexpected; others led to new questions. The unexpected findings were the minimal contribution of genes to autism, the extremely evident neurological differences, the interpersonal quality of the psychological findings (that lacked evidence of parents' behaviour), the relational evidence that mothers' childhood trauma, perinatal stress and marital stress increased the risk of autism, and the reciprocal relation between funding for treatment of autism and diagnoses of autism. Notably, there was an abundance of genetic studies, numerous neurological studies and only scattered psychological, relational and cultural studies, thus rendering those findings speculative. The new questions included whether mothers used postural/gestural signs to signal their children to maintain distance and whether mothers experienced wariness of males as a result of childhood trauma, with their sons possibly experiencing gender confusion. Following the literature review, a small archival set of video-recorded and transcribed assessments of attachment of cases of autism were examined for evidence to corroborate or refute the psychological and relational findings of the literature review. The findings were striking in their support of mothers' use of postural/gestural communication regarding distance, children's close attention to mothers' bodily signals, without looking at mothers' face, mothers' greater comfort when they approached their sons than when their sons approached them, one boy's lack of verbal self-representation and mothers' childhood triangulation. These became hypotheses regarding what to look for in Part 2 of this article, a prospective, 12-year case study.

How many populations set foot through the Patagonian door? Genetic composition of the current population of Bahía Blanca (Argentina) based on data from 19 Alu polymorphisms.

PubMed

Resano, M; Esteban, E; González-Pérez, E; Vía, M; Athanasiadis, G; Avena, S; Goicoechea, A; Bartomioli, M; Fernández, V; Cabrera, A; Dejean, C; Carnese, F; Moral, P

2007-01-01

The city of Bahía Blanca occupies a strategic place in Argentina south of the Pampean region in the north-east corner of the Patagonia. Since 1828, this city has been the historical and political border between Amerindian lands in the south, and the lands of European colonists. Nowadays, Bahía Blanca is an urban population mainly composed by descendents of immigrants from Spain and other European countries with apparently low admixture with Amerindians. In view of the unexpectedly high Amerindian admixture levels (about 46.7%) suggested by mtDNA data, and protein markers (19.5%), we analyzed a set of 19 Alu polymorphisms (18 autosomal, 1 of Chromosome Y) in a well-documented genealogical sample from Bahía Blanca. The genotyped sample was made up of 119 unrelated healthy individuals whose birth place and grandparent origins were fully documented. According to available genealogical records, the total sample has been subdivided into two groups: Bahía Blanca Original (64 individuals with all 4 gandparents born in Argentina) and Bahía Blanca Mix (55 individuals with one to three grandparents born out of Argentina). Allele frequencies and gene diversity values in Bahía Blanca fit well into the European ranges. Population relationships have been tested for 8 Alu markers, whose variation has been described in several Amerindian and European samples. Reynolds genetic distances underline the significant genetic similarity of Bahía Blanca to Europeans (mean distance 0.044) and their differentiation from Amerindians (0.146). Interestingly enough, when the general sample is divided, Bahía Blanca Original appears slightly closer to Amerindians (0.127) in contrast to Bahía Blanca Mix (0.161). Furthermore, the genetic relationships depicted through a principal components analysis emphasize the relative similarity of Bahía Blanca Original to Amerindians. A thorough knowledge of the sample origins has allowed us to make a subtle distinction of the genetic composition of Bahía Blanca. Copyright 2007 Wiley-Liss, Inc.

Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.

PubMed

Hoyte, Ashley C; Jamin, Augusta V; Koneru, Pratibha C; Kobe, Matthew J; Larue, Ross C; Fuchs, James R; Engelman, Alan N; Kvaratskhelia, Mamuka

2017-12-01

The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Mature Hepatocytes Exhibit Unexpected Plasticity by Direct Dedifferentiation into Liver Progenitor Cells in Culture

PubMed Central

Chen, Yixin; Wong, Philip P.; Sjeklocha, Lucas; Steer, Clifford J.; Sahin, M. Behnan

2011-01-01

Although there have been numerous reports describing the isolation of liver progenitor cells from adult liver, their exact origin has not been clearly defined; and the role played by mature hepatocytes as direct contributors to the hepatic progenitor cell pool has remained largely unknown. Here we report strong evidence that mature hepatocytes in culture have the capacity to dedifferentiate into a population of adult liver progenitors without genetic or epigenetic manipulations. By using highly-purified mature hepatocytes, which were obtained from untreated, healthy rat liver and labeled with fluorescent dye PKH2, we found that hepatocytes in culture gave rise to a population of PKH2-positive liver progenitor cells. These cells, Liver Derived Progenitor Cells or LDPCS, which share phenotypic similarities with oval cells, were previously reported to be capable of forming mature hepatocytes both in culture and in animals. Studies done at various time points during the course of dedifferentiation cultures revealed that hepatocytes rapidly transformed into liver progenitors within one week through a transient oval cell-like stage. This finding was supported by lineage-tracing studies involving double-transgenic AlbuminCreXRosa26 mice expressing β-galactosidase exclusively in hepatocytes. Cultures set up with hepatocytes obtained from these mice resulted in generation of β-galactosidase-positive liver progenitor cells demonstrating that they were a direct dedifferentiation product of mature hepatocytes. Additionally, these progenitors differentiated into hepatocytes in vivo when transplanted into rats that had undergone retrorsine pretreatment and partial hepatectomy. Conclusion Our studies provide strong evidence for the unexpected plasticity of mature hepatocytes to dedifferentiate into progenitor cells in culture; and this may potentially have a significant impact on the treatment of liver diseases requiring liver or hepatocyte transplantation. PMID:21953633

Release of inattentional blindness by high working memory load: elucidating the relationship between working memory and selective attention.

PubMed

de Fockert, Jan W; Bremner, Andrew J

2011-12-01

An unexpected stimulus often remains unnoticed if attention is focused elsewhere. This inattentional blindness has been shown to be increased under conditions of high memory load. Here we show that increasing working memory load can also have the opposite effect of reducing inattentional blindness (i.e., improving stimulus detection) if stimulus detection is competing for attention with a concurrent visual task. Participants were required to judge which of two lines was the longer while holding in working memory either one digit (low load) or six digits (high load). An unexpected visual stimulus was presented once alongside the line judgment task. Detection of the unexpected stimulus was significantly improved under conditions of higher working memory load. This improvement in performance prompts the striking conclusion that an effect of cognitive load is to increase attentional spread, thereby enhancing our ability to detect perceptual stimuli to which we would normally be inattentionally blind under less taxing cognitive conditions. We discuss the implications of these findings for our understanding of the relationship between working memory and selective attention. Copyright © 2011 Elsevier B.V. All rights reserved.

Investigation of major genetic alterations in neuroblastoma.

PubMed

Costa, Régis Afonso; Seuánez, Héctor N

2018-06-01

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. This malignancy shows a wide spectrum of clinical outcome and its prognosis is conditioned by manifold biological and genetic factors. We investigated the tumor genetic profile and clinical data of 29 patients with NB by multiplex ligation-dependent probe amplification (MLPA) to assess therapeutic risk. In 18 of these tumors, MYCN status was assessed by fluorescence in situ hybridization (FISH). Copy number variation was also determined for confirming MLPA findings in two 6p loci. We found 2p, 7q and 17q gains, and 1p and 11q losses as the most frequent chromosome alterations in this cohort. FISH confirmed all cases of MYCN amplification detected by MLPA. In view of unexpected 6p imbalance, copy number variation of two 6p loci was assessed for validating MLPA findings. Based on clinical data and genetic profiles, patients were stratified in pretreatment risk groups according to international consensus. MLPA proved to be effective for detecting multiple genetic alterations in all chromosome regions as requested by the International Neuroblastoma Risk Group (INRG) for therapeutic stratification. Moreover, this technique proved to be cost effective, reliable, only requiring standard PCR equipment, and attractive for routine analysis. However, the observed 6p imbalances made PKHD1 and DCDC2 inadequate for control loci. This must be considered when designing commercial MLPA kits for NB. Finally, four patients showed a normal MLPA profile, suggesting that NB might have a more complex genetic pattern than the one assessed by presently available MLPA kits.

Residence rule flexibility and descent groups dynamics shape uniparental genetic diversities in South East Asia.

PubMed

Ly, Goki; Alard, Bérénice; Laurent, Romain; Lafosse, Sophie; Toupance, Bruno; Monidarin, Chou; Diffloth, Gérard; Bourdier, Frédéric; Evrard, Olivier; Pavard, Samuel; Chaix, Raphaëlle

2018-03-01

Social organization plays a major role in shaping human population genetic diversity. In particular, matrilocal populations tend to exhibit less mitochondrial diversity than patrilocal populations, and the other way around for Y chromosome diversity. However, several studies have not replicated such findings. The objective of this study is to understand the reasons for such inconsistencies and further evaluate the influence of social organization on genetic diversity. We explored uniparental diversity patterns using mitochondrial HV1 sequences and 17 Y-linked short tandem repeats (STRs) in 12 populations (n = 619) from mainland South-East Asia exhibiting a wide range of social organizations, along with quantitative ethno-demographic information sampled at the individual level. MtDNA diversity was lower in matrilocal than in multilocal and patrilocal populations while Y chromosome diversity was similar among these social organizations. The reasons for such asymmetry at the genetic level were understood by quantifying sex-specific migration rates from our ethno-demographic data: while female migration rates varied between social organizations, male migration rates did not. This unexpected lack of difference in male migrations resulted from a higher flexibility in residence rule in patrilocal than in matrilocal populations. In addition, our data suggested an impact of clan fission process on uniparental genetic patterns. The observed lack of signature of patrilocality on Y chromosome patterns might be attributed to the higher residence flexibility in the studied patrilocal populations, thus providing a potential explanation for the apparent discrepancies between social and genetic structures. Altogether, this study highlights the need to quantify the actual residence and descent patterns to fit social to genetic structures. © 2018 Wiley Periodicals, Inc.

Timing the tides: Genetic control of diurnal and lunar emergence times is correlated in the marine midge Clunio marinus

PubMed Central

2011-01-01

Background The intertidal zone of seacoasts, being affected by the superimposed tidal, diurnal and lunar cycles, is temporally the most complex environment on earth. Many marine organisms exhibit lunar rhythms in reproductive behaviour and some show experimental evidence of endogenous control by a circalunar clock, the molecular and genetic basis of which is unexplored. We examined the genetic control of lunar and diurnal rhythmicity in the marine midge Clunio marinus (Chironomidae, Diptera), a species for which the correct timing of adult emergence is critical in natural populations. Results We crossed two strains of Clunio marinus that differ in the timing of the diurnal and lunar rhythms of emergence. The phenotype distribution of the segregating backcross progeny indicates polygenic control of the lunar emergence rhythm. Diurnal timing of emergence is also under genetic control, and is influenced by two unlinked genes with major effects. Furthermore, the lunar and diurnal timing of emergence is correlated in the backcross generation. We show that both the lunar emergence time and its correlation to the diurnal emergence time are adaptive for the species in its natural environment. Conclusions The correlation implies that the unlinked genes affecting lunar timing and the two unlinked genes affecting diurnal timing could be the same, providing an unexpectedly close interaction of the two clocks. Alternatively, the genes could be genetically linked in a two-by-two fashion, suggesting that evolution has shaped the genetic architecture to stabilize adaptive combinations of lunar and diurnal emergence times by tightening linkage. Our results, the first on genetic control of lunar rhythms, offer a new perspective to explore their molecular clockwork. PMID:21599938

Timing the tides: genetic control of diurnal and lunar emergence times is correlated in the marine midge Clunio marinus.

PubMed

Kaiser, Tobias S; Neumann, Dietrich; Heckel, David G

2011-05-20

The intertidal zone of seacoasts, being affected by the superimposed tidal, diurnal and lunar cycles, is temporally the most complex environment on earth. Many marine organisms exhibit lunar rhythms in reproductive behaviour and some show experimental evidence of endogenous control by a circalunar clock, the molecular and genetic basis of which is unexplored. We examined the genetic control of lunar and diurnal rhythmicity in the marine midge Clunio marinus (Chironomidae, Diptera), a species for which the correct timing of adult emergence is critical in natural populations. We crossed two strains of Clunio marinus that differ in the timing of the diurnal and lunar rhythms of emergence. The phenotype distribution of the segregating backcross progeny indicates polygenic control of the lunar emergence rhythm. Diurnal timing of emergence is also under genetic control, and is influenced by two unlinked genes with major effects. Furthermore, the lunar and diurnal timing of emergence is correlated in the backcross generation. We show that both the lunar emergence time and its correlation to the diurnal emergence time are adaptive for the species in its natural environment. The correlation implies that the unlinked genes affecting lunar timing and the two unlinked genes affecting diurnal timing could be the same, providing an unexpectedly close interaction of the two clocks. Alternatively, the genes could be genetically linked in a two-by-two fashion, suggesting that evolution has shaped the genetic architecture to stabilize adaptive combinations of lunar and diurnal emergence times by tightening linkage. Our results, the first on genetic control of lunar rhythms, offer a new perspective to explore their molecular clockwork.

Openness to the unexpected: Our Pathways to Careers in a Federal Research Laboratory.

USGS Publications Warehouse

Newman, Kurt R.; Bunnell, David B.; Hondorp, Darryl W.; Taylor, William W.; Lynch, Abigail J.; Léonard, Nancy J.

2014-01-01

Many fisheries professionals may not be in the job they originally envisioned for themselves when they began their undergraduate studies. Rather, their current positions could be the result of unexpected, opportunistic, or perhaps even “lucky” open doors that led them down an unexpected path. In many cases, a mentor helped facilitate the unforeseen trajectory. We offer three unique stories about joining a federal fisheries research laboratory, from the perspective of a scientist, a joint manager-scientist, and a manager. We also use our various experiences to form recommendations that should help the next generation of fisheries professionals succeed in any stop along their journey, including being open to opportunities, setting high expectations, and finding a strong and supportive team environment to work in.

What Goes Around Can Come Around: An Unexpected Deleterious Effect of Using Mouse Running Wheels for Environmental Enrichment

PubMed Central

Leduc, Renee Y M; Rauw, Gail; Baker, Glen B; McDermid, Heather E

2017-01-01

Environmental enrichment items such as running wheels can promote the wellbeing of laboratory mice. Growing evidence suggests that wheel running simulates exercise effects in many mouse models of human conditions, but this activity also might change other aspects of mouse behavior. In this case study, we show that the presence of running wheels leads to pronounced and permanent circling behavior with route-tracing in a proportion of the male mice of a genetically distinct cohort. The genetic background of this cohort includes a mutation in Arhgap19, but genetic crosses showed that an unknown second-site mutation likely caused the induced circling behavior. Behavioral tests for inner-ear function indicated a normal sense of gravity in the circling mice. However, the levels of dopamine, serotonin, and some dopamine metabolites were lower in the brains of circling male mice than in mice of the same genetic background that were weaned without wheels. Circling was seen in both singly and socially housed male mice. The additional stress of fighting may have exacerbated the predisposition to circling in the socially housed animals. Singly and socially housed male mice without wheels did not circle. Our current findings highlight the importance and possibly confounding nature of the environmental and genetic background in mouse behavioral studies, given that the circling behavior and alterations in dopamine and serotonin levels in this mouse cohort occurred only when the male mice were housed with running wheels. PMID:28315651

High-Dose Hook Effect in 17-Hydroxyprogesterone Assay in a Patient with 21-Hydroxylase Deficiency.

PubMed

Parlak, Mesut; Ellidağ, Hamit Yaşar; Türkkahraman, Doğa

2015-12-01

Congenital adrenal hyperplasia (CAH) describes a group of disorders characterized by enzyme defects in adrenal steroidogenesis. 21-hydroxylase deficiency (21-OHD) is the most commonly encountered form. The analysis of steroids in pediatric cases requires high-sensitivity assays. A 14-year-old Syrian girl was referred for evaluation of short stature, amenorrhea, and hirsutism. On physical examination, breast development was Tanner stage 1. She had a phallic clitoris with a single urogenital orifice. Laboratory findings revealed primary adrenal deficiency with high androgen levels and low levels of 17-hydroxyprogesterone (17-OHP), (<0.05 ng/mL) and estrogen. This unexpected result led to suspicion of a high-dose hook effect. The measurement was repeated after 1/10 dilution of serum, and a high level of 17-OHP (115.4 ng/mL) was detected with the same test-enzyme-linked immunosorbent assay (ELISA). Simple virilizing form of CAH (21-OHD) was suspected and confirmed with genetic analysis. After initiation of glucocorticoid therapy, breast development was noted along with a decrease in testosterone level and an increase in estrogen level. To our knowledge, this is the first case report of hook effect for 17-OHP immunoassay in a patient with 21-OHD. High-dose hook effect should be suspected in patients with CAH when the test results are incompatible with one another. Additionally, this case demonstrates that a high testosterone level can block aromatase activity and consequently also estrogen production and breast development.

Transgenic mice reveal unexpected diversity of On-Off direction selective retinal ganglion cell subtypes and brain structures involved in motion processing

PubMed Central

Rivlin-Etzion, Michal; Zhou, Kaili; Wei, Wei; Elstrott, Justin; Nguyen, Phong L.; Barres, Ben; Huberman, Andrew D.; Feller, Marla B.

2011-01-01

On-Off direction selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, ‘null’, direction. Historically, On-Off DSGCs were classified into 4 subtypes according to their directional preference (anterior, posterior, superior or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: DRD4-DSGCs and TRHR-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction-tuned visual information. Our findings reveal unexpected diversity among mouse On-Off DSGC subtypes that uniquely process and convey image motion to the brain. PMID:21677160

An unexpected role for the yeast nucleotide exchange factor Sil1 as a reductant acting on the molecular chaperone BiP

PubMed Central

Siegenthaler, Kevin D; Pareja, Kristeen A; Wang, Jie; Sevier, Carolyn S

2017-01-01

Unfavorable redox conditions in the endoplasmic reticulum (ER) can decrease the capacity for protein secretion, altering vital cell functions. While systems to manage reductive stress are well-established, how cells cope with an overly oxidizing ER remains largely undefined. In previous work (Wang et al., 2014), we demonstrated that the chaperone BiP is a sensor of overly oxidizing ER conditions. We showed that modification of a conserved BiP cysteine during stress beneficially alters BiP chaperone activity to cope with suboptimal folding conditions. How this cysteine is reduced to reestablish 'normal' BiP activity post-oxidative stress has remained unknown. Here we demonstrate that BiP's nucleotide exchange factor – Sil1 – can reverse BiP cysteine oxidation. This previously unexpected reductant capacity for yeast Sil1 has potential implications for the human ataxia Marinesco-Sjögren syndrome, where it is interesting to speculate that a disruption in ER redox-signaling (due to genetic defects in SIL1) may influence disease pathology. DOI: http://dx.doi.org/10.7554/eLife.24141.001 PMID:28257000

Photosynthetic variation and responsiveness to CO2 in a widespread riparian tree

PubMed Central

Quentin, Audrey; Ivković, Milos; Furbank, Robert T.; Pinkard, Elizabeth

2018-01-01

Phenotypic responses to rising CO2 will have consequences for the productivity and management of the world’s forests. This has been demonstrated through extensive free air and controlled environment CO2 enrichment studies. However intraspecific variation in plasticity remains poorly characterised in trees, with the capacity to produce unexpected trends in response to CO2 across a species distribution. Here we examined variation in photosynthesis traits across 43 provenances of a widespread, genetically diverse eucalypt, E. camaldulensis, under ambient and elevated CO2 conditions. Genetic variation suggestive of local adaptation was identified for some traits under ambient conditions. Evidence of genotype by CO2 interaction in responsiveness was limited, however support was identified for quantum yield (φ). In this case local adaptation was invoked to explain trends in provenance variation in response. The results suggest potential for genetic variation to influence a limited set of photosynthetic responses to rising CO2 in seedlings of E. camaldulensis, however further assessment in mature stage plants in linkage with growth and fitness traits is needed to understand whether trends in φ could have broader implications for productivity of red gum forests. PMID:29293528

Photosynthetic variation and responsiveness to CO2 in a widespread riparian tree.

PubMed

Dillon, Shannon; Quentin, Audrey; Ivković, Milos; Furbank, Robert T; Pinkard, Elizabeth

2018-01-01

Phenotypic responses to rising CO2 will have consequences for the productivity and management of the world's forests. This has been demonstrated through extensive free air and controlled environment CO2 enrichment studies. However intraspecific variation in plasticity remains poorly characterised in trees, with the capacity to produce unexpected trends in response to CO2 across a species distribution. Here we examined variation in photosynthesis traits across 43 provenances of a widespread, genetically diverse eucalypt, E. camaldulensis, under ambient and elevated CO2 conditions. Genetic variation suggestive of local adaptation was identified for some traits under ambient conditions. Evidence of genotype by CO2 interaction in responsiveness was limited, however support was identified for quantum yield (φ). In this case local adaptation was invoked to explain trends in provenance variation in response. The results suggest potential for genetic variation to influence a limited set of photosynthetic responses to rising CO2 in seedlings of E. camaldulensis, however further assessment in mature stage plants in linkage with growth and fitness traits is needed to understand whether trends in φ could have broader implications for productivity of red gum forests.

Hemiclonal analysis of interacting phenotypes in male and female Drosophila melanogaster

PubMed Central

2014-01-01

Background Identifying the sources of variation in mating interactions between males and females is important because this variation influences the strength and/or the direction of sexual selection that populations experience. While the origins and effects of variation in male attractiveness and ornamentation have received much scrutiny, the causes and consequences of intraspecific variation in females have been relatively overlooked. We used cytogenetic cloning techniques developed for Drosophila melanogaster to create “hemiclonal” males and females with whom we directly observed sexual interaction between individuals of different known genetic backgrounds and measured subsequent reproductive outcomes. Using this approach, we were able to quantify the genetic contribution of each mate to the observed phenotypic variation in biologically important traits including mating speed, copulation duration, and subsequent offspring production, as well as measure the magnitude and direction of intersexual genetic correlation between female choosiness and male attractiveness. Results We found significant additive genetic variation contributing to mating speed that can be attributed to male genetic identity, female genetic identity, but not their interaction. Furthermore we found that phenotypic variation in copulation duration had a significant male-associated genetic component. Female genetic identity and the interaction between male and female genetic identity accounted for a substantial amount of the observed phenotypic variation in egg size. Although previous research predicts a trade-off between egg size and fecundity, this was not evident in our results. We found a strong negative genetic correlation between female choosiness and male attractiveness, a result that suggests a potentially important role for sexually antagonistic alleles in sexual selection processes in our population. Conclusion These results further our understanding of sexual selection because they identify that genetic identity plays a significant role in phenotypic variation in female behaviour and fecundity. This variation may be potentially due to ongoing sexual conflict found between the sexes for interacting phenotypes. Our unexpected observation of a negative correlation between female choosiness and male attractiveness highlights the need for more explicit theoretical models of genetic covariance to investigate the coevolution of female choosiness and male attractiveness. PMID:24884361

Large inserts for big data: artificial chromosomes in the genomic era.

PubMed

Tocchetti, Arianna; Donadio, Stefano; Sosio, Margherita

2018-05-01

The exponential increase in available microbial genome sequences coupled with predictive bioinformatic tools is underscoring the genetic capacity of bacteria to produce an unexpected large number of specialized bioactive compounds. Since most of the biosynthetic gene clusters (BGCs) present in microbial genomes are cryptic, i.e. not expressed under laboratory conditions, a variety of cloning systems and vectors have been devised to harbor DNA fragments large enough to carry entire BGCs and to allow their transfer in suitable heterologous hosts. This minireview provides an overview of the vectors and approaches that have been developed for cloning large BGCs, and successful examples of heterologous expression.

Incorporating uncertainty into medical decision making: an approach to unexpected test results.

PubMed

Bianchi, Matt T; Alexander, Brian M; Cash, Sydney S

2009-01-01

The utility of diagnostic tests derives from the ability to translate the population concepts of sensitivity and specificity into information that will be useful for the individual patient: the predictive value of the result. As the array of available diagnostic testing broadens, there is a temptation to de-emphasize history and physical findings and defer to the objective rigor of technology. However, diagnostic test interpretation is not always straightforward. One significant barrier to routine use of probability-based test interpretation is the uncertainty inherent in pretest probability estimation, the critical first step of Bayesian reasoning. The context in which this uncertainty presents the greatest challenge is when test results oppose clinical judgment. It is this situation when decision support would be most helpful. The authors propose a simple graphical approach that incorporates uncertainty in pretest probability and has specific application to the interpretation of unexpected results. This method quantitatively demonstrates how uncertainty in disease probability may be amplified when test results are unexpected (opposing clinical judgment), even for tests with high sensitivity and specificity. The authors provide a simple nomogram for determining whether an unexpected test result suggests that one should "switch diagnostic sides.'' This graphical framework overcomes the limitation of pretest probability uncertainty in Bayesian analysis and guides decision making when it is most challenging: interpretation of unexpected test results.

Public health issues related with the consumption of food obtained from genetically modified organisms.

PubMed

Paparini, Andrea; Romano-Spica, Vincenzo

2004-01-01

Genetically Modified Organisms (GMOs) are a fact of modern agriculture and a major field of discussion in biotechnology. As science incessantly achieves innovative and unexpected breakthroughs, new medical, political, ethical and religious debates arise over the production and consumption of transgenic organisms. Despite no described medical condition being directly associated with a diet including approved GM crops in large exposed populations such as 300,000,000 Americans and a billion Chinese, public opinion seems to look at this new technology with either growing concern or even disapproval. It is generally recognized that a high level of vigilance is necessary and highly desirable, but it should also be considered that GMOs are a promising new challenge for the III Millennium societies, with remarkable impact on many disciplines and fields related to biotechnology. To acquire a basic knowledge on GMO production, GM-food consumption, GMO interaction with humans and environment is of primary importance for risk assessment. It requires availability of clear data and results from rigorous experiments. This review will focus on public health risks related with a GMO-containing diet. The objective is to summarize state of the art research, provide fundamental technical information, point out problems and perspectives, and make available essential tools for further research. Are GMO based industries and GMO-derived foods safe to human health? Can we consider both social, ethical and public health issues by means of a constant and effective monitoring of the food chain and by a clear, informative labeling of the products? Which are the so far characterized or alleged hazards of GMOs? And, most importantly, are these hazards actual, potential or merely contrived? Several questions remain open; answers and solutions belong to science, to politics and to the personal opinion of each social subject.

Urine proteome analysis in Dent's disease shows high selective changes potentially involved in chronic renal damage.

PubMed

Santucci, Laura; Candiano, Giovanni; Anglani, Franca; Bruschi, Maurizio; Tosetto, Enrica; Cremasco, Daniela; Murer, Luisa; D'Ambrosio, Chiara; Scaloni, Andrea; Petretto, Andrea; Caridi, Gianluca; Rossi, Roberta; Bonanni, Alice; Ghiggeri, Gian Marco

2016-01-01

Definition of the urinary protein composition would represent a potential tool for diagnosis in many clinical conditions. The use of new proteomic technologies allows detection of genetic and post-trasductional variants that increase sensitivity of the approach but complicates comparison within a heterogeneous patient population. Overall, this limits research of urinary biomarkers. Studying monogenic diseases are useful models to address this issue since genetic variability is reduced among first- and second-degree relatives of the same family. We applied this concept to Dent's disease, a monogenic condition characterised by low-molecular-weight proteinuria that is inherited following an X-linked trait. Results are presented here on a combined proteomic approach (LC-mass spectrometry, Western blot and zymograms for proteases and inhibitors) to characterise urine proteins in a large family (18 members, 6 hemizygous patients, 6 carrier females, and 6 normals) with Dent's diseases due to the 1070G>T mutation of the CLCN5. Gene ontology analysis on more than 1000 proteins showed that several clusters of proteins characterised urine of affected patients compared to carrier females and normal subjects: proteins involved in extracellular matrix remodelling were the major group. Specific analysis on metalloproteases and their inhibitors underscored unexpected mechanisms potentially involved in renal fibrosis. Studying with new-generation techniques for proteomic analysis of the members of a large family with Dent's disease sharing the same molecular defect allowed highly repetitive results that justify conclusions. Identification in urine of proteins actively involved in interstitial matrix remodelling poses the question of active anti-fibrotic drugs in Dent's patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Newcastle Disease Viruses Causing Recent Outbreaks Worldwide Show Unexpectedly High Genetic Similarity to Historical Virulent Isolates from the 1940s

PubMed Central

Dimitrov, Kiril M.; Lee, Dong-Hun; Williams-Coplin, Dawn; Olivier, Timothy L.; Miller, Patti J.

2016-01-01

Virulent strains of Newcastle disease virus (NDV) cause Newcastle disease (ND), a devastating disease of poultry and wild birds. Phylogenetic analyses clearly distinguish historical isolates (obtained prior to 1960) from currently circulating viruses of class II genotypes V, VI, VII, and XII through XVIII. Here, partial and complete genomic sequences of recent virulent isolates of genotypes II and IX from China, Egypt, and India were found to be nearly identical to those of historical viruses isolated in the 1940s. Phylogenetic analysis, nucleotide distances, and rates of change demonstrate that these recent isolates have not evolved significantly from the most closely related ancestors from the 1940s. The low rates of change for these virulent viruses (7.05 × 10−5 and 2.05 × 10−5 per year, respectively) and the minimal genetic distances existing between these and historical viruses (0.3 to 1.2%) of the same genotypes indicate an unnatural origin. As with any other RNA virus, Newcastle disease virus is expected to evolve naturally; thus, these findings suggest that some recent field isolates should be excluded from evolutionary studies. Furthermore, phylogenetic analyses show that these recent virulent isolates are more closely related to virulent strains isolated during the 1940s, which have been and continue to be used in laboratory and experimental challenge studies. Since the preservation of viable viruses in the environment for over 6 decades is highly unlikely, it is possible that the source of some of the recent virulent viruses isolated from poultry and wild birds might be laboratory viruses. PMID:26888902

The genomes of three stocks comprising the most widely utilized live sporozoite Theileria parva vaccine exhibit very different degrees and patterns of sequence divergence.

PubMed

Norling, Martin; Bishop, Richard P; Pelle, Roger; Qi, Weihong; Henson, Sonal; Drábek, Elliott F; Tretina, Kyle; Odongo, David; Mwaura, Stephen; Njoroge, Thomas; Bongcam-Rudloff, Erik; Daubenberger, Claudia A; Silva, Joana C

2015-09-24

There are no commercially available vaccines against human protozoan parasitic diseases, despite the success of vaccination-induced long-term protection against infectious diseases. East Coast fever, caused by the protist Theileria parva, kills one million cattle each year in sub-Saharan Africa, and contributes significantly to hunger and poverty in the region. A highly effective, live, multi-isolate vaccine against T. parva exists, but its component isolates have not been characterized. Here we sequence and compare the three component T. parva stocks within this vaccine, the Muguga Cocktail, namely Muguga, Kiambu5 and Serengeti-transformed, aiming to identify genomic features that contribute to vaccine efficacy. We find that Serengeti-transformed, originally isolated from the wildlife carrier, the African Cape buffalo, is remarkably and unexpectedly similar to the Muguga isolate. The 420 detectable non-synonymous SNPs were distributed among only 53 genes, primarily subtelomeric antigens and antigenic families. The Kiambu5 isolate is considerably more divergent, with close to 40,000 SNPs relative to Muguga, including >8,500 non-synonymous mutations distributed among >1,700 (42.5 %) of the predicted genes. These genetic markers of the component stocks can be used to characterize the composition of new batches of the Muguga Cocktail. Differences among these three isolates, while extensive, represent only a small proportion of the genetic variation in the entire species. Given the efficacy of the Muguga Cocktail in inducing long-lasting protection against infections in the field, our results suggest that whole-organism vaccines against parasitic diseases can be highly efficacious despite considerable genome-wide differences relative to the isolates against which they protect.

Development of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone.

PubMed

Li, Xiao-Feng; Dong, Hao-Long; Wang, Hong-Jiang; Huang, Xing-Yao; Qiu, Ye-Feng; Ji, Xue; Ye, Qing; Li, Chunfeng; Liu, Yang; Deng, Yong-Qiang; Jiang, Tao; Cheng, Gong; Zhang, Fu-Chun; Davidson, Andrew D; Song, Ya-Jun; Shi, Pei-Yong; Qin, Cheng-Feng

2018-02-14

The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. Here we report the development and characterization of a recombinant chimeric ZIKV vaccine candidate (termed ChinZIKV) that expresses the prM-E proteins of ZIKV using the licensed Japanese encephalitis live-attenuated vaccine SA14-14-2 as the genetic backbone. ChinZIKV retains its replication activity and genetic stability in vitro, while exhibiting an attenuation phenotype in multiple animal models. Remarkably, immunization of mice and rhesus macaques with a single dose of ChinZIKV elicits robust and long-lasting immune responses, and confers complete protection against ZIKV challenge. Significantly, female mice immunized with ChinZIKV are protected against placental and fetal damage upon ZIKV challenge during pregnancy. Overall, our study provides an alternative vaccine platform in response to the ZIKV emergency, and the safety, immunogenicity, and protection profiles of ChinZIKV warrant further clinical development.

Strategies for identifying new prions in yeast

PubMed Central

MacLea, Kyle S

2011-01-01

The unexpected discovery of two prions, [URE3] and [PSI+], in Saccharomyces cerevisiae led to questions about how many other proteins could undergo similar prion-based structural conversions. However, [URE3] and [PSI+] were discovered by serendipity in genetic screens. Cataloging the full range of prions in yeast or in other organisms will therefore require more systematic search methods. Taking advantage of some of the unique features of prions, various researchers have developed bioinformatic and experimental methods for identifying novel prion proteins. These methods have generated long lists of prion candidates. The systematic testing of some of these prion candidates has led to notable successes; however, even in yeast, where rapid growth rate and ease of genetic manipulation aid in testing for prion activity, such candidate testing is laborious. Development of better methods to winnow the field of prion candidates will greatly aid in the discovery of new prions, both in yeast and in other organisms, and help us to better understand the role of prions in biology. PMID:22052351

Gas1 extends the range of Hedgehog action by facilitating its signaling

PubMed Central

Martinelli, David C.; Fan, Chen-Ming

2007-01-01

Cellular signaling initiated by Hedgehog binding to Patched1 has profound importance in mammalian embryogenesis, genetic disease, and cancer. Hedgehog acts as a morphogen to specify distinctive cell fates using different concentration thresholds, but our knowledge of how the concentration gradient is interpreted into the activity gradient is incomplete. The membrane protein Growth Arrest-Specific Gene 1 (GAS1) was thought to be a negative regulator of the Hedgehog concentration gradient. Here, we report unexpected genetic evidence that Gas1 positively regulates Hedgehog signaling in multiple developmental contexts, an effect particularly noticeable at regions where Hedgehog acts at low concentration. Using a combination of in vitro cell culture and in ovo electroporation assays, we demonstrate that GAS1 acts cooperatively with Patched1 for Hedgehog binding and enhances signaling activity in a cell-autonomous manner. Our data support a model in which GAS1 helps transform the Hedgehog protein gradient into the observed activity gradient. We propose that Gas1 is an evolutionarily novel, vertebrate-specific Hedgehog pathway regulator. PMID:17504940

Fusion, fission, and transport control asymmetric inheritance of mitochondria and protein aggregates

PubMed Central

Böckler, Stefan; Chelius, Xenia; Hock, Nadine; Weiss, Matthias

2017-01-01

Partitioning of cell organelles and cytoplasmic components determines the fate of daughter cells upon asymmetric division. We studied the role of mitochondria in this process using budding yeast as a model. Anterograde mitochondrial transport is mediated by the myosin motor, Myo2. A genetic screen revealed an unexpected interaction of MYO2 and genes required for mitochondrial fusion. Genetic analyses, live-cell microscopy, and simulations in silico showed that fused mitochondria become critical for inheritance and transport across the bud neck in myo2 mutants. Similarly, fused mitochondria are essential for retention in the mother when bud-directed transport is enforced. Inheritance of a less than critical mitochondrial quantity causes a severe decline of replicative life span of daughter cells. Myo2-dependent mitochondrial distribution also is critical for the capture of heat stress–induced cytosolic protein aggregates and their retention in the mother cell. Together, these data suggest that coordination of mitochondrial transport, fusion, and fission is critical for asymmetric division and rejuvenation of daughter cells. PMID:28615194

Evolutionary Dynamics of Influenza A Viruses in US Exhibition Swine

PubMed Central

Nelson, Martha I.; Wentworth, David E.; Das, Suman R.; Sreevatsan, Srinand; Killian, Mary L.; Nolting, Jacqueline M.; Slemons, Richard D.; Bowman, Andrew S.

2016-01-01

The role of exhibition swine in influenza A virus transmission was recently demonstrated by >300 infections with influenza A(H3N2) variant viruses among individuals who attended agricultural fairs. Through active influenza A virus surveillance in US exhibition swine and whole-genome sequencing of 380 isolates, we demonstrate that exhibition swine are actively involved in the evolution of influenza A viruses, including zoonotic strains. First, frequent introduction of influenza A viruses from commercial swine populations provides new genetic diversity in exhibition pigs each year locally. Second, genomic reassortment between viruses cocirculating in exhibition swine increases viral diversity. Third, viral migration between exhibition swine in neighboring states demonstrates that movements of exhibition pigs contributes to the spread of genetic diversity. The unexpected frequency of viral exchange between commercial and exhibition swine raises questions about the understudied interface between these populations. Overall, the complexity of viral evolution in exhibition swine indicates that novel viruses are likely to continually reemerge, presenting threats to humans. PMID:26243317

Unexpectedly high pressure for molecular dissociation in liquid hydrogen by electronic simulation.

PubMed

Mazzola, Guglielmo; Yunoki, Seiji; Sorella, Sandro

2014-03-19

The study of the high pressure phase diagram of hydrogen has continued with renewed effort for about one century as it remains a fundamental challenge for experimental and theoretical techniques. Here we employ an efficient molecular dynamics based on the quantum Monte Carlo method, which can describe accurately the electronic correlation and treat a large number of hydrogen atoms, allowing a realistic and reliable prediction of thermodynamic properties. We find that the molecular liquid phase is unexpectedly stable, and the transition towards a fully atomic liquid phase occurs at much higher pressure than previously believed. The old standing problem of low-temperature atomization is, therefore, still far from experimental reach.

Incidence of sudden unexpected death in epilepsy in community-based cohort in China.

PubMed

Ge, Yan; Ding, Ding; Zhang, Qing; Yang, Bin; Wang, Taiping; Li, Beixu; Wang, Jie; Luo, Jianfeng; Kwan, Patrick; Wang, Wenzhi; Hong, Zhen; Sander, Josemir W

2017-11-01

Sudden unexpected death in epilepsy (SUDEP) is associated with the high premature mortality observed among people with epilepsy. It is, however, considered a rare event in China, probably because of lack of awareness and limitation of studies in the country. We aimed to provide some initial estimation of the burden of SUDEP in China. We established a large Chinese community-based cohort of people with epilepsy between January 2010 and December 2011. For any participant who died during follow-up, detailed information on cause of death was obtained using a specifically designed Verbal Autopsy Questionnaire. All cases were reviewed by a multidisciplinary expert panel and reinvestigated if necessary. Sudden unexpected death in epilepsy incidence rates were estimated and case details provided. The cohort consisted of 1562 people and during a median 5years follow-up, 72 deaths were reported. The all-causes death incidence was 11.23 (95% CI 8.86-14.07) per 1000 person-years. Fifteen died suddenly and unexpectedly in a reasonable state of health in the week preceding death. We recorded detailed information of these 15 deaths. Thirteen were considered to be probable SUDEP and two possible SUDEP. The incidence of probable SUDEP was 2.03 (95% CI 1.13-3.38) per 1000 person-years, and the incidence of all suspected (probable and possible) SUDEP was 2.34 (95% CI 1.36-3.77) per 1000 person-years. The incidence of SUDEP was relatively high among Chinese people with epilepsy when compared with that in previous community-based studies from high-income countries. The burden of SUDEP in China requires further assessments. Copyright © 2017 Elsevier Inc. All rights reserved.

Extensive Horizontal Gene Transfer during Staphylococcus aureus Co-colonization In Vivo

PubMed Central

McCarthy, Alex J.; Loeffler, Anette; Witney, Adam A.; Gould, Katherine A.; Lloyd, David H.; Lindsay, Jodi A.

2014-01-01

Staphylococcus aureus is a commensal and major pathogen of humans and animals. Comparative genomics of S. aureus populations suggests that colonization of different host species is associated with carriage of mobile genetic elements (MGE), particularly bacteriophages and plasmids capable of encoding virulence, resistance, and immune evasion pathways. Antimicrobial-resistant S. aureus of livestock are a potential zoonotic threat to human health if they adapt to colonize humans efficiently. We utilized the technique of experimental evolution and co-colonized gnotobiotic piglets with both human- and pig-associated variants of the lineage clonal complex 398, and investigated growth and genetic changes over 16 days using whole genome sequencing. The human isolate survived co-colonization on piglets more efficiently than in vitro. During co-colonization, transfer of MGE from the pig to the human isolate was detected within 4 h. Extensive and repeated transfer of two bacteriophages and three plasmids resulted in colonization with isolates carrying a wide variety of mobilomes. Whole genome sequencing of progeny bacteria revealed no acquisition of core genome polymorphisms, highlighting the importance of MGE. Staphylococcus aureus bacteriophage recombination and integration into novel sites was detected experimentally for the first time. During colonization, clones coexisted and diversified rather than a single variant dominating. Unexpectedly, each piglet carried unique populations of bacterial variants, suggesting limited transmission of bacteria between piglets once colonized. Our data show that horizontal gene transfer occurs at very high frequency in vivo and significantly higher than that detectable in vitro. PMID:25260585

Motor neuron mitochondrial dysfunction in spinal muscular atrophy

PubMed Central

Miller, Nimrod; Shi, Han; Zelikovich, Aaron S.; Ma, Yong-Chao

2016-01-01

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. PMID:27488123

Genetic recombination is directed away from functional genomic elements in mice.

PubMed

Brick, Kevin; Smagulova, Fatima; Khil, Pavel; Camerini-Otero, R Daniel; Petukhova, Galina V

2012-05-13

Genetic recombination occurs during meiosis, the key developmental programme of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyltransferase, PR domain containing 9 (PRDM9), the product of the only known speciation-associated gene in mammals. PRDM9 is thought to determine the preferred recombination sites--recombination hotspots--through sequence-specific binding of its highly polymorphic multi-Zn-finger domain. Nevertheless, Prdm9 knockout mice are proficient at initiating recombination. Here we map and analyse the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F(1) hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the exception of the pseudo-autosomal region (PAR)--the only area of the genome that undergoes recombination in 100% of cells. Surprisingly, hotspots are still observed in Prdm9 knockout mice, and as in wild type, these hotspots are found at H3 lysine 4 (H3K4) trimethylation marks. However, in the absence of PRDM9, most recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice, indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene-promoter regions and other functional genomic elements.

Reclassification of non-type strain Clostridium pasteurianum NRRL B-598 as Clostridium beijerinckii NRRL B-598.

PubMed

Sedlar, Karel; Kolek, Jan; Provaznik, Ivo; Patakova, Petra

2017-02-20

The complete genome sequence of non-type strain Clostridium pasteurianum NRRL B-598 was introduced last year; it is an oxygen tolerant, spore-forming, mesophilic heterofermentative bacterium with high hydrogen production and acetone-butanol fermentation ability. The basic genome statistics have shown its similarity to C. beijerinckii rather than the C. pasteurianum species. Here, we present a comparative analysis of the strain with several other complete clostridial genome sequences. Besides a 16S rRNA gene sequence comparison, digital DNA-DNA hybridization (dDDH) and phylogenomic analysis confirmed an inaccuracy of the taxonomic status of strain Clostridium pasteurianum NRRL B-598. Therefore, we suggest its reclassification to be Clostridium beijerinckii NRRL B-598. This is a specific strain and is not identical to other C. beijerinckii strains. This misclassification explains its unexpected behavior, different from other C. pasteurianum strains; it also permits better understanding of the bacterium for a future genetic manipulation that might increase its biofuel production potential. Copyright © 2017 Elsevier B.V. All rights reserved.

Noncoding origins of anthropoid traits and a new null model of transposon functionalization

PubMed Central

del Rosario, Ricardo C.H.; Rayan, Nirmala Arul

2014-01-01

Little is known about novel genetic elements that drove the emergence of anthropoid primates. We exploited the sequencing of the marmoset genome to identify 23,849 anthropoid-specific constrained (ASC) regions and confirmed their robust functional signatures. Of the ASC base pairs, 99.7% were noncoding, suggesting that novel anthropoid functional elements were overwhelmingly cis-regulatory. ASCs were highly enriched in loci associated with fetal brain development, motor coordination, neurotransmission, and vision, thus providing a large set of candidate elements for exploring the molecular basis of hallmark primate traits. We validated ASC192 as a primate-specific enhancer in proliferative zones of the developing brain. Unexpectedly, transposable elements (TEs) contributed to >56% of ASCs, and almost all TE families showed functional potential similar to that of nonrepetitive DNA. Three L1PA repeat-derived ASCs displayed coherent eye-enhancer function, thus demonstrating that the “gene-battery” model of TE functionalization applies to enhancers in vivo. Our study provides fundamental insights into genome evolution and the origins of anthropoid phenotypes and supports an elegantly simple new null model of TE exaptation. PMID:25043600

RasGRP1 opposes proliferative EGFR–SOS1–Ras signals and restricts intestinal epithelial cell growth

PubMed Central

Depeille, Philippe; Henricks, Linda M.; van de Ven, Robert A. H.; Lemmens, Ed; Wang, Chih-Yang; Matli, Mary; Werb, Zena; Haigis, Kevin M.; Donner, David; Warren, Robert; Roose, Jeroen P.

2015-01-01

The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR–SOS1–Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras–ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR–RasGRP1 and EGFR–SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma. PMID:26005835

ATG5 mediates a positive feedback loop between Wnt signaling and autophagy in melanoma

PubMed Central

Ndoye, Abibatou; Budina-Kolomets, Anna; Kugel, Curtis H.; Webster, Marie; Kaur, Amanpreet; Behera, Reeti; Rebecca, Vito; Li, Ling; Brafford, Patricia; Liu, Qin; Gopal, Y.N. Vashisht; Davies, Michael A.; Mills, Gordon B.; Xu, Xiaowei; Wu, Hong; Herlyn, Meenhard; Nicastri, Michael; Winkler, Jeffrey; Soengas, Maria S.; Amaravadi, Ravi; Murphy, Maureen; Weeraratna, Ashani T.

2017-01-01

Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiological relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. PMID:28887323

Prolonged hypoglycemia after a suicidal ingestion of repaglinide with unexpected slow plasma elimination.

PubMed

Elling, Roland; Spehl, Marco Simon; Wohlfarth, Ariane; Auwaerter, Volker; Hermanns-Clausen, Maren

2016-01-01

Repaglinide is a short-acting insulin secretagogue with high interindividual variability in pharmacokinetics due to genetic polymorphisms. Little is known about repaglinide overdoses, both with respect to pharmacokinetics and appropriate management. Given its short serum half-life of less than 1 h, hypoglycemic effects of repaglinide are expected to cease within a few hours post-ingestion. A 15-year-old girl ingested 10.5 mg of repaglinide in a suicide attempt. Few hours later, she developed a strong food craving, nausea, abdominal pain, and a headache. The lowest recorded serum glucose was 44 mg/dl (2.4 mmol/l) 14 h post-ingestion. Using liquid chromatography-mass spectrometry, we detected repaglinide serum levels of 5.3, 2.6, and 1.0 ng/ml at 14, 20, and 26 h post-ingestion, respectively. This case illustrates that in the context of overdose, repaglinide can lead to prolonged hypoglycemia. We therefore recommend glucose monitoring and observation for 24 h in all patients who remain hypoglycemic or show symptoms of hypoglycemia for an unusually long period of time.

Development of the Large-Scale Oligonucleotide Chip for the Diagnosis of Plant Viruses and its Practical Use

PubMed Central

Nam, Moon; Kim, Jeong-Seon; Lim, Seungmo; Park, Chung Youl; Kim, Jeong-Gyu; Choi, Hong-Soo; Lim, Hyoun-Sub; Moon, Jae Sun; Lee, Su-Heon

2014-01-01

A large-scale oligonucleotide (LSON) chip was developed for the detection of the plant viruses with known genetic information. The LSON chip contains two sets of 3,978 probes for 538 species of targets including plant viruses, satellite RNAs and viroids. A hundred forty thousand probes, consisting of isolate-, species- and genus-specific probes respectively, are designed from 20,000 of independent nucleotide sequence of plant viruses. Based on the economic importance, the amount of genome information, and the number of strains and/or isolates, one to fifty-one probes for each target virus are selected and spotted on the chip. The standard and field samples for the analysis of the LSON chip have been prepared and tested by RT-PCR. The probe’s specific and/or nonspecific reaction patterns by LSON chip allow us to diagnose the unidentified viruses. Thus, the LSON chip in this study could be highly useful for the detection of unexpected plant viruses, the monitoring of emerging viruses and the fluctuation of the population of major viruses in each plant. PMID:25288985

Use of pantothenate as a metabolic switch increases the genetic stability of farnesene producing Saccharomyces cerevisiae.

PubMed

Sandoval, Celeste M; Ayson, Marites; Moss, Nathan; Lieu, Bonny; Jackson, Peter; Gaucher, Sara P; Horning, Tizita; Dahl, Robert H; Denery, Judith R; Abbott, Derek A; Meadows, Adam L

2014-09-01

We observed that removing pantothenate (vitamin B5), a precursor to co-enzyme A, from the growth medium of Saccharomyces cerevisiae engineered to produce β-farnesene reduced the strain׳s farnesene flux by 70%, but increased its viability, growth rate and biomass yield. Conversely, the growth rate and biomass yield of wild-type yeast were reduced. Cultivation in media lacking pantothenate eliminates the growth advantage of low-producing mutants, leading to improved production upon scale-up to lab-scale bioreactor testing. An omics investigation revealed that when exogenous pantothenate levels are limited, acyl-CoA metabolites decrease, β-oxidation decreases from unexpectedly high levels in the farnesene producer, and sterol and fatty acid synthesis likely limits the growth rate of the wild-type strain. Thus pantothenate supplementation can be utilized as a "metabolic switch" for tuning the synthesis rates of molecules relying on CoA intermediates and aid the economic scale-up of strains producing acyl-CoA derived molecules to manufacturing facilities. Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling.

PubMed

Honda, Takuya; Morii, Mariko; Nakayama, Yuji; Suzuki, Ko; Yamaguchi, Noritaka; Yamaguchi, Naoto

2018-01-18

v-Src is the first identified oncogene product and has a strong tyrosine kinase activity. Much of the literature indicates that v-Src expression induces anchorage-independent and infinite cell proliferation through continuous stimulation of growth signaling by v-Src activity. Although all of v-Src-expressing cells are supposed to form transformed colonies, low frequencies of v-Src-induced colony formation have been observed so far. Using cells that exhibit high expression efficiencies of inducible v-Src, we show that v-Src expression causes cell-cycle arrest through p21 up-regulation despite ERK activation. v-Src expression also induces chromosome abnormalities and unexpected suppression of v-Src expression, leading to p21 down-regulation and ERK inactivation. Importantly, among v-Src-suppressed cells, only a limited number of cells gain the ability to re-proliferate and form transformed colonies. Our findings provide the first evidence that v-Src-driven transformation is attributed to chromosome abnormalities, but not continuous stimulation of growth signaling, possibly through stochastic genetic alterations.

Detection of Unexpected High Correlations between Balance Calibration Loads and Load Residuals

NASA Technical Reports Server (NTRS)

Ulbrich, N.; Volden, T.

2014-01-01

An algorithm was developed for the assessment of strain-gage balance calibration data that makes it possible to systematically investigate potential sources of unexpected high correlations between calibration load residuals and applied calibration loads. The algorithm investigates correlations on a load series by load series basis. The linear correlation coefficient is used to quantify the correlations. It is computed for all possible pairs of calibration load residuals and applied calibration loads that can be constructed for the given balance calibration data set. An unexpected high correlation between a load residual and a load is detected if three conditions are met: (i) the absolute value of the correlation coefficient of a residual/load pair exceeds 0.95; (ii) the maximum of the absolute values of the residuals of a load series exceeds 0.25 % of the load capacity; (iii) the load component of the load series is intentionally applied. Data from a baseline calibration of a six-component force balance is used to illustrate the application of the detection algorithm to a real-world data set. This analysis also showed that the detection algorithm can identify load alignment errors as long as repeat load series are contained in the balance calibration data set that do not suffer from load alignment problems.

A molecular phylogenetic study on South Korean Tettigonia species (Orthoptera: Tettigoniidae) using five genetic loci: The possibility of multiple allopatric speciation.

PubMed

Kim, Tae-Kyu; Han, Taeman; Kim, Tae-Woo; Park, In Gyun; Kim, Seonghyun; Park, Haechul

2016-03-15

In Korea, members of the genus Tettigonia have been known as two species, T. ussuriana and T. dolichoptera dolichoptera. However, the taxonomic status of the Jeju Island population of T. ussuriana (JJ-TU) is in question, relative to the mainland population (ML-TU), because of their different body sizes and ratios of wing length. To clarify the relatedness of JJ-TU and ML-TU, we examined the genetic variation and phylogenetic relationships within and between T. ussuriana and related species collected in South Korea, using five genetic loci: three mitochondrial genes (cytochrome c oxidase subunit 1 [CO1], cytochrome c oxidase subunit 2 [CO2], NADH dehydrogenase 1 [ND1]) and two nuclear loci (second internal transcribed spacer [ITS2], and tubulin alpha-1 [TA1]). Unexpectedly, the JJ-TU population is explicitly sister to T. d. dolichoptera, with low genetic distance (0.76-1.22% in CO1), indicating no direct connection with the ML-TU population; this finding suggests a recent divergence involving rapid morphological change without gene flow between JJ-TU and mainland T. d. dolichoptera. The separation of these populations from their common ancestor was caused by geographical isolation during last glacial age. This finding indicates that the JJ-TU population should be elevated to the rank of subspecies, at the very least. Furthermore, the ML-TU population was also revealed to have four genetically divided groups (group A-D) from four localized populations, but no significant morphological differences exist among them. The genetic difference (range 3.19-4.10% in CO1) between group A + B and C + D was especially large, suggesting that cryptic speciation has widely occurred within the mainland areas, caused by allopatric isolations resulting from mountain barriers.

Metabolism, growth, and the energetic definition of fitness: a quantitative genetic study in the land snail Cornu aspersum.

PubMed

Bruning, Andrea; Gaitán-Espitia, Juan Diego; González, Avia; Bartheld, José Luis; Nespolo, Roberto F

2013-01-01

Life-history evolution-the way organisms allocate time and energy to reproduction, survival, and growth-is a central question in evolutionary biology. One of its main tenets, the allocation principle, predicts that selection will reduce energy costs of maintenance in order to divert energy to survival and reproduction. The empirical support for this principle is the existence of a negative relationship between fitness and metabolic rate, which has been observed in some ectotherms. In juvenile animals, a key function affecting fitness is growth rate, since fast growers will reproduce sooner and maximize survival. In principle, design constraints dictate that growth rate cannot be reduced without affecting maintenance costs. Hence, it is predicted that juveniles will show a positive relationship between fitness (growth rate) and metabolic rate, contrarily to what has been observed in adults. Here we explored this problem using land snails (Cornu aspersum). We estimated the additive genetic variance-covariance matrix for growth and standard metabolic rate (SMR; rate of CO2 production) using 34 half-sibling families. We measured eggs, hatchlings, and juveniles in 208 offspring that were isolated right after egg laying (i.e., minimizing maternal and common environmental variance). Surprisingly, our results showed that additive genetic effects (narrow-sense heritabilities, h(2)) and additive genetic correlations (rG) were small and nonsignificant. However, the nonadditive proportion of phenotypic variances and correlations (rC) were unexpectedly large and significant. In fact, nonadditive genetic effects were positive for growth rate and SMR ([Formula: see text]; [Formula: see text]), supporting the idea that fitness (growth rate) cannot be maximized without incurring maintenance costs. Large nonadditive genetic variances could result as a consequence of selection eroding the additive genetic component, which suggests that past selection could have produced nonadditive genetic correlation. It is predicted that this correlation is reduced when adulthood is attained and selection starts to promote the reduction in metabolic rate.

Transfusion associated peak in hb HPLC chromatogram - a case report.

PubMed

Jain, Sonal; Dass, Jasmita; Pati, Hara Prasad

2012-01-01

High performance liquid chromatography (HPLC) and electrophoresis are commonly used to diagnose various hemoglobinopathies. However, insufficient information about the transfusion history can lead to unexpected and confusing results. We are reporting a case of Juvenile myelomonocytic leukemia (JMML) in which HbHPLC was done to quantify fetal hemoglobin (HbF). The chromatogram showed elevated HbF along with a peak in the HbD window. A transfusion acquired peak was suspected based on the unexpectedly low percentage of HbD and was subsequently confirmed using parental HbHPLC.

Transfusion Associated Peak in Hb HPLC Chromatogram – a Case Report

PubMed Central

Jain, Sonal; Dass, Jasmita; Pati, Hara Prasad

2012-01-01

High performance liquid chromatography (HPLC) and electrophoresis are commonly used to diagnose various hemoglobinopathies. However, insufficient information about the transfusion history can lead to unexpected and confusing results. We are reporting a case of Juvenile myelomonocytic leukemia (JMML) in which HbHPLC was done to quantify fetal hemoglobin (HbF). The chromatogram showed elevated HbF along with a peak in the HbD window. A transfusion acquired peak was suspected based on the unexpectedly low percentage of HbD and was subsequently confirmed using parental HbHPLC. PMID:22348188

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

PubMed

Goji, Katsumi; Ozaki, Kayo; Sadewa, Ahmad H; Nishio, Hisahide; Matsuo, Masafumi

2006-02-01

Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

MULTILOCUS SEQUENCE TYPING OF BRUCELLA ISOLATES FROM THAILAND.

PubMed

Chawjiraphan, Wireeya; Sonthayanon, Piengchan; Chanket, Phanita; Benjathummarak, Surachet; Kerdsin, Anusak; Kalambhaheti, Thareerat

2016-11-01

Although brucellosis outbreaks in Thailand are rare, they cause abortions and infertility in animals, resulting in significant economic loss. Because Brucella spp display > 90% DNA homology, multilocus sequence typing (MLST) was employed to categorize local Brucella isolates into sequence types (STs) and to determine their genetic relatedness. Brucella samples were isolated from vaginal secretion of cows and goats, and from blood cultures of infected individuals. Brucella species were determined by multiplex PCR of eight loci, in addition to MLST based on partial DNA sequences of nine house-keeping genes. MLST analysis of 36 isolates revealed 78 distinct novel allele types and 34 novel STs, while two isolates possessed the known ST8. Sequence alignments identified polymorphic sites in each allele, ranging from 2-6%, while overall genetic diversity was 3.6%. MLST analysis of the 36 Brucella isolates classified them into three species, namely, B. melitensis, B. abortus and B. suis, in agreement with multiplex PCR results. Genetic relatedness among ST members of B. melitensis and B. abortus determined by eBURST program revealed ST2 as founder of B. abortus isolates and ST8 the founder of B. melitensis isolates. ST 36, 41 and 50 of Thai Brucella isolates were identified as single locus variants of clonal cluster (CC) 8, while the majority of STs were diverse. The genetic diversity and relatedness identified using MLST revealed hitherto unexpected diversity among Thai Brucella isolates. Genetic classification of isolates could reveal the route of brucellosis transmission among humans and farm animals and also reveal their relationship with other isolates in the region and other parts of the world.

Raman study of CaDNA films as a function of water content and excess CaCl2 concentration: Stability of the B conformation.

NASA Astrophysics Data System (ADS)

Schwenker, Megan; Marlowe, Robert; Lee, Scott; Rupprecht, Allan

2006-03-01

Highly oriented, wet-spun films of CaDNA expand in the direction perpendicular to the helical axis as the hydration of the film is increased. CaDNA films with a high CaCl2 content show an unexpected shrinkage at a relative humidity of about 93%. We have performed Raman experiments on CaDNA films as a function of both water content and excess CaCl2 concentration in order to determine if this unexpected shrinkage might be related to a conformational transition of the DNA molecules. We find that the DNA molecules remain in the B conformation for all salt contents down to a relative humidity of 59%.

Diversity and mineral substrate preference in endolithic microbial communities from marine intertidal outcrops (Isla de Mona, Puerto Rico)

NASA Astrophysics Data System (ADS)

Couradeau, Estelle; Roush, Daniel; Guida, Brandon Scott; Garcia-Pichel, Ferran

2017-01-01

Endolithic microbial communities are prominent features of intertidal marine habitats, where they colonize a variety of substrates, contributing to their erosion. Almost 2 centuries worth of naturalistic studies focused on a few true-boring (euendolithic) phototrophs, but substrate preference has received little attention. The Isla de Mona (Puerto Rico) intertidal zone offers a unique setting to investigate substrate specificity of endolithic communities since various phosphate rock, limestone and dolostone outcrops occur there. High-throughput 16S rDNA genetic sampling, enhanced by targeted cultivation, revealed that, while euendolithic cyanobacteria were dominant operational taxonomic units (OTUs), the communities were invariably of high diversity, well beyond that reported in traditional studies and implying an unexpected metabolic complexity potentially contributed by secondary colonizers. While the overall community composition did not show differences traceable to the nature of the mineral substrate, we detected specialization among particular euendolithic cyanobacterial clades towards the type of substrate they excavate but only at the OTU phylogenetic level, implying that close relatives have specialized recurrently into particular substrates. The cationic mineral component was determinant in this preference, suggesting the existence in nature of alternatives to the boring mechanism described in culture that is based exclusively on transcellular calcium transport.

High and novel genetic diversity of Francisella tularensis in Germany and indication of environmental persistence.

PubMed

Schulze, C; Heuner, K; Myrtennäs, K; Karlsson, E; Jacob, D; Kutzer, P; GROßE, K; Forsman, M; Grunow, R

2016-10-01

In Germany tularemia is a re-emerging zoonotic disease. Therefore, we investigated wild animals and environmental water samples for the presence and phylogenetic diversity of Francisella tularensis in the poorly studied Berlin/Brandenburg region. The phylogenomic analysis of three isolates from wild animals revealed three new subclades within the phylogenetic tree of F. tularensis [B.71 from a raccoon dog (Nyctereutes procyonoides); B.74 from a red fox (Vulpes vulpes), and B.75 from a Eurasian beaver (Castor fiber albicus)]. The results from histological, PCR, and genomic investigations on the dead beaver showed that the animal suffered from a systemic infection. Indications were found that the bacteria were released from the beaver carcass into the surrounding environment. We demonstrated unexpectedly high and novel phylogenetic diversity of F. tularensis in Germany and the fact that the bacteria persist in the environment for at least one climatic season. These findings support a broader host species diversity than previously known regarding Germany. Our data further support the assumption derived from previous serological studies of an underestimated frequency of occurrence of the pathogen in the environment and in wild animals. F. tularensis was isolated from animal species not previously reported as natural hosts in Germany.

The significance of multiple mating in the social wasp Vespula maculifrons.

PubMed

Goodisman, Michael A D; Kovacs, Jennifer L; Hoffman, Eric A

2007-09-01

The evolution of the complex societies displayed by social insects depended partly on high relatedness among interacting group members. Therefore, behaviors that depress group relatedness, such as multiple mating by reproductive females (polyandry), are unexpected in social insects. Nevertheless, the queens of several social insect species mate multiply, suggesting that polyandry provides some benefits that counteract the costs. However, few studies have obtained evidence for links between rates of polyandry and fitness in naturally occurring social insect populations. We investigated if polyandry was beneficial in the social wasp Vespula maculifrons. We used genetic markers to estimate queen mate number in V. maculifrons colonies and assessed colony fitness by counting the number of cells that colonies produced. Our results indicated that queen mate number was directly, strongly, and significantly correlated with the number of queen cells produced by colonies. Because V. maculifrons queens are necessarily reared in queen cells, our results demonstrate that high levels of polyandry are associated with colonies capable of producing many new queens. These data are consistent with the explanation that polyandry is adaptive in V. maculifrons because it provides a fitness advantage to queens. Our research may provide a rare example of an association between polyandry and fitness in a natural social insect population and help explain why queens in this taxon mate multiply.

Hidden diversity within the lizard genus Liolaemus: Genetic vs morphological divergence in the L. rothi complex (Squamata:Liolaeminae).

PubMed

Olave, Melisa; Avila, Luciano J; Sites, Jack W; Morando, Mariana

2017-02-01

Currently, Liolaemus is the second most species-rich reptile genus in the world (257 species), and predictions of its real diversity suggest that it may be the most diverse genus. Originally, Liolaemus species were described as widely distributed and morphologically variable taxa, but extensive sampling in previously unexplored geographic areas, coupled with molecular and more extensive morphological studies, have discovered an unexpectedly high number of previously undetected species. Here, we study the level of molecular vs. morphological divergence within the L. rothi complex, combining a total of 14 loci (2 mitochondrial and 12 nuclear loci) for 97 individuals, as well as morphological data (nine morphometric and 15 color pattern variables), that represent all six described species of the L. rothi complex, plus two candidate species. We use the multi-coalescent species delimitation program iBPP and resolve strong differences in molecular divergence; and each species is inferred as an independent lineage supported by high posterior probabilities. However, morphological differences are not that clear, and our modeling of morphological characters suggests differential selection pressures implying some level of morphological stasis. We discuss the role of natural selection on phenotypic traits, which may be an important factor in "hiding" the real diversity of the genus. Copyright © 2016. Published by Elsevier Inc.

Evidence for montmorillonite or its compositional equivalent in Columbia Hills, Mars

USGS Publications Warehouse

Clark, B. C.; Arvidson, R. E.; Gellert, Ralf; Morris, R.V.; Ming, D. W.; Richter, L.; Ruff, S.W.; Michalski, J.R.; Farrand, W. H.; Yen, A. S.; Herkenhoff, K. E.; Li, R.; Squyres, S. W.; Schroder, C.; Klingelhofer, G.; Bell, J.F.

2007-01-01

During its exploration of the Columbia Hills, the Mars Exploration Rover "Spirit" encountered several similar samples that are distinctly different from Martian meteorites and known Gusev crater soils, rocks, and sediments. Occurring in a variety of contexts and locations, these "Independence class" samples are rough-textured, iron-poor (equivalent FeO ??? 4 wt%), have high Al/Si ratios, and often contain unexpectedly high concentrations of one or more minor or trace elements (including Cr, Ni, Cu, Sr, and Y). Apart from accessory minerals, the major component common to these samples has a compositional profile of major and minor elements which is similar to the smectite montmorillonite, implicating this mineral, or its compositional equivalent. Infrared thermal emission spectra do not indicate the presence of crystalline smectite. One of these samples was found spatially associated with a ferric sulfate-enriched soil horizon, possibly indicating a genetic relationship between these disparate types of materials. Compared to the nearby Wishstone and Watchtower class rocks, major aqueous alteration involving mineral dissolution and mobilization with consequent depletions of certain elements is implied for this setting and may be undetectable by remote sensing from orbit because of the small scale of the occurrences and obscuration by mantling with soil and dust. Copyright 2007 by the American Geophysical Union.

Data Mining and Complex Problems: Case Study in Composite Materials

NASA Technical Reports Server (NTRS)

Rabelo, Luis; Marin, Mario

2009-01-01

Data mining is defined as the discovery of useful, possibly unexpected, patterns and relationships in data using statistical and non-statistical techniques in order to develop schemes for decision and policy making. Data mining can be used to discover the sources and causes of problems in complex systems. In addition, data mining can support simulation strategies by finding the different constants and parameters to be used in the development of simulation models. This paper introduces a framework for data mining and its application to complex problems. To further explain some of the concepts outlined in this paper, the potential application to the NASA Shuttle Reinforced Carbon-Carbon structures and genetic programming is used as an illustration.

Repeat expansion disease: Progress and puzzles in disease pathogenesis

PubMed Central

La Spada, Albert R.; Taylor, J. Paul

2015-01-01

Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, for example, RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade, and has shown that the autophagy pathway plays an important role in the degradation of misfolded proteins – two themes likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalyzing new lines of study that should not only elucidate molecular mechanisms of disease, but also highlight opportunities for therapeutic intervention for these currently untreatable disorders. PMID:20177426

Tailoring communication in cancer genetic counseling through individual video-supported feedback: a controlled pretest-posttest design.

PubMed

Pieterse, Arwen H; van Dulmen, Alexandra M; Beemer, Frits A; Ausems, Margreet G E M; Bensing, Jozien M

2006-03-01

To assess the influence of a 1-day individual video-feedback training for cancer genetic counselors on the interaction during initial visits. Feedback was intended to help counselors make counselees' needs more explicit and increase counselors' sensitivity to these. In total 158 counselees, mainly referred for breast or colon cancer and visiting 1 of 10 counselors, received a pre- and post-visit questionnaire assessing needs (fulfillment). Visits were videotaped, counselor eye gaze was assessed, and verbal communication was analyzed by Roter Interaction Analysis System (RIAS) adapted to the genetic setting. Halfway the study, five counselors were trained. Trained counselors provided more psychosocial information, and with trained counselors emotional consequences of DNA-testing was more often discussed. Counselees seen by a trained counselor considered their need for explanations on (emotional) consequences of counseling as better fulfilled. Unexpectedly, counselees' contribution to the interaction was smaller with trained counselors. Feedback appeared to result in greater emphasis on psychosocial issues, without lengthening the visit. However, counselors did not become more verbally supportive in other ways than by providing information. A 1 day individual training appears effective to some extend; increased opportunities for watching and practicing behavioral alternatives and arranging consolidating sessions may improve training results.

Three clinical experiences with SNP array results consistent with parental incest: a narrative with lessons learned.

PubMed

Helm, Benjamin M; Langley, Katherine; Spangler, Brooke; Vergano, Samantha

2014-08-01

Single nucleotide polymorphism microarrays have the ability to reveal parental consanguinity which may or may not be known to healthcare providers. Consanguinity can have significant implications for the health of patients and for individual and family psychosocial well-being. These results often present ethical and legal dilemmas that can have important ramifications. Unexpected consanguinity can be confounding to healthcare professionals who may be unprepared to handle these results or to communicate them to families or other appropriate representatives. There are few published accounts of experiences with consanguinity and SNP arrays. In this paper we discuss three cases where molecular evidence of parental incest was identified by SNP microarray. We hope to further highlight consanguinity as a potential incidental finding, how the cases were handled by the clinical team, and what resources were found to be most helpful. This paper aims to contribute further to professional discourse on incidental findings with genomic technology and how they were addressed clinically. These experiences may provide some guidance on how others can prepare for these findings and help improve practice. As genetic and genomic testing is utilized more by non-genetics providers, we also hope to inform about the importance of engaging with geneticists and genetic counselors when addressing these findings.

Smooth to Rough Dissociation in Brucella: The Missing Link to Virulence.

PubMed

Mancilla, Marcos

2015-01-01

Dissociation encompasses changes in a series of phenotypes: colony and cell morphology, inmunological and biochemical reactions and virulence. The concept is generally associated to the in vitro transition between smooth (S) and rough (R) colonies, a phenotypic observation in Gram-negative bacteria commonly made since the beginning of microbiology as a science. It is also well known that the loss of the O-polysaccharide, the most external lipopolysaccharide (LPS) moiety, triggers the change in the colony phenotype. Although dissociation is related to one of the most basic features used to distinguish between species, i.e., colony morphology, and, in the case of pathogens, predict their virulence behavior, it has been considered a laboratory artifact and thus did not gain further attention. However, recent insights into genetics and pathogenesis of members of Brucella, causative agents of brucellosis, have brought a new outlook on this experimental fact, suggesting that it plays a role beyond the laboratory observations. In this perspective article, the current knowledge on Brucella LPS genetics and its connection with dissociation in the frame of evolution is discussed. Latest reports support the notion that, by means of a better understanding of genetic pathways linked to R phenotype and the biological impact of this intriguing "old" phenomenon, unexpected applications can be achieved.

Unlocking the Bottleneck in Forward Genetics Using Whole-Genome Sequencing and Identity by Descent to Isolate Causative Mutations

PubMed Central

Siggs, Owen M.; Miosge, Lisa A.; Roots, Carla M.; Enders, Anselm; Bertram, Edward M.; Crockford, Tanya L.; Whittle, Belinda; Potter, Paul K.; Simon, Michelle M.; Mallon, Ann-Marie; Brown, Steve D. M.; Beutler, Bruce; Goodnow, Christopher C.; Lunter, Gerton; Cornall, Richard J.

2013-01-01

Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis. PMID:23382690

Pitfalls of the Geographic Population Structure (GPS) Approach Applied to Human Genetic History: A Case Study of Ashkenazi Jews

PubMed Central

Flegontov, Pavel; Kassian, Alexei; Thomas, Mark G.; Fedchenko, Valentina; Changmai, Piya; Starostin, George

2016-01-01

In a recent interdisciplinary study, Das et al. have attempted to trace the homeland of Ashkenazi Jews and of their historical language, Yiddish (Das et al. 2016. Localizing Ashkenazic Jews to Primeval Villages in the Ancient Iranian Lands of Ashkenaz. Genome Biol Evol. 8:1132–1149). Das et al. applied the geographic population structure (GPS) method to autosomal genotyping data and inferred geographic coordinates of populations supposedly ancestral to Ashkenazi Jews, placing them in Eastern Turkey. They argued that this unexpected genetic result goes against the widely accepted notion of Ashkenazi origin in the Levant, and speculated that Yiddish was originally a Slavic language strongly influenced by Iranian and Turkic languages, and later remodeled completely under Germanic influence. In our view, there are major conceptual problems with both the genetic and linguistic parts of the work. We argue that GPS is a provenancing tool suited to inferring the geographic region where a modern and recently unadmixed genome is most likely to arise, but is hardly suitable for admixed populations and for tracing ancestry up to 1,000 years before present, as its authors have previously claimed. Moreover, all methods of historical linguistics concur that Yiddish is a Germanic language, with no reliable evidence for Slavic, Iranian, or Turkic substrata. PMID:27389685

Smooth to Rough Dissociation in Brucella: The Missing Link to Virulence

PubMed Central

Mancilla, Marcos

2016-01-01

Dissociation encompasses changes in a series of phenotypes: colony and cell morphology, inmunological and biochemical reactions and virulence. The concept is generally associated to the in vitro transition between smooth (S) and rough (R) colonies, a phenotypic observation in Gram-negative bacteria commonly made since the beginning of microbiology as a science. It is also well known that the loss of the O-polysaccharide, the most external lipopolysaccharide (LPS) moiety, triggers the change in the colony phenotype. Although dissociation is related to one of the most basic features used to distinguish between species, i.e., colony morphology, and, in the case of pathogens, predict their virulence behavior, it has been considered a laboratory artifact and thus did not gain further attention. However, recent insights into genetics and pathogenesis of members of Brucella, causative agents of brucellosis, have brought a new outlook on this experimental fact, suggesting that it plays a role beyond the laboratory observations. In this perspective article, the current knowledge on Brucella LPS genetics and its connection with dissociation in the frame of evolution is discussed. Latest reports support the notion that, by means of a better understanding of genetic pathways linked to R phenotype and the biological impact of this intriguing “old” phenomenon, unexpected applications can be achieved. PMID:26779449

Modification of orthogonal tRNAs: unexpected consequences for sense codon reassignment.

PubMed

Biddle, Wil; Schmitt, Margaret A; Fisk, John D

2016-12-01

Breaking the degeneracy of the genetic code via sense codon reassignment has emerged as a way to incorporate multiple copies of multiple non-canonical amino acids into a protein of interest. Here, we report the modification of a normally orthogonal tRNA by a host enzyme and show that this adventitious modification has a direct impact on the activity of the orthogonal tRNA in translation. We observed nearly equal decoding of both histidine codons, CAU and CAC, by an engineered orthogonal M. jannaschii tRNA with an AUG anticodon: tRNA Opt We suspected a modification of the tRNA Opt AUG anticodon was responsible for the anomalous lack of codon discrimination and demonstrate that adenosine 34 of tRNA Opt AUG is converted to inosine. We identified tRNA Opt AUG anticodon loop variants that increase reassignment of the histidine CAU codon, decrease incorporation in response to the histidine CAC codon, and improve cell health and growth profiles. Recognizing tRNA modification as both a potential pitfall and avenue of directed alteration will be important as the field of genetic code engineering continues to infiltrate the genetic codes of diverse organisms. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Rarely reported, widely distributed, and unexpectedly diverse: molecular characterization of mermithid nematodes (Nematoda: Mermithidae) infecting bumble bees (Hymenoptera: Apidae: Bombus) in the USA.

PubMed

Tripodi, Amber D; Strange, James P

2018-03-16

Mermithid nematodes (Nematoda: Mermithida: Mermithidae) parasitize a wide range of both terrestrial and aquatic invertebrate hosts, yet are recorded in bumble bees (Insecta: Hymenoptera: Apidae: Bombus) only six times historically. Little is known about the specific identity of these parasites. In a single-season nationwide survey of internal parasites of 3646 bumble bees, we encountered six additional instances of mermithid parasitism in four bumble bee species and genetically characterized them using two regions of 18S to identify the specific host-parasite relationships. Three samples from the northeastern USA are morphologically and genetically identified as Mermis nigrescens, whereas three specimens collected from a single agricultural locality in the southeast USA fell into a clade with currently undescribed species. Nucleotide sequences of the V2-V6 region of 18S from the southeastern specimens were 2.6-3.0% divergent from one another, and 2.2-4.0% dissimilar to the nearest matches to available data. The dearth of available data prohibits positive identification of this parasite and its affinity for specific bumble bee hosts. By doubling the records of mermithid parasitism of bumble bee hosts and providing genetic data, this work will inform future investigations of this rare phenomenon.

Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones.

PubMed

Mafessoni, Fabrizio; Lachmann, Michael

2015-12-01

In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations. Copyright © 2015 by the Genetics Society of America.

Nonadverse effects on allergenicity of isopentenyltransferase-transformed broccoli.

PubMed

Liao, E C; Chen, J T; Chao, M L; Yu, S C; Chang, C Y; Chu, W S; Tsai, J J

2013-01-01

Genetically modified organisms (GMOs) provide modern agriculture with improvements in efficiency and the benefits of enhanced food production; however, the potential impact of GMOs on human health has not yet been clarified. To investigate the allergenicity of isopentenyltransferase (ipt)-transformed broccoli compared with non-GM broccoli. Sera from allergic individuals were used to identify the allergenicity of GM and non-GM broccoli. Immunoglobulin (Ig) binding of different lines of GM and non-GM broccoli was identified using immunoblotting, enzyme-linked immunosorbent assay, and the histamin release assay. Positive reactions to broccoli (Brassica Oleracea) were observed in 7.02% of individuals. Specific IgE to broccoli and total IgE fro allergic individuals were well correlated. The different tests performed showed no significant differences in the allergenicity of conventionally raised and GM broccoli, indicating the absence of unexpected effects on allergenicity in ipt-transformed plants. Using Western blot analysis we detected heterogeneous IgE-reactive allergenic components in broccoli-allergic sera, but no significant differences between GM an non-GM broccoli were observed in serum from the same patients. Our study demonstrates that there are no differences between GM (ipt-transformed) broccoli and non-GM broccoli, as determined by specific IgE in sera from broccoli-allergic patients. This indicates that there were no unexpected effects on allergenicity in this GM broccoli.

The unexpected but understandable dynamics of mating, paternity and paternal care in the ocellated wrasse

PubMed Central

Alonzo, Suzanne H.; Heckman, Kellie L.

2010-01-01

Although theory generally predicts that males should reduce paternal care in response to cues that predict increased sperm competition and decreased paternity, empirical patterns are equivocal. Some studies have found the predicted decrease in male care with increased sperm competition, while even more studies report no effect of paternity or sperm competition on male care. Here, we report the first example, to our knowledge, of paternal care increasing with the risk and intensity of sperm competition, in the ocellated wrasse (Symphodus ocellatus). Theory also predicts that if paternal care varies and is important to female fitness, female choice among males and male indicators traits of expected paternal care should evolve. Despite a non-random distribution of mating success among nests, we found no evidence for female choice among parental males. Finally, we document the highest published levels of extra-pair paternity for a species with exclusive and obligate male care: genetic paternity analyses revealed cuckoldry at 100 per cent of nests and 28 per cent of all offspring were not sired by the male caring for them. While not predicted by any existing theory, these unexpected reproductive patterns become understandable if we consider how male and female mating and parental care interact simultaneously in this and probably many other species. PMID:19812085

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii

USGS Publications Warehouse

Farias, Margaret E.M.; Atkinson, Carter T.; LaPointe, Dennis A.; Jarvi, Susan I.

2012-01-01

Background: The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. Methods: In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Results: Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. Conclusions: The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition.

Breaking difficult news in a newborn setting: Down syndrome as a paradigm.

PubMed

Dent, Karin M; Carey, John C

2006-08-15

Breaking the difficult news of an unexpected diagnosis to parents in the newborn setting is a common occurrence in genetic counseling. Many clinical geneticists and genetic counselors have had the challenge of delivering a postnatal diagnosis of Down syndrome to parents of newborns. Down syndrome is a common chromosome condition occurring in approximately 1 in 800 live births. Presenting the diagnosis to families must be accomplished in a supportive, positive, caring, and honest manner. However, there are few scientific data and little instruction in training programs on how best to convey this news in an appropriate manner. Several articles in the literature over the last three decades have proposed various guidelines for the so-called informing interview. Discussions of parents' preferences and experiences in receiving this news have also been documented. Few reports, however, have focused on breaking difficult news of the diagnosis of a genetic condition to parents in a newborn setting in the genetics literature. In this paper, we will review the medical literature on delivering difficult news, specifically focused on that regarding the diagnosis of Down syndrome in the newborn setting. We propose a theoretical framework from which the informing interview can be planned and future outcome data can be measured. In this way, researchers of this theme can investigate the process, including the healthcare professionals' delivery of difficult news and make recommendations for continued improvement of the process. Our model can be generalized to breaking difficult news for a variety of other congenital conditions.

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii

PubMed Central

2012-01-01

Background The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. Methods In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Results Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. Conclusions The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition. PMID:22943788

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii.

PubMed

Farias, Margaret E M; Atkinson, Carter T; LaPointe, Dennis A; Jarvi, Susan I

2012-09-03

The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition.

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy.

PubMed

Löscher, Wolfgang; Ferland, Russell J; Ferraro, Thomas N

2017-08-01

It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons

PubMed Central

2017-01-01

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function. SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. PMID:28887386

Anxiety sensitivity and expectation of arousal differentially affect the respiratory response to caffeine.

PubMed

Pané-Farré, Christiane A; Alius, Manuela G; Modeß, Christiane; Methling, Karen; Blumenthal, Terry; Hamm, Alfons O

2015-06-01

This study aimed to test how expectations and anxiety sensitivity influence respiratory and autonomic responses to caffeine. The current study investigated the effects of expected vs. unexpected caffeine ingestion in a group of persons prone to the anxiety-provoking effect of caffeine (high anxiety sensitive persons, that is, persons scoring at least one SD above the mean on the Anxiety Sensitivity Index (Peterson and Reiss 1992)) as compared to low-anxious controls. Autonomic arousal (heart rate, skin conductance level), respiratory responding (expired CO2, minute ventilation), and subjective report were assessed in high and low anxiety sensitive participants immediately after beverage consumption and at absorption peak (30 min post-consumption) in four separate sessions during which either coffee (expectation of caffeine) or bitter lemon soda (no expectation of caffeine) was crossed with 4 mg/kg caffeine vs. no drug. High and low anxiety sensitive persons showed comparable autonomic arousal and symptom reports to caffeine which was modulated by expectation, i.e., greater for coffee. Respiratory responding (CO2 decrease, minute ventilation increase) was more accentuated when caffeine was both expected and administered in the low anxiety sensitive group but more accentuated when caffeine was unexpectedly administered in the high anxiety sensitive group. Autonomic arousal and respiratory effects were observable within a few minutes after caffeine administration and were most pronounced at maximum absorption. The results highlight the modulating role of expectancies in respiratory responding to caffeine in low vs. high anxiety sensitive persons and might have important implications for the better understanding of unexpected panic attacks.

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharkey, Leslie C., E-mail: shark009@umn.edu; Radin, M. Judith, E-mail: radin.1@osu.edu; Heller, Lois, E-mail: lheller@d.umn.edu

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure ormore » mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity. - Highlights: • Late doxorubicin toxicity evaluated in normal, hypertensive, and cardiomyopathic rats. • Hypertension enhances the delayed toxicity of doxorubicin. • Genetic predisposition to cardiomyopathy did not further enhance toxicity. • Epoxyeicosatrienoic acids increased in response to doxorubicin in SHR and SHHF. • Altered leukotriene metabolism may contribute greater toxicity in SHR vs. SHHF rats.« less

Human cancers converge at the HIF-2alpha oncogenic axis.

PubMed

Franovic, Aleksandra; Holterman, Chet E; Payette, Josianne; Lee, Stephen

2009-12-15

Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.

Demographic modelling reveals a history of divergence with gene flow for a glacially tied stonefly in a changing post-Pleistocene landscape

USGS Publications Warehouse

Hotaling, Scott; Muhlfeld, Clint C.; Giersch, J. Joseph; Ali, Omar; Jordan, Steve; Miller, Michael R.; Luikart, Gordon; Weisrock, David W.

2018-01-01

AimClimate warming is causing extensive loss of glaciers in mountainous regions, yet our understanding of how glacial recession influences evolutionary processes and genetic diversity is limited. Linking genetic structure with the influences shaping it can improve understanding of how species respond to environmental change. Here, we used genome-scale data and demographic modelling to resolve the evolutionary history of Lednia tumana, a rare, aquatic insect endemic to alpine streams. We also employed a range of widely used data filtering approaches to quantify how they influenced population structure results.LocationAlpine streams in the Rocky Mountains of Glacier National Park, Montana, USA.TaxonLednia tumana, a stonefly (Order Plecoptera) in the family Nemouridae.MethodsWe generated single nucleotide polymorphism data through restriction-site associated DNA sequencing to assess contemporary patterns of genetic structure for 11 L. tumana populations. Using identified clusters, we assessed demographic history through model selection and parameter estimation in a coalescent framework. During population structure analyses, we filtered our data to assess the influence of singletons, missing data and total number of markers on results.ResultsContemporary patterns of population structure indicate that L. tumana exhibits a pattern of isolation-by-distance among populations within three genetic clusters that align with geography. Mean pairwise genetic differentiation (FST) among populations was 0.033. Coalescent-based demographic modelling supported divergence with gene flow among genetic clusters since the end of the Pleistocene (~13-17 kya), likely reflecting the south-to-north recession of ice sheets that accumulated during the Wisconsin glaciation.Main conclusionsWe identified a link between glacial retreat, evolutionary history and patterns of genetic diversity for a range-restricted stonefly imperiled by climate change. This finding included a history of divergence with gene flow, an unexpected conclusion for a mountaintop species. Beyond L. tumana, this study demonstrates the complexity of assessing genetic structure for weakly differentiated species, shows the degree to which rare alleles and missing data may influence results, and highlights the usefulness of genome-scale data to extend population genetic inquiry in non-model species.

Managing unexpected events in the manufacturing of biologic medicines.

PubMed

Grampp, Gustavo; Ramanan, Sundar

2013-08-01

The manufacturing of biologic medicines (biologics) requires robust process and facility design, rigorous regulatory compliance, and a well-trained workforce. Because of the complex attributes of biologics and their sensitivity to production and handling conditions, manufacturing of these medicines also requires a high-reliability manufacturing organization. As required by regulators, such an organization must monitor the state-of-control for the manufacturing process. A high-reliability organization also invests in an experienced and fully engaged technical support staff and fosters a management culture that rewards in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures. Such a combination of infrastructure, technology, human capital, management, and a science-based operations culture does not occur without a strong organizational and financial commitment. These attributes of a high-reliability biologics manufacturer are difficult to achieve and may be differentiating factors as the supply of biologics diversifies in future years.

On the globality of motor suppression: unexpected events and their influence on behavior and cognition

PubMed Central

Wessel, Jan R.; Aron, Adam R.

2016-01-01

SUMMARY Unexpected events are part of everyday experience. They come in several varieties – action errors, unexpected action outcomes, and unexpected perceptual events – and they lead to motor slowing and cognitive distraction. While different varieties of unexpected events have been studied largely independently, and many different mechanisms are thought to explain their effects on action and cognition, we suggest a unifying theory. We propose that unexpected events recruit a fronto-basal-ganglia network for stopping. This network includes specific prefrontal cortical nodes and is posited to project to the subthalamic nucleus, with a putative global suppressive effect on basal-ganglia output. We argue that unexpected events interrupt action and impact cognition, partly at least, by recruiting this global suppressive network. This provides a common mechanistic basis for different types of unexpected events, links the literatures on motor inhibition, performance-monitoring, attention, and working memory, and is relevant for understanding clinical symptoms of distractibility and mental inflexibility. PMID:28103476

On the Globality of Motor Suppression: Unexpected Events and Their Influence on Behavior and Cognition.

PubMed

Wessel, Jan R; Aron, Adam R

2017-01-18

Unexpected events are part of everyday experience. They come in several varieties-action errors, unexpected action outcomes, and unexpected perceptual events-and they lead to motor slowing and cognitive distraction. While different varieties of unexpected events have been studied largely independently, and many different mechanisms are thought to explain their effects on action and cognition, we suggest a unifying theory. We propose that unexpected events recruit a fronto-basal-ganglia network for stopping. This network includes specific prefrontal cortical nodes and is posited to project to the subthalamic nucleus, with a putative global suppressive effect on basal-ganglia output. We argue that unexpected events interrupt action and impact cognition, partly at least, by recruiting this global suppressive network. This provides a common mechanistic basis for different types of unexpected events; links the literatures on motor inhibition, performance monitoring, attention, and working memory; and is relevant for understanding clinical symptoms of distractibility and mental inflexibility. Copyright © 2017 Elsevier Inc. All rights reserved.

Superconductivity: Technology meets quantum criticality

NASA Astrophysics Data System (ADS)

Zaanen, Jan

2005-09-01

Superconductivity and antiferromagnetism are in fierce competition in high-temperature superconductors. However, this competition has the unexpected benefit that the antiferromagnetism improves the capacity of the superconductor to resist magnetic fields.

Theory of mind for processing unexpected events across contexts.

PubMed

Dungan, James A; Stepanovic, Michael; Young, Liane

2016-08-01

Theory of mind, or mental state reasoning, may be particularly useful for making sense of unexpected events. Here, we investigated unexpected behavior across both social and non-social contexts in order to characterize the precise role of theory of mind in processing unexpected events. We used functional magnetic resonance imaging to examine how people respond to unexpected outcomes when initial expectations were based on (i) an object's prior behavior, (ii) an agent's prior behavior and (iii) an agent's mental states. Consistent with prior work, brain regions for theory of mind were preferentially recruited when people first formed expectations about social agents vs non-social objects. Critically, unexpected vs expected outcomes elicited greater activity in dorsomedial prefrontal cortex, which also discriminated in its spatial pattern of activity between unexpected and expected outcomes for social events. In contrast, social vs non-social events elicited greater activity in precuneus across both expected and unexpected outcomes. Finally, given prior information about an agent's behavior, unexpected vs expected outcomes elicited an especially robust response in right temporoparietal junction, and the magnitude of this difference across participants correlated negatively with autistic-like traits. Together, these findings illuminate the distinct contributions of brain regions for theory of mind for processing unexpected events across contexts. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Unexpected High Digestion Rate of Cooked Starch by the Ct-Maltase-Glucoamylase Small Intestine Mucosal α-Glucosidase Subunit

PubMed Central

Lin, Amy Hui-Mei; Nichols, Buford L.; Quezada-Calvillo, Roberto; Avery, Stephen E.; Sim, Lyann; Rose, David R.; Naim, Hassan Y.; Hamaker, Bruce R.

2012-01-01

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies. PMID:22563462

Unexpected high digestion rate of cooked starch by the Ct-maltase-glucoamylase small intestine mucosal α-glucosidase subunit.

PubMed

Lin, Amy Hui-Mei; Nichols, Buford L; Quezada-Calvillo, Roberto; Avery, Stephen E; Sim, Lyann; Rose, David R; Naim, Hassan Y; Hamaker, Bruce R

2012-01-01

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies.

Species replacement along a linear coastal habitat: phylogeography and speciation in the red alga Mazzaella laminarioides along the south east pacific

PubMed Central

2012-01-01

Background The Chilean shoreline, a nearly strait line of coast expanding across 35 latitudinal degrees, represents an interesting region to assess historical processes using phylogeographic analyses. Stretching along the temperate section of the East Pacific margin, the region is characterized by intense geologic activity and has experienced drastic geomorphological transformations linked to eustatic and isostatic changes during the Quaternary. In this study, we used two molecular markers to evaluate the existence of phylogeographic discontinuities and detect the genetic footprints of Pleistocene glaciations among Patagonian populations of Mazzaella laminarioides, a low-dispersal benthic intertidal red seaweed that inhabits along ~3,700 km of the Chilean coastal rocky shore. Results Three main genetic lineages were found within M. laminarioides. They are distributed along the Chilean coast in strict parapatry. The deep divergence among lineages suggests that they could be considered putative genetic sibling species. Unexpectedly, genetic breaks were not strictly concordant with the biogeographic breaks described in the region. A Northern lineage was restricted to a broad transition zone located between 30°S and 33°S and showed signals of a recent bottleneck. The reduction of population size could be related to warm events linked to El Niño Southern Oscillation, which is known to cause massive seaweed mortality in this region. To the south, we propose that transient habitat discontinuities driven by episodic tectonic uplifting of the shoreline around the Arauco region (37°S-38°S); one of the most active forearc-basins in the South East Pacific; could be at the origin of the Central/South genetic break. The large beaches, located around 38°S, are likely to contribute to the lineages’ integrity by limiting present gene flow. Finally, the Southern lineage, occupies an area affected by ice-cover during the last glaciations. Phylogeny suggested it is a derived clade and demographic analyses showed the lineage has a typical signature of postglacial recolonization from a northern glacial refugium area. Conclusions Even if environmental adaptation could have strengthened divergence among lineages in M. laminarioides, low dispersal capacity and small population size are sufficient to generate phylogeographic discontinuities determined by genetic drift alone. Interestingly, our results confirm that seaweed population connectivity over large geographic scales does not rely only on dispersal capacity but also seem to depend highly on substratum availability and population density of the receiving locality. PMID:22731925

Mapping Genetic Variants Associated with Beta-Adrenergic Responses in Inbred Mice

PubMed Central

Hersch, Micha; Peter, Bastian; Kang, Hyun Min; Schüpfer, Fanny; Abriel, Hugues; Pedrazzini, Thierry; Eskin, Eleazar; Beckmann, Jacques S.

2012-01-01

β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β 1-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10−8). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10−6). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied. PMID:22859963

(Cryptic) sex in the microsporidian Nosema granulosis--evidence from parasite rDNA and host mitochondrial DNA.

PubMed

Krebes, Lukas; Zeidler, Lisza; Frankowski, Jens; Bastrop, Ralf

2014-01-01

Microsporidia are single-celled, intracellular eukaryotes that parasitise a wide range of animals. The Nosema/Vairimorpha group includes some putative asexual species, and asexuality is proposed to have originated multiple times from sexual ancestors. Here, we studied the variation in the ribosomal DNA (rDNA) of 14 isolates of the presumed apomictic and vertically transmitted Nosema granulosis to evaluate its sexual status. The analysed DNA fragment contained a part of the small-subunit ribosomal gene (SSU) and the entire intergenic spacer (IGS). The mitochondrial cox1 gene of the host Gammarus duebeni (Crustacea) was analysed to temporally calibrate the system and to test the expectation of cophylogeny of host and parasite genealogies. Genetic variability of the SSU gene was very low within and between the isolates. In contrast, intraisolate (within a single host) variability of the IGS felt in two categories, because 12 isolates possess a very high IGS genetic diversity and two isolates were almost invariable in the IGS. This difference suggests variable models of rDNA evolution involving birth-and-death and unexpectedly concerted evolution. An alternative explanation could be a likewise unattended mixed infection of host individuals by more than one parasite strain. Despite considerable genetic divergence between associated host mitochondrial haplotypes, some N. granulosis 'IGS populations' seem not to belong to different gene pools; the relevant tests failed to show significant differences between populations. A set of recombinant IGS sequences made our data incompatible with the model of a solely maternally inherited, asexual species. In line with recent reports, our study supports the hypothesis that some assumed apomictic Microsporidia did not entirely abstain from the evolutionary advantages of sex. In addition, the presented data indicate that horizontal transmission may occur occasionally. This transmission mode could be a survival strategy of N. granulosis whose host often populates ephemeral habitats. Copyright © 2013 Elsevier B.V. All rights reserved.

HLA DNA Sequence Variation among Human Populations: Molecular Signatures of Demographic and Selective Events

PubMed Central

Buhler, Stéphane; Sanchez-Mazas, Alicia

2011-01-01

Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC) genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies. Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model). However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used to explore the genetic history of human populations, and that their analysis allows a more thorough investigation of human MHC molecular evolution. PMID:21408106

Long-Distance Travellers: Phylogeography of a Generalist Parasite, Pholeter gastrophilus, from Cetaceans

PubMed Central

Lehnert, Kristina; Raga, Juan Antonio; Siebert, Ursula

2017-01-01

We studied the phylogeography and historical demography of the most generalist digenean from cetaceans, Pholeter gastrophilus, exploring the effects of isolation by distance, ecological barriers and hosts’ dispersal ability on the population structure of this parasite. The ITS2 rDNA, and the mitochondrial COI and ND1 from 68 individual parasites were analysed. Worms were collected from seven oceanic and coastal cetacean species from the south western Atlantic (SWA), central eastern Atlantic, north eastern Atlantic (NEA), and Mediterranean Sea. Pholeter gastrophilus was considered a single lineage because reciprocal monophyly was not detected in the ML cladogram of all individuals, and sequence variability was <1% for mtDNA and 0% for ITS2. These results rule out a recent suggestion that P. gastrophilus would actually be a cryptic-species complex. The genetic cohesion of P. gastrophilus could rely on the extensive exploitation of wide-ranging and highly mobile cetaceans, with a putative secondary role, if any, of intermediate hosts. Unique haplotypes were detected in SWA and NEA, and an AMOVA revealed significant population structure associated to the genetic variation in these regions. The Equator possibly acts as a significant geographical barrier for cetacean movements, possibly limiting gene flow between northern and southern populations of P. gastrophilus. A partial Mantel tests revealed that the significant isolation of NEA populations resulted from geographic clustering. Apparently, the limited mobility of cetaceans used by P. gastrophilus as definitive hosts in this region, coupled with oceanographic barriers and a patchy distribution of potential intermediate hosts could contribute to significant ecological isolation of P. gastrophilus in NEA. Rather unexpectedly, no genetic differentiation was found in the Mediterranean samples of this parasite. Historical demographic analyses suggested a recent population expansion of P. gastrophilus in the Atlantic Ocean, perhaps linked to initial association and subsequent spreading in cetaceans. PMID:28085945

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

PubMed

Ng, Yi Shiau; Grady, John P; Lax, Nichola Z; Bourke, John P; Alston, Charlotte L; Hardy, Steven A; Falkous, Gavin; Schaefer, Andrew G; Radunovic, Aleksandar; Mohiddin, Saidi A; Ralph, Matilda; Alhakim, Ali; Taylor, Robert W; McFarland, Robert; Turnbull, Douglass M; Gorman, Gráinne S

2016-08-21

To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 in 5000. Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the m.3243A>G mutation. Systematic review of cause of death in our m.3243A>G patient cohort showed the person-time incidence rate of sudden adult death is 2.4 per 1000 person-years. A further six cases of sudden death among extended family members have been identified from interrogation of family pedigrees. Our findings suggest that SADS is an important cause of death in patients with m.3243A>G and likely to be due to widespread respiratory chain deficiency in cardiac muscle. The involvement of asymptomatic relatives highlights the importance of family tracing in patients with m.3243A>G and the need for specific cardiac arrhythmia surveillance in the management of this common genetic disease. In addition, these findings have prompted the derivation of cardiac guidelines specific to patients with m.3243A>G-related mitochondrial disease. Finally, due to the prevalence of this mtDNA point mutation, we recommend inclusion of testing for m.3243A>G mutations in the genetic autopsy of all unexplained cases of SADS. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Diverse variation of reproductive barriers in three intraspecific rice crosses.

PubMed Central

Harushima, Yoshiaki; Nakagahra, Masahiro; Yano, Masahiro; Sasaki, Takuji; Kurata, Nori

2002-01-01

Reproductive barriers are thought to play an important role in the processes of speciation and differentiation. Asian rice cultivars, Oryza sativa, can be classified into two main types, Japonica and Indica, on the basis of several characteristics. The fertility of Japonica-Indica hybrids differs from one cross to another. Many genes involved in reproductive barriers (hybrid sterility, hybrid weakness, and gametophytic competition genes) have been reported in different Japonica-Indica crosses. To clarify the state of Japonica-Indica differentiation, all reproductive barriers causing deviation from Mendelian segregation ratios in F(2) populations were mapped and compared among three different Japonica-Indica crosses: Nipponbare/Kasalath (NK), Fl1084/Dao Ren Qiao (FD), and Fl1007/Kinandang puti (FK). Mapping of reproductive barriers was performed by regression analysis of allele frequencies of DNA markers covering the entire genome. Allele frequencies were explained by 33 reproductive barriers (15 gametophytic and 18 zygotic) in NK, 32 barriers (15 gametophytic and 17 zygotic) in FD, and 37 barriers (19 gametophytic and 18 zygotic) in FK. The number of reproductive barriers in the three crosses was similar; however, most of the barriers were mapped at different loci. Therefore, these reproductive barriers formed after Japonica-Indica differentiation. Considering the high genetic similarity within Japonica and Indica cultivars, the differences in the reproductive barriers of each cross were unexpectedly numerous. The reproductive barriers of Japonica-Indica hybrids likely evolved more rapidly than other genetic elements. One possible force responsible for such rapid evolution of the barriers may have been the domestication of rice. PMID:11805066

Genetic profiling to determine potential origins of boll weevils (Coleoptera: Curculionidae) captured in a Texas eradication zone: endemicity, immigration, or sabotage?

PubMed

Kim, Kyung Seok; Sappington, Thomas W; Allen, Charles T

2008-12-01

Thirty-seven boll weevils, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), were captured in pheromone traps near Lubbock, TX, in the Southern High Plains/Caprock eradication zone during August-October 2006. No boll weevils had been captured in this zone or neighboring zones to the north earlier in the year, and only very low numbers had been captured in neighboring zones to the south and east. Therefore, the captures near Lubbock were unexpected. Five of the weevils captured the last week of August were preserved and genotyped at 10 microsatellite loci for comparison with a database of genotypes for 22 boll weevil populations sampled from eight U.S. states and four locations in Mexico. The Lubbock population itself is an unlikely source, suggesting that the captured weevils probably did not originate from a low-level endemic population. Populations from eastern states, Mexico, and Big Spring, TX, can be confidently excluded as potential source regions. Although the Weslaco and Kingsville, TX, areas cannot be statistically excluded, they are unlikely sources. The most likely sources are nearby areas in New Mexico, TX, or southwest Oklahoma, or from areas of eastern Texas represented by Waxahachie and El Campo populations. Together, genetic and circumstantial evidence suggest either that the trapped boll weevils are the offspring of alone mated female that immigrated from eastern Texas earlier in the summer or that weevils originally captured near Waxahachie but now long-dead were planted in the traps by a disgruntled employee of the eradication program.

Extensive horizontal gene transfer during Staphylococcus aureus co-colonization in vivo.

PubMed

McCarthy, Alex J; Loeffler, Anette; Witney, Adam A; Gould, Katherine A; Lloyd, David H; Lindsay, Jodi A

2014-09-25

Staphylococcus aureus is a commensal and major pathogen of humans and animals. Comparative genomics of S. aureus populations suggests that colonization of different host species is associated with carriage of mobile genetic elements (MGE), particularly bacteriophages and plasmids capable of encoding virulence, resistance, and immune evasion pathways. Antimicrobial-resistant S. aureus of livestock are a potential zoonotic threat to human health if they adapt to colonize humans efficiently. We utilized the technique of experimental evolution and co-colonized gnotobiotic piglets with both human- and pig-associated variants of the lineage clonal complex 398, and investigated growth and genetic changes over 16 days using whole genome sequencing. The human isolate survived co-colonization on piglets more efficiently than in vitro. During co-colonization, transfer of MGE from the pig to the human isolate was detected within 4 h. Extensive and repeated transfer of two bacteriophages and three plasmids resulted in colonization with isolates carrying a wide variety of mobilomes. Whole genome sequencing of progeny bacteria revealed no acquisition of core genome polymorphisms, highlighting the importance of MGE. Staphylococcus aureus bacteriophage recombination and integration into novel sites was detected experimentally for the first time. During colonization, clones coexisted and diversified rather than a single variant dominating. Unexpectedly, each piglet carried unique populations of bacterial variants, suggesting limited transmission of bacteria between piglets once colonized. Our data show that horizontal gene transfer occurs at very high frequency in vivo and significantly higher than that detectable in vitro. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

An Outbreak of Respiratory Tularemia Caused by Diverse Clones of Francisella tularensis

PubMed Central

Johansson, Anders; Lärkeryd, Adrian; Widerström, Micael; Mörtberg, Sara; Myrtännäs, Kerstin; Öhrman, Caroline; Birdsell, Dawn; Keim, Paul; Wagner, David M.; Forsman, Mats; Larsson, Pär

2014-01-01

Background. The bacterium Francisella tularensis is recognized for its virulence, infectivity, genetic homogeneity, and potential as a bioterrorism agent. Outbreaks of respiratory tularemia, caused by inhalation of this bacterium, are poorly understood. Such outbreaks are exceedingly rare, and F. tularensis is seldom recovered from clinical specimens. Methods. A localized outbreak of tularemia in Sweden was investigated. Sixty-seven humans contracted laboratory-verified respiratory tularemia. F. tularensis subspecies holarctica was isolated from the blood or pleural fluid of 10 individuals from July to September 2010. Using whole-genome sequencing and analysis of single-nucleotide polymorphisms (SNPs), outbreak isolates were compared with 110 archived global isolates. Results. There were 757 SNPs among the genomes of the 10 outbreak isolates and the 25 most closely related archival isolates (all from Sweden/Finland). Whole genomes of outbreak isolates were >99.9% similar at the nucleotide level and clustered into 3 distinct genetic clades. Unexpectedly, high-sequence similarity grouped some outbreak and archival isolates that originated from patients from different geographic regions and up to 10 years apart. Outbreak and archival genomes frequently differed by only 1–3 of 1 585 229 examined nucleotides. Conclusions. The outbreak was caused by diverse clones of F. tularensis that occurred concomitantly, were widespread, and apparently persisted in the environment. Multiple independent acquisitions of F. tularensis from the environment over a short time period suggest that natural outbreaks of respiratory tularemia are triggered by environmental cues. The findings additionally caution against interpreting genome sequence identity for this pathogen as proof of a direct epidemiological link. PMID:25097081

Linking the potato genome to the conserved ortholog set (COS) markers

PubMed Central

2013-01-01

Background Conserved ortholog set (COS) markers are an important functional genomics resource that has greatly improved orthology detection in Asterid species. A comprehensive list of these markers is available at Sol Genomics Network (http://solgenomics.net/) and many of these have been placed on the genetic maps of a number of solanaceous species. Results We amplified over 300 COS markers from eight potato accessions involving two diploid landraces of Solanum tuberosum Andigenum group (formerly classified as S. goniocalyx, S. phureja), and a dihaploid clone derived from a modern tetraploid cultivar of S. tuberosum and the wild species S. berthaultii, S. chomatophilum, and S. paucissectum. By BLASTn (Basic Local Alignment Search Tool of the NCBI, National Center for Biotechnology Information) algorithm we mapped the DNA sequences of these markers into the potato genome sequence. Additionally, we mapped a subset of these markers genetically in potato and present a comparison between the physical and genetic locations of these markers in potato and in comparison with the genetic location in tomato. We found that most of the COS markers are single-copy in the reference genome of potato and that the genetic location in tomato and physical location in potato sequence are mostly in agreement. However, we did find some COS markers that are present in multiple copies and those that map in unexpected locations. Sequence comparisons between species show that some of these markers may be paralogs. Conclusions The sequence-based physical map becomes helpful in identification of markers for traits of interest thereby reducing the number of markers to be tested for applications like marker assisted selection, diversity, and phylogenetic studies. PMID:23758607

Genetic landscape and deregulated pathways in B-cell lymphoid malignancies.

PubMed

Rosenquist, R; Beà, S; Du, M-Q; Nadel, B; Pan-Hammarström, Q

2017-11-01

With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B-cell receptor/NF-κB pathway, NOTCH signalling, JAK-STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B-cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy-resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Levels of select PCB and PBDE congeners in human post-mortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder

PubMed Central

Mitchell, Michelle M.; Woods, Rima; Chi, Lai-Har; Schmidt, Rebecca J.; Pessah, Isaac N.; Kostyniak, Paul J.; LaSalle, Janine M.

2013-01-01

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) that bioaccumulate in lipid-rich tissues are of concern as developmental neurotoxicants. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental factors implicated in autism-spectrum disorders. The relationship between POP levels and DNA methylation patterns in individuals with and without neurodevelopmental disorders has not been previously investigated. In this study, a total of 107 human frozen post-mortem brain samples were analyzed for 8 PCBs and 7 PBDEs by GC-micro electron capture detector and GC/MS using negative chemical ionization. Human brain samples were grouped as neurotypical controls (n=43), neurodevelopmental disorders with known genetic basis (n=32, including Down, Rett, Prader-Willi, Angelman, and 15q11-q13 duplication syndromes), and autism of unknown etiology (n=32). Unexpectedly, PCB 95 was significantly higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls. Interestingly, samples with detectable PCB 95 levels were almost exclusively those with maternal 15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome. When sorted by birth year, Dup15q samples represented five out of six of genetic neurodevelopmental samples born after the 1976 PCB ban exhibiting detectable PCB 95 levels. Dup15q was the strongest predictor of PCB 95 exposure over age, gender, or year of birth. Dup15q brain showed lower levels of repetitive DNA methylation measured by LINE-1 pyrosequencing, but methylation levels were confounded by year of birth. These results demonstrate a novel paradigm by which specific POPs may predispose to genetic copy number variation of 15q11-q13. PMID:22930557

A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1).

PubMed

Mauri, Nico; Kleiter, Miriam; Leschnik, Michael; Högler, Sandra; Dietschi, Elisabeth; Wiedmer, Michaela; Dietrich, Joëlle; Henke, Diana; Steffen, Frank; Schuller, Simone; Gurtner, Corinne; Stokar-Regenscheit, Nadine; O'Toole, Donal; Bilzer, Thomas; Herden, Christiane; Oevermann, Anna; Jagannathan, Vidhya; Leeb, Tosso

2017-02-09

Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ∼1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10 :c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome. Copyright © 2017 Mauri et al.

Falls Risk and Simulated Driving Performance in Older Adults

PubMed Central

Gaspar, John G.; Neider, Mark B.; Kramer, Arthur F.

2013-01-01

Declines in executive function and dual-task performance have been related to falls in older adults, and recent research suggests that older adults at risk for falls also show impairments on real-world tasks, such as crossing a street. The present study examined whether falls risk was associated with driving performance in a high-fidelity simulator. Participants were classified as high or low falls risk using the Physiological Profile Assessment and completed a number of challenging simulated driving assessments in which they responded quickly to unexpected events. High falls risk drivers had slower response times (~2.1 seconds) to unexpected events compared to low falls risk drivers (~1.7 seconds). Furthermore, when asked to perform a concurrent cognitive task while driving, high falls risk drivers showed greater costs to secondary task performance than did low falls risk drivers, and low falls risk older adults also outperformed high falls risk older adults on a computer-based measure of dual-task performance. Our results suggest that attentional differences between high and low falls risk older adults extend to simulated driving performance. PMID:23509627

Calcium specificity signaling mechanisms in abscisic acid signal transduction in Arabidopsis guard cells

PubMed Central

Brandt, Benjamin; Munemasa, Shintaro; Wang, Cun; Nguyen, Desiree; Yong, Taiming; Yang, Paul G; Poretsky, Elly; Belknap, Thomas F; Waadt, Rainer; Alemán, Fernando; Schroeder, Julian I

2015-01-01

A central question is how specificity in cellular responses to the eukaryotic second messenger Ca2+ is achieved. Plant guard cells, that form stomatal pores for gas exchange, provide a powerful system for in depth investigation of Ca2+-signaling specificity in plants. In intact guard cells, abscisic acid (ABA) enhances (primes) the Ca2+-sensitivity of downstream signaling events that result in activation of S-type anion channels during stomatal closure, providing a specificity mechanism in Ca2+-signaling. However, the underlying genetic and biochemical mechanisms remain unknown. Here we show impairment of ABA signal transduction in stomata of calcium-dependent protein kinase quadruple mutant plants. Interestingly, protein phosphatase 2Cs prevent non-specific Ca2+-signaling. Moreover, we demonstrate an unexpected interdependence of the Ca2+-dependent and Ca2+-independent ABA-signaling branches and the in planta requirement of simultaneous phosphorylation at two key phosphorylation sites in SLAC1. We identify novel mechanisms ensuring specificity and robustness within stomatal Ca2+-signaling on a cellular, genetic, and biochemical level. DOI: http://dx.doi.org/10.7554/eLife.03599.001 PMID:26192964

Can mathematics explain the evolution of human language?

PubMed

Witzany, Guenther

2011-09-01

Investigation into the sequence structure of the genetic code by means of an informatic approach is a real success story. The features of human language are also the object of investigation within the realm of formal language theories. They focus on the common rules of a universal grammar that lies behind all languages and determine generation of syntactic structures. This universal grammar is a depiction of material reality, i.e., the hidden logical order of things and its relations determined by natural laws. Therefore mathematics is viewed not only as an appropriate tool to investigate human language and genetic code structures through computer science-based formal language theory but is itself a depiction of material reality. This confusion between language as a scientific tool to describe observations/experiences within cognitive constructed models and formal language as a direct depiction of material reality occurs not only in current approaches but was the central focus of the philosophy of science debate in the twentieth century, with rather unexpected results. This article recalls these results and their implications for more recent mathematical approaches that also attempt to explain the evolution of human language.

Lost at sea: genetic, oceanographic and meteorological evidence for storm-forced dispersal.

PubMed

Monzón-Argüello, C; Dell'Amico, F; Morinière, P; Marco, A; López-Jurado, L F; Hays, Graeme C; Scott, Rebecca; Marsh, Robert; Lee, Patricia L M

2012-08-07

For many species, there is broad-scale dispersal of juvenile stages and/or long-distance migration of individuals and hence the processes that drive these various wide-ranging movements have important life-history consequences. Sea turtles are one of these paradigmatic long-distance travellers, with hatchlings thought to be dispersed by ocean currents and adults often shuttling between distant breeding and foraging grounds. Here, we use multi-disciplinary oceanographic, atmospheric and genetic mixed stock analyses to show that juvenile turtles are encountered 'downstream' at sites predicted by currents. However, in some cases, unusual occurrences of juveniles are more readily explained by storm events and we show that juvenile turtles may be displaced thousands of kilometres from their expected dispersal based on prevailing ocean currents. As such, storms may be a route by which unexpected areas are encountered by juveniles which may in turn shape adult migrations. Increased stormy weather predicted under climate change scenarios suggests an increasing role of storms in dispersal of sea turtles and other marine groups with life-stages near the ocean surface.

Mouse genetic corneal disease resulting from transgenic insertional mutagenesis

PubMed Central

Ramalho, J S; Gregory-Evans, K; Huxley, C; Seabra, M C

2004-01-01

Background/aims: To report the generation of a new mouse model for a genetically determined corneal abnormality that occurred in transgenesis experiments. Methods: Transgenic mice expressing mutant forms of Rab27a, a GTPase that has been implicated in the pathogenesis of choroideremia, were generated. Results: Only one transgenic line (T27aT15) exhibited an unexpected eye phenotype. T27aT15 mice developed corneal opacities, usually unilateral, and cataracts, resulting in some cases in phthisical eyes. Histologically, the corneal stroma was thickened and vacuolated, and both epithelium and endothelium were thinned. The posterior segment of the eye was also affected with abnormal pigmentation, vessel narrowing, and abnormal leakage of dye upon angiography but was histologically normal. Conclusion: Eye abnormality in T27aT15 mice results from random insertional mutagenesis of the transgene as it was only observed in one line. The corneal lesion observed in T27aT15 mice most closely resembles posterior polymorphous corneal dystrophy and might result from the disruption of the equivalent mouse locus. PMID:14977782

Correction: Calcium specificity signaling mechanisms in abscisic acid signal transduction in Arabidopsis guard cells

DOE PAGES

Brandt, Benjamin; Munemasa, Shintaro; Wang, Cun; ...

2015-07-20

One central question is how specificity in cellular responses to the eukaryotic second messenger Ca 2+ is achieved. Plant guard cells, that form stomatal pores for gas exchange, provide a powerful system for in depth investigation of Ca 2+-signaling specificity in plants. In intact guard cells, abscisic acid (ABA) enhances (primes) the Ca 2+-sensitivity of downstream signaling events that result in activation of S-type anion channels during stomatal closure, providing a specificity mechanism in Ca 2+-signaling. However, the underlying genetic and biochemical mechanisms remain unknown. Here we show impairment of ABA signal transduction in stomata of calcium-dependent protein kinase quadruplemore » mutant plants. Interestingly, protein phosphatase 2Cs prevent non-specific Ca 2+-signaling. Moreover, we demonstrate an unexpected interdependence of the Ca 2+-dependent and Ca 2+-independent ABA-signaling branches and the in planta requirement of simultaneous phosphorylation at two key phosphorylation sites in SLAC1. We identify novel mechanisms ensuring specificity and robustness within stomatal Ca 2+-signaling on a cellular, genetic, and biochemical level.« less

A Forward Genetic Screen in Zebrafish Identifies the G-Protein-Coupled Receptor CaSR as a Modulator of Sensorimotor Decision Making.

PubMed

Jain, Roshan A; Wolman, Marc A; Marsden, Kurt C; Nelson, Jessica C; Shoenhard, Hannah; Echeverry, Fabio A; Szi, Christina; Bell, Hannah; Skinner, Julianne; Cobbs, Emilia N; Sawada, Keisuke; Zamora, Amy D; Pereda, Alberto E; Granato, Michael

2018-05-07

Animals continuously integrate sensory information and select contextually appropriate responses. Here, we show that zebrafish larvae select a behavioral response to acoustic stimuli from a pre-existing choice repertoire in a context-dependent manner. We demonstrate that this sensorimotor choice is modulated by stimulus quality and history, as well as by neuromodulatory systems-all hallmarks of more complex decision making. Moreover, from a genetic screen coupled with whole-genome sequencing, we identified eight mutants with deficits in this sensorimotor choice, including mutants of the vertebrate-specific G-protein-coupled extracellular calcium-sensing receptor (CaSR), whose function in the nervous system is not well understood. We demonstrate that CaSR promotes sensorimotor decision making acutely through Gα i/o and Gα q/11 signaling, modulated by clathrin-mediated endocytosis. Combined, our results identify the first set of genes critical for behavioral choice modulation in a vertebrate and reveal an unexpected critical role for CaSR in sensorimotor decision making. Copyright © 2018 Elsevier Ltd. All rights reserved.

Lost at sea: genetic, oceanographic and meteorological evidence for storm-forced dispersal

PubMed Central

Monzón-Argüello, C.; Dell'Amico, F.; Morinière, P.; Marco, A.; López-Jurado, L. F.; Hays, Graeme C.; Scott, Rebecca; Marsh, Robert; Lee, Patricia L. M.

2012-01-01

For many species, there is broad-scale dispersal of juvenile stages and/or long-distance migration of individuals and hence the processes that drive these various wide-ranging movements have important life-history consequences. Sea turtles are one of these paradigmatic long-distance travellers, with hatchlings thought to be dispersed by ocean currents and adults often shuttling between distant breeding and foraging grounds. Here, we use multi-disciplinary oceanographic, atmospheric and genetic mixed stock analyses to show that juvenile turtles are encountered ‘downstream’ at sites predicted by currents. However, in some cases, unusual occurrences of juveniles are more readily explained by storm events and we show that juvenile turtles may be displaced thousands of kilometres from their expected dispersal based on prevailing ocean currents. As such, storms may be a route by which unexpected areas are encountered by juveniles which may in turn shape adult migrations. Increased stormy weather predicted under climate change scenarios suggests an increasing role of storms in dispersal of sea turtles and other marine groups with life-stages near the ocean surface. PMID:22319111

Neural sex modifies the function of a C. elegans sensory circuit.

PubMed

Lee, Kyunghwa; Portman, Douglas S

2007-11-06

Though sex differences in animal behavior are ubiquitous, their neural and genetic underpinnings remain poorly understood. In particular, the role of functional differences in the neural circuitry that is shared by both sexes has not been extensively investigated. We have addressed these issues with C. elegans olfaction, a simple innate behavior mediated by sexually isomorphic neurons. Though males respond to the same olfactory attractants as do hermaphrodites, we find that each sex has a characteristic repertoire of olfactory preferences. These are not secondary to other sex-specific behaviors and do not require signaling from the gonad. Sex-specific olfactory preferences are controlled by tra-1, the master regulator of C. elegans sexual differentiation. Moreover, the genetic masculinization of neurons in an otherwise wild-type hermaphrodite is sufficient to switch the sexual phenotype of olfactory preference behavior. These studies reveal novel and unexpected sex differences in a C. elegans sensory behavior that is exhibited by both sexes. Our results indicate that these differences are a function of the chromosomally determined sexual identity of shared neural circuitry.

Epigenetics: Beyond Chromatin Modifications and Complex Genetic Regulation1

PubMed Central

Eichten, Steven R.; Schmitz, Robert J.; Springer, Nathan M.

2014-01-01

Chromatin modifications and epigenetics may play important roles in many plant processes, including developmental regulation, responses to environmental stimuli, and local adaptation. Chromatin modifications describe biochemical changes to chromatin state, such as alterations in the specific type or placement of histones, modifications of DNA or histones, or changes in the specific proteins or RNAs that associate with a genomic region. The term epigenetic is often used to describe a variety of unexpected patterns of gene regulation or inheritance. Here, we specifically define epigenetics to include the key aspects of heritability (stable transmission of gene expression states through mitotic or meiotic cell divisions) and independence from DNA sequence changes. We argue against generically equating chromatin and epigenetics; although many examples of epigenetics involve chromatin changes, those chromatin changes are not always heritable or may be influenced by genetic changes. Careful use of the terms chromatin modifications and epigenetics can help separate the biochemical mechanisms of regulation from the inheritance patterns of altered chromatin states. Here, we also highlight examples in which chromatin modifications and epigenetics affect important plant processes. PMID:24872382

The ancient Yakuts: a population genetic enigma

PubMed Central

Keyser, Christine; Hollard, Clémence; Gonzalez, Angela; Fausser, Jean-Luc; Rivals, Eric; Alexeev, Anatoly Nikolayevich; Riberon, Alexandre; Crubézy, Eric; Ludes, Bertrand

2015-01-01

This study is part of an ongoing project aiming at determining the ethnogenesis of an eastern Siberian ethnic group, the Yakuts, on the basis of archaeological excavations carried out over a period of 10 years in three regions of Yakutia: Central Yakutia, the Vilyuy River basin and the Verkhoyansk area. In this study, genetic analyses were carried out on skeletal remains from 130 individuals of unknown ancestry dated mainly from the fifteenth to the nineteenth century AD. Kinship studies were conducted using sets of commercially available autosomal and Y-chromosomal short tandem repeats (STRs) along with hypervariable region I sequences of the mitochondrial DNA. An unexpected and intriguing finding of this work was that the uniparental marker systems did not always corroborate results from autosomal DNA analyses; in some cases, false-positive relationships were observed. These discrepancies revealed that 15 autosomal STR loci are not sufficient to discriminate between first degree relatives and more distantly related individuals in our ancient Yakut sample. The Y-STR analyses led to similar conclusions, because the current Y-STR panels provided the limited resolution of the paternal lineages. PMID:25487336

Correction: Calcium specificity signaling mechanisms in abscisic acid signal transduction in Arabidopsis guard cells

DOE PAGES

Brandt, Benjamin; Munemasa, Shintaro; Wang, Cun; ...

2015-07-29

A central question is how specificity in cellular responses to the eukaryotic second messenger Ca 2+ is achieved. Plant guard cells, that form stomatal pores for gas exchange, provide a powerful system for in depth investigation of Ca 2+-signaling specificity in plants. In intact guard cells, abscisic acid (ABA) enhances (primes) the Ca 2+-sensitivity of downstream signaling events that result in activation of S-type anion channels during stomatal closure, providing a specificity mechanism in Ca 2+-signaling. However, the underlying genetic and biochemical mechanisms remain unknown. Here we show impairment of ABA signal transduction in stomata of calcium-dependent protein kinase quadruplemore » mutant plants. Interestingly, protein phosphatase 2Cs prevent non-specific Ca 2+-signaling. Moreover, we demonstrate an unexpected interdependence of the Ca 2+-dependent and Ca 2+-independent ABA-signaling branches and the in planta requirement of simultaneous phosphorylation at two key phosphorylation sites in SLAC1. We identify novel mechanisms ensuring specificity and robustness within stomatal Ca 2+-signaling on a cellular, genetic, and biochemical level.« less

Atlantic salmon eggs favour sperm in competition that have similar major histocompatibility alleles.

PubMed

Yeates, Sarah E; Einum, Sigurd; Fleming, Ian A; Megens, Hendrik-Jan; Stet, René J M; Hindar, Kjetil; Holt, William V; Van Look, Katrien J W; Gage, Matthew J G

2009-02-07

Polyandry and post-copulatory sexual selection provide opportunities for the evolution of female differential sperm selection. Here, we examined the influence of variation in major histocompatibility (MH) class I allelic composition upon sperm competition dynamics in Atlantic salmon. We ran in vitro fertilization competitions that mimicked the gametic microenvironment, and replicated a paired-male experimental design that allowed us to compare differences in sperm competition success among males when their sperm compete for eggs from females that were genetically either similar or dissimilar at the MH class I locus. Concurrently, we measured variation in spermatozoal traits that are known to influence relative fertilization success under these conditions. Contrary to the findings demonstrating mechanisms that promote MH complex heterozygosity, our results showed that males won significantly greater relative fertilization success when competing for eggs from genetically similar females at the MH class I. This result also showed covariation with the known influences of sperm velocity on relative fertilization success. We discuss these unexpected findings in relation to sperm-egg recognition and hybridization avoidance mechanisms based upon immunogenetic variation.

Transfection of Capsaspora owczarzaki, a close unicellular relative of animals.

PubMed

Parra-Acero, Helena; Ros-Rocher, Núria; Perez-Posada, Alberto; Kożyczkowska, Aleksandra; Sánchez-Pons, Núria; Nakata, Azusa; Suga, Hiroshi; Najle, Sebastián R; Ruiz-Trillo, Iñaki

2018-05-11

How animals emerged from their unicellular ancestor remains a major evolutionary question. New genome data from the closest unicellular relatives of animals has provided important insights into animal origins. We know that the unicellular ancestor of animals had an unexpectedly complex genetic repertoire, including many genes key to animal development and multicellularity. Thus, assessing the function of these genes among unicellular relatives of animals is key to understand how were they co-opted at the onset of Metazoa. However, those analyses have been hampered by the lack of genetic tools. Progress has been made in choanoflagellates and teretosporeans, two of the three lineages closely related to animals, while in filastereans no tools are yet available for functional analysis. Importantly, filastereans possess a striking repertoire of genes involved in transcriptional regulation and other developmental processes. Here, we describe a reliable transfection method for the filasterean Capsaspora owczarzaki We also provide a set of constructs for visualizing subcellular structures in live cells. These tools convert Capsaspora into a unique experimentally tractable organism to address the origin and evolution of animal multicellularity. © 2018. Published by The Company of Biologists Ltd.

Off and back-on again: a tumor suppressor's tale.

PubMed

Acosta, Jonuelle; Wang, Walter; Feldser, David M

2018-06-01

Tumor suppressor genes play critical roles orchestrating anti-cancer programs that are both context dependent and mechanistically diverse. Beyond canonical tumor suppressive programs that control cell division, cell death, and genome stability, unexpected tumor suppressor gene activities that regulate metabolism, immune surveillance, the epigenetic landscape, and others have recently emerged. This diversity underscores the important roles these genes play in maintaining cellular homeostasis to suppress cancer initiation and progression, but also highlights a tremendous challenge in discerning precise context-specific programs of tumor suppression controlled by a given tumor suppressor. Fortunately, the rapid sophistication of genetically engineered mouse models of cancer has begun to shed light on these context-dependent tumor suppressor activities. By using techniques that not only toggle "off" tumor suppressor genes in nascent tumors, but also facilitate the timely restoration of gene function "back-on again" in disease specific contexts, precise mechanisms of tumor suppression can be revealed in an unbiased manner. This review discusses the development and implementation of genetic systems designed to toggle tumor suppressor genes off and back-on again and their potential to uncover the tumor suppressor's tale.

Community structure analysis of rejection sensitive personality profiles: A common neural response to social evaluative threat?

PubMed

Kortink, Elise D; Weeda, Wouter D; Crowley, Michael J; Gunther Moor, Bregtje; van der Molen, Melle J W

2018-06-01

Monitoring social threat is essential for maintaining healthy social relationships, and recent studies suggest a neural alarm system that governs our response to social rejection. Frontal-midline theta (4-8 Hz) oscillatory power might act as a neural correlate of this system by being sensitive to unexpected social rejection. Here, we examined whether frontal-midline theta is modulated by individual differences in personality constructs sensitive to social disconnection. In addition, we examined the sensitivity of feedback-related brain potentials (i.e., the feedback-related negativity and P3) to social feedback. Sixty-five undergraduate female participants (mean age = 19.69 years) participated in the Social Judgment Paradigm, a fictitious peer-evaluation task in which participants provided expectancies about being liked/disliked by peer strangers. Thereafter, they received feedback signaling social acceptance/rejection. A community structure analysis was employed to delineate personality profiles in our data. Results provided evidence of two subgroups: one group scored high on attachment-related anxiety and fear of negative evaluation, whereas the other group scored high on attachment-related avoidance and low on fear of negative evaluation. In both groups, unexpected rejection feedback yielded a significant increase in theta power. The feedback-related negativity was sensitive to unexpected feedback, regardless of valence, and was largest for unexpected rejection feedback. The feedback-related P3 was significantly enhanced in response to expected social acceptance feedback. Together, these findings confirm the sensitivity of frontal midline theta oscillations to the processing of social threat, and suggest that this alleged neural alarm system behaves similarly in individuals that differ in personality constructs relevant to social evaluation.

Comments on "A Closed-Form Solution to Tensor Voting: Theory and Applications".

PubMed

Maggiori, Emmanuel; Lotito, Pablo; Manterola, Hugo Luis; del Fresno, Mariana

2014-12-01

We comment on a paper that describes a closed-form formulation to Tensor Voting, a technique to perceptually group clouds of points, usually applied to infer features in images. The authors proved an analytic solution to the technique, a highly relevant contribution considering that the original formulation required numerical integration, a time-consuming task. Their work constitutes the first closed-form expression for the Tensor Voting framework. In this work we first observe that the proposed formulation leads to unexpected results which do not satisfy the constraints for a Tensor Voting output, hence they cannot be interpreted. Given that the closed-form expression is said to be an analytic equivalent solution, unexpected outputs should not be encountered unless there are flaws in the proof. We analyzed the underlying math to find which were the causes of these unexpected results. In this commentary we show that their proposal does not in fact provide a proper analytic solution to Tensor Voting and we indicate the flaws in the proof.

Polymorphic haplotypes and recombination rates at the LDL receptor gene locus in subjects with and without familial hypercholesterolemia who are from different populations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miserez, A.R.; Chiodetti, N.; Keller, U.

1993-04-01

RFLPs at the low-density lipoprotein (LDL) receptor locus for TaqI, StuI, HincII, AvaII, ApaLI (5[prime] and 3[prime]), PvuII, and NcoI were studied in Swiss and German families with familial hypercholesterolemia (FH). A total of 1,104 LDL receptor alleles were analyzed using Southern blotting and new PCR-based techniques for detection of the TaqI, StuI, HincII, AvaII, NcoI RFLPs. Two hundred fifty-six independent haplotypes from 368 individuals of 61 unrelated Swiss families, as well as 114 independent haplotypes from 184 subjects of 25 unrelated German families, were constructed. In 76 families, clinical diagnosis of FH was confirmed by cosegregation analysis. Of themore » 43 unique haplotypes consisting of seven RFLPs detected in the Swiss and Germans, only 9 were common in both population samples. Analysis of linkage disequilibrium revealed nonrandom associations between several of the investigated RFLPs. ApaLI (5[prime]), NcoI, PvuII, TaqI, and AvaII or HincII were particularly informative. Relative frequencies, heterozygosity indexes, and PICs of the RFLPs from the Swiss and Germans were compared with values calculated from reported haplotype data for Italians, Icelanders, North American Caucasians, South African Caucasians, and Japanese. Pairwise comparisons of population samples by common RFLPs demonstrated unexpected differences even between geographically adjacent populations (e.g., the Swiss and Germans). Furthermore, genetic distances from the Germans to the other Caucasians were larger than to the Japanese. An unexpected lack of correlation between linkage disequilibria and physical distances was detected for the German and Japanese data, possibly because of nonuniform recombination with excessively high rates between exon 13 and intron 15. Hence, the present study revealed a striking variety of polymorphic haplotypes and heterogeneity of RFLP frequencies and recombination rates among the seven population samples. 60 refs., 2 figs., 8 tabs.« less

Effects of anxiety sensitivity and expectations on the modulation of the startle eyeblink response during a caffeine challenge.

PubMed

Benke, Christoph; Blumenthal, Terry D; Modeß, Christiane; Hamm, Alfons O; Pané-Farré, Christiane A

2015-09-01

The way in which the tendency to fear somatic arousal sensations (anxiety sensitivity), in interaction with the created expectations regarding arousal induction, might affect defensive responding to a symptom provocation challenge is not yet understood. The present study investigated the effect of anxiety sensitivity on autonomic arousal, startle eyeblink responses, and reported arousal and alertness to expected vs. unexpected caffeine consumption. To create a match/mismatch of expected and experienced arousal, high and low anxiety sensitive participants received caffeine vs. no drug either mixed in coffee (expectation of arousal induction) or in bitter lemon soda (no expectation of arousal induction) on four separate occasions. Autonomic arousal (heart rate, skin conductance level), respiration (end-tidal CO2, minute ventilation), defensive reflex responses (startle eyeblink), and reported arousal and alertness were recorded prior to, immediately and 30 min after beverage ingestion. Caffeine increased ventilation, autonomic arousal, and startle response magnitudes. Both groups showed comparable levels of autonomic and respiratory responses. The startle eyeblink responses were decreased when caffeine-induced arousal occurred unexpectedly, e.g., after administering caffeine in bitter lemon. This effect was more accentuated in high anxiety sensitive persons. Moreover, in high anxiety sensitive persons, the expectation of arousal (coffee consumption) led to higher subjective alertness when administering caffeine and increased arousal even if no drug was consumed. Unexpected symptom provocation leads to increased attention allocation toward feared arousal sensations in high anxiety sensitive persons. This finding broadens our understanding of modulatory mechanisms in defensive responding to bodily symptoms.

High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death.

PubMed

Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Hall, Kathi; Stein, C Michael

2017-02-01

Studies demonstrating that higher doses of citalopram (> 40 mg) and escitalopram (> 20 mg) prolong the corrected QT interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these selective serotonin reuptake inhibitors (SSRIs) to that for equivalent doses of fluoxetine, paroxetine, and sertraline. The Tennessee Medicaid retrospective cohort study included 54,220 persons 30-74 years of age without cancer or other life-threatening illness who were prescribed high-dose SSRIs from 1998 through 2011. The mean age was 47 years, and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of proarrhythmic effects. The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% CI, 0.40-1.75), 1.24 (95% CI, 0.75-2.05), 0.75 (95% CI, 0.45-1.24), and 1.53 (95% CI, 0.91-2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥ 60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study end point. We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline. © Copyright 2016 Physicians Postgraduate Press, Inc.

High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death

PubMed Central

Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Hall, Kathi; Stein, C. Michael

2018-01-01

Objective Studies demonstrating higher doses of citalopram (>40mg) and escitalopram (>20mg) prolong the QTc interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these SSRIs to that for equivalent doses of fluoxetine, paroxetine, and sertraline. Method The Tennessee Medicaid retrospective cohort study included 54,220 persons 30–74 years of age without cancer or other life-threatening illness prescribed high-dose SSRIs. The mean age was 47 years and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of pro-arrhythmic effects. Results The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% confidence interval [CI], 0.40–1.75), 1.24 (0.75–2.05), 0.75 (0.45–1.24), and 1.53 (0.91–2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study endpoint. Conclusions We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline. PMID:27736049

From neural development to cognition: unexpected roles for chromatin

PubMed Central

Ronan, Jehnna L.; Wu, Wei

2014-01-01

Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have uncovered mutations in many chromatin regulators. These human genetic studies, along with studies in model organisms, are providing insight into chromatin regulatory mechanisms in neural development and how alterations to these mechanisms can cause cognitive deficits, such as intellectual disability. We discuss several implicated chromatin regulators, including BAF (also known as SWI/SNF) and CHD8 chromatin remodellers, HDAC4 and the Polycomb component EZH2. Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains. We speculate on the contribution of these similar mutations to disparate disorders. PMID:23568486

Infectious disease and quality assurance considerations for the transfer of cryopreserved fish gametes

USGS Publications Warehouse

Jenkins, Jill A.; Tiersch, Terrence R.

2011-01-01

Although cryopreservation of sperm has become an accepted technique for selective breeding and genetic improvement in livestock industries, no systematic approach is available for banking germplasm of aquatic species (i.e. embryos, semen and ova). The intent of this chapter is not to provide recommendations for specific measures to eliminate particular pathogens and subsequent diseases, but rather to develop a general framework and strategies for facing the new and unexpected. This chapter presents microbiological and quality assurance concerns for a cryopreservation program. In particular, the chapter identifies organisms transmittable in semen of animals, microorganisms and diseases of importance to aquatic species, pathogen detection issues, methods for prevention and control and how sperm quality can be assessed. 

Mechanosensory Interactions Drive Collective Behaviour in Drosophila

PubMed Central

Ramdya, Pavan; Lichocki, Pawel; Cruchet, Steeve; Frisch, Lukas; Tse, Winnie; Floreano, Dario; Benton, Richard

2014-01-01

Collective behaviour enhances environmental sensing and decision-making in groups of animals1,2. Experimental and theoretical investigations of schooling fish, flocking birds and human crowds have demonstrated that simple interactions between individuals can explain emergent group dynamics3,4. These findings imply the existence of neural circuits that support distributed behaviours, but the molecular and cellular identities of relevant sensory pathways are unknown. Here we show that Drosophila melanogaster exhibits collective responses to an aversive odour: individual flies weakly avoid the stimulus, but groups show enhanced escape reactions. Using high-resolution behavioural tracking, computational simulations, genetic perturbations, neural silencing and optogenetic activation we demonstrate that this collective odour avoidance arises from cascades of appendage touch interactions between pairs of flies. Inter-fly touch sensing and collective behaviour require the activity of distal leg mechanosensory sensilla neurons and the mechanosensory channel NOMPC5,6. Remarkably, through these inter-fly encounters, wild-type flies can elicit avoidance behaviour in mutant animals that cannot sense the odour – a basic form of communication. Our data highlight the unexpected importance of social context in the sensory responses of a solitary species and open the door to a neural circuit level understanding of collective behaviour in animal groups. PMID:25533959

Noncoding origins of anthropoid traits and a new null model of transposon functionalization.

PubMed

del Rosario, Ricardo C H; Rayan, Nirmala Arul; Prabhakar, Shyam

2014-09-01

Little is known about novel genetic elements that drove the emergence of anthropoid primates. We exploited the sequencing of the marmoset genome to identify 23,849 anthropoid-specific constrained (ASC) regions and confirmed their robust functional signatures. Of the ASC base pairs, 99.7% were noncoding, suggesting that novel anthropoid functional elements were overwhelmingly cis-regulatory. ASCs were highly enriched in loci associated with fetal brain development, motor coordination, neurotransmission, and vision, thus providing a large set of candidate elements for exploring the molecular basis of hallmark primate traits. We validated ASC192 as a primate-specific enhancer in proliferative zones of the developing brain. Unexpectedly, transposable elements (TEs) contributed to >56% of ASCs, and almost all TE families showed functional potential similar to that of nonrepetitive DNA. Three L1PA repeat-derived ASCs displayed coherent eye-enhancer function, thus demonstrating that the "gene-battery" model of TE functionalization applies to enhancers in vivo. Our study provides fundamental insights into genome evolution and the origins of anthropoid phenotypes and supports an elegantly simple new null model of TE exaptation. © 2014 del Rosario et al.; Published by Cold Spring Harbor Laboratory Press.

Formation and loss of large, unstable tandem arrays of the piggyBac transposable element in the yellow fever mosquito, Aedes aegypti.

PubMed

Adelman, Zach N; Jasinskiene, Nijole; Vally, K J M; Peek, Corrie; Travanty, Emily A; Olson, Ken E; Brown, Susan E; Stephens, Janice L; Knudson, Dennis L; Coates, Craig J; James, Anthony A

2004-10-01

The Class II transposable element, piggyBac, was used to transform the yellow fever mosquito, Aedes aegypti. In two transformed lines only 15-30% of progeny inherited the transgene, with these individuals displaying mosaic expression of the EGFP marker gene. Southern analyses, gene amplification of genomic DNA, and plasmid rescue experiments provided evidence that these lines contained a high copy number of piggyBac transformation constructs and that much of this DNA consisted of both donor and helper plasmids. A detailed analysis of one line showed that the majority of piggyBac sequences were unit-length donor or helper plasmids arranged in a large tandem array that could be lost en masse in a single generation. Despite the presence of a transposase source and many intact donor elements, no conservative (cut and paste) transposition of piggyBac was observed in these lines. These results reveal one possible outcome of uncontrolled and/or unexpected recombination in this mosquito, and support the conclusion that further investigation is necessary before transposable elements such as piggyBac can be used as genetic drive mechanisms to move pathogen-resistance genes into mosquito populations.

Pediatric Brain Tumors: Genomics and Epigenomics Pave the Way.

PubMed

Fontebasso, Adam M; Jabado, Nada

2015-01-01

Primary malignant brain tumors remain a disproportionate cause of morbidity and mortality in humans. A number of studies exploring the cancer genome of brain tumors across ages using integrated genetics and epigenetics and next-generation sequencing technologies have recently emerged. This has led to considerable advances in the understanding of the basic biology and pathogenesis of brain tumors, including the most malignant and common variants in children: gliomas and medulloblastoma. Notably, studies of pediatric brain tumors have identified unexpected oncogenic pathways implicated in tumorigenesis. These range from a single pathway/molecule defect such as abnormalities of the mitogen-activated protein kinase pathway, considered to be a hallmark of pilocytic astrocytomas, to alterations in the epigenome as a critical component altered in many subgroups of high-grade brain tumors. Importantly, the type, timing, and spatial clustering of these molecular alterations provide a better understanding of the pathogenesis of the respective brain tumor they target and critical markers for therapy that will help refine pathological grading. We summarize these novel findings in pediatric brain tumors, which also are put in the context of the evolving notion of molecular pathology, now a mandated tool for proper classification and therapy assignment in the clinical setting.

Single nucleotide polymorphism analysis reveals heterogeneity within a seedling tree population of a polyembryonic mango cultivar.

PubMed

Winterhagen, Patrick; Wünsche, Jens-Norbert

2016-05-01

Within a polyembryonic mango seedling tree population, the genetic background of individuals should be identical because vigorous plants for cultivation are expected to develop from nucellar embryos representing maternal clones. Due to the fact that the mango cultivar 'Hôi' is assigned to the polyembryonic ecotype, an intra-cultivar variability of ethylene receptor genes was unexpected. Ethylene receptors in plants are conserved, but the number of receptors or receptor isoforms is variable regarding different plant species. However, it is shown here that the ethylene receptor MiETR1 is present in various isoforms within the mango cultivar 'Hôi'. The investigation of single nucleotide polymorphisms revealed that different MiETR1 isoforms can not be discriminated simply by individual single nucleotide exchanges but by the specific arrangement of single nucleotide polymorphisms at certain positions in the exons of MiETR1. Furthermore, an MiETR1 isoform devoid of introns in the genomic sequence was identified. The investigation demonstrates some limitations of high resolution melting and ScreenClust analysis and points out the necessity of sequencing to identify individual isoforms and to determine the variability within the tree population.

Arabidopsis Duodecuple Mutant of PYL ABA Receptors Reveals PYL Repression of ABA-Independent SnRK2 Activity.

PubMed

Zhao, Yang; Zhang, Zhengjing; Gao, Jinghui; Wang, Pengcheng; Hu, Tao; Wang, Zegang; Hou, Yueh-Ju; Wan, Yizhen; Liu, Wenshan; Xie, Shaojun; Lu, Tianjiao; Xue, Liang; Liu, Yajie; Macho, Alberto P; Tao, W Andy; Bressan, Ray A; Zhu, Jian-Kang

2018-06-12

Abscisic acid (ABA) is an important phytohormone controlling responses to abiotic stresses and is sensed by proteins from the PYR/PYL/RCAR family. To explore the genetic contribution of PYLs toward ABA-dependent and ABA-independent processes, we generated and characterized high-order Arabidopsis mutants with mutations in the PYL family. We obtained a pyl quattuordecuple mutant and found that it was severely impaired in growth and failed to produce seeds. Thus, we carried out a detailed characterization of a pyl duodecuple mutant, pyr1pyl1/2/3/4/5/7/8/9/10/11/12. The duodecuple mutant was extremely insensitive to ABA effects on seed germination, seedling growth, stomatal closure, leaf senescence, and gene expression. The activation of SnRK2 protein kinases by ABA was blocked in the duodecuple mutant, but, unexpectedly, osmotic stress activation of SnRK2s was enhanced. Our results demonstrate an important role of basal ABA signaling in growth, senescence, and abscission and reveal that PYLs antagonize ABA-independent activation of SnRK2s by osmotic stress. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Making a big thing of a small cell--recent advances in single cell analysis.

PubMed

Galler, Kerstin; Bräutigam, Katharina; Große, Christina; Popp, Jürgen; Neugebauer, Ute

2014-03-21

Single cell analysis is an emerging field requiring a high level interdisciplinary collaboration to provide detailed insights into the complex organisation, function and heterogeneity of life. This review is addressed to life science researchers as well as researchers developing novel technologies. It covers all aspects of the characterisation of single cells (with a special focus on mammalian cells) from morphology to genetics and different omics-techniques to physiological, mechanical and electrical methods. In recent years, tremendous advances have been achieved in all fields of single cell analysis: (1) improved spatial and temporal resolution of imaging techniques to enable the tracking of single molecule dynamics within single cells; (2) increased throughput to reveal unexpected heterogeneity between different individual cells raising the question what characterizes a cell type and what is just natural biological variation; and (3) emerging multimodal approaches trying to bring together information from complementary techniques paving the way for a deeper understanding of the complexity of biological processes. This review also covers the first successful translations of single cell analysis methods to diagnostic applications in the field of tumour research (especially circulating tumour cells), regenerative medicine, drug discovery and immunology.

ELEMENTAL MERCURY IN COPPER, SILVER, AND GOLD ORES: AN UNEXPECTED CONTRIBUTION TO LAKE SUPERIOR SEDIMENTS WITH GLOBAL IMPLICATIONS

EPA Science Inventory

Mercury and copper inventories are low in central Lake Superior and increase markedly towards the Keweenaw Peninsula...where copper, mercury, and silver inventories are elevated and highly correlated. High copper, silver, and mercury inventories can be traced back to shoreline st...

"It's Being Done": Academic Success in Unexpected Schools

ERIC Educational Resources Information Center

Chenoweth, Karin

2007-01-01

This straightforward and inspiring book takes readers into schools where educators believe--and prove--that all children, even those considered "hard-to-teach," can learn to high standards. Their teachers and principals refuse to write them off and instead show how thoughtful instruction, high expectations, stubborn commitment, and…

Unexpected Events Induce Motor Slowing via a Brain Mechanism for Action-Stopping with Global Suppressive Effects

PubMed Central

Aron, Adam R.

2013-01-01

When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression. PMID:24259571

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians.

PubMed

Scott, William R; Zhang, Weihua; Loh, Marie; Tan, Sian-Tsung; Lehne, Benjamin; Afzal, Uzma; Peralta, Juan; Saxena, Richa; Ralhan, Sarju; Wander, Gurpreet S; Bozaoglu, Kiymet; Sanghera, Dharambir K; Elliott, Paul; Scott, James; Chambers, John C; Kooner, Jaspal S

2016-01-01

South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.

Unexpected effects of different genetic backgrounds on identification of genomic rearrangements via whole-genome next generation sequencing.

PubMed

Chen, Zhangguo; Gowan, Katherine; Leach, Sonia M; Viboolsittiseri, Sawanee S; Mishra, Ameet K; Kadoishi, Tanya; Diener, Katrina; Gao, Bifeng; Jones, Kenneth; Wang, Jing H

2016-10-21

Whole genome next generation sequencing (NGS) is increasingly employed to detect genomic rearrangements in cancer genomes, especially in lymphoid malignancies. We recently established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells. This mouse model spontaneously develops mature B cell lymphomas (termed G1XP lymphomas). Here, we attempt to employ whole genome NGS to identify novel structural rearrangements, in particular inter-chromosomal translocations (CTXs), in these G1XP lymphomas. We sequenced six lymphoma samples, aligned our NGS data with mouse reference genome (in C57BL/6J (B6) background) and identified CTXs using CREST algorithm. Surprisingly, we detected widespread CTXs in both lymphomas and wildtype control samples, majority of which were false positive and attributable to different genetic backgrounds. In addition, we validated our NGS pipeline by sequencing multiple control samples from distinct tissues of different genetic backgrounds of mouse (B6 vs non-B6). Lastly, our studies showed that widespread false positive CTXs can be generated by simply aligning sequences from different genetic backgrounds of mouse. We conclude that mapping and alignment with reference genome might not be a preferred method for analyzing whole-genome NGS data obtained from a genetic background different from reference genome. Given the complex genetic background of different mouse strains or the heterogeneity of cancer genomes in human patients, in order to minimize such systematic artifacts and uncover novel CTXs, a preferred method might be de novo assembly of personalized normal control genome and cancer cell genome, instead of mapping and aligning NGS data to mouse or human reference genome. Thus, our studies have critical impact on the manner of data analysis for cancer genomics.

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians

PubMed Central

Scott, William R.; Zhang, Weihua; Loh, Marie; Tan, Sian-Tsung; Lehne, Benjamin; Afzal, Uzma; Peralta, Juan; Saxena, Richa; Ralhan, Sarju; Wander, Gurpreet S.; Bozaoglu, Kiymet; Sanghera, Dharambir K.; Elliott, Paul; Scott, James; Chambers, John C.; Kooner, Jaspal S.

2016-01-01

South Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans. PMID:27195708

The mechanism and control of DNA transfer by the conjugative relaxase of resistance plasmid pCU1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nash, Rebekah Potts; Habibi, Sohrab; Cheng, Yuan

2010-11-15

Bacteria expand their genetic diversity, spread antibiotic resistance genes, and obtain virulence factors through the highly coordinated process of conjugative plasmid transfer (CPT). A plasmid-encoded relaxase enzyme initiates and terminates CPT by nicking and religating the transferred plasmid in a sequence-specific manner. We solved the 2.3 {angstrom} crystal structure of the relaxase responsible for the spread of the resistance plasmid pCU1 and determined its DNA binding and nicking capabilities. The overall fold of the pCU1 relaxase is similar to that of the F plasmid and plasmid R388 relaxases. However, in the pCU1 structure, the conserved tyrosine residues (Y18,19,26,27) that aremore » required for DNA nicking and religation were displaced up to 14 {angstrom} out of the relaxase active site, revealing a high degree of mobility in this region of the enzyme. In spite of this flexibility, the tyrosines still cleaved the nic site of the plasmid's origin of transfer, and did so in a sequence-specific, metal-dependent manner. Unexpectedly, the pCU1 relaxase lacked the sequence-specific DNA binding previously reported for the homologous F and R388 relaxase enzymes, despite its high sequence and structural similarity with both proteins. In summary, our work outlines novel structural and functional aspects of the relaxase-mediated conjugative transfer of plasmid pCU1.« less

2. GORGE HIGH DAM. UNUSUALLY HIGH WATER IN GORGE LAKE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. GORGE HIGH DAM. UNUSUALLY HIGH WATER IN GORGE LAKE DUE TO THE COMBINATION OF UNIT 24 BEING DOWN FOR REWINDING AND TWO UNITS COMING ON LINE UNEXPECTEDLY AT ROSS POWERHOUSE LED TO WATER FLOWING OVER THE SPILLGATES. EACH GATE IF 47 FEET WIDE AND 50 FEET HIGH, 1989. - Skagit Power Development, Gorge High Dam, On Skagit River, 2.9 miles upstream from Newhalem, Newhalem, Whatcom County, WA

Malaria Evolution in South Asia: Knowledge for Control and Elimination

PubMed Central

Narayanasamy, Krishnamoorthy; Chery, Laura; Basu, Analabha; Duraisingh, Manoj T.; Escalante, Ananias; Fowble, Joseph; Guler, Jennifer L.; Herricks, Thurston; Kumar, Ashwani; Majumder, Partha; Maki, Jennifer; Mascarenhas, Anjali; Rodrigues, Janneth; Roy, Bikram; Sen, Somdutta; Shastri, Jayanthi; Smith, Joseph; Valecha, Neena; White, John; Rathod, Pradipsinh K.

2013-01-01

The study of malaria parasites on the Indian subcontinent should help us understand unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and from Plasmodium vivax infections. The Malaria Evolution in South Asia (MESA) research program is one of ten International Centers of Excellence for Malaria Research (ICEMR) sponsored by the US National Institute of Health. In this second of two reviews, we describe why population structures of Plasmodia in India will be characterized and how we will determine their consequences on disease presentation, outcome and patterns. Specific projects will determine if genetic diversity, possibly driven by parasites with higher genetic plasticity, plays a role in changing epidemiology, pathogenesis, vector competence of parasite populations, and whether innate human genetic traits protect Indians from malaria today. Deep local clinical knowledge of malaria in India will be supplemented by basic scientists who bring new research tools. Such tools will include whole genome sequencing and analysis methods; in vitro assays to measure genome plasticity, RBC cytoadhesion, invasion, and deformability; mosquito infectivity assays to evaluate changing parasite-vector compatibilities; and host genetics to understand protective traits in Indian populations. The MESA-ICEMR study sites span diagonally across India, including a mixture of very urban and rural hospitals, each with very different disease patterns and patient populations. Research partnerships include government-associated research institutes, private medical schools, city and state government hospitals, and hospitals with industry ties. Between 2012-2017, in addition to developing clinical research and basic science infrastructure at new clinical sites, our training workshops will engage new scientists and clinicians throughout South Asia in the malaria research field. PMID:22266213

Multiple origins and incursions of the Atlantic barnacle Chthamalus proteus in the Pacific.

PubMed

Zardus, John D; Hadfield, Michael G

2005-10-01

Chthamalus proteus, a barnacle native to the Caribbean and western Atlantic, was introduced to the Pacific within the last few decades. Using direct sequencing of mitochondrial DNA (COI), we characterized genetic variation in native and introduced populations and searched for genetic matches between regions to determine if there were multiple geographical sources and introduction points for this barnacle. In the native range, we found great genetic differences among populations (max. F(ST) = 0.613) encompassing four lineages: one endemic to Panama, one endemic to Brazil, and two occurring Caribbean-wide. All four lineages were represented in the Pacific, but not equally; the Brazilian lineage was most prevalent and the Panamanian least common. Twenty-one individuals spread among nearly every island from where the barnacle is known in the Pacific, exactly matched six haplotypes scattered among Curaçao, the Netherlands Antilles; St John, US Virgin Islands; Puerto Rico; and Brazil, confirming a multigeographical origin for the Pacific populations. Significant genetic differences were also found in introduced populations from the Hawaiian Islands (F(CT) = 0.043, P < 0.001), indicating introduction events have occurred at more than one locality. However, the sequence, timing and number of arrival events remains unknown. Possible reasons for limited transport of this barnacle through the Panama Canal are discussed. This and a preponderance of Brazilian-type individuals in the Pacific suggest an unexpected route of entry from around Cape Horn, South America. Unification in the Pacific of historically divergent lineages of this barnacle raises the possibility for selection of 'hybrids' with novel ecological adaptations in its new environment.

The use (or misuse) of microsatellite allelic distances in the context of inbreeding and conservation genetics.

PubMed

Hansson, Bengt

2010-03-01

In line with inbreeding theory, genetic diversity at a set of molecular markers may explain variation in fitness-associated traits in partially inbred populations, and such associations will appear as 'genotype-fitness correlations'. An individual genetic diversity index specifically used for microsatellites is 'mean d(2)', i.e. the mean squared distance between alleles. The original hypothesis for mean d(2)-fitness correlations assumes that mean d(2) captures fitness effects at both ends of the inbreeding-outbreeding spectrum. This hypothesis received strong criticism from work showing that even a plain diversity estimate such as multi-locus heterozygosity (MLH) outperforms mean d(2) as a predictor of the inbreeding coefficient and fitness in most realistic situations. Despite this critique, the mean d(2)-approach is still used frequently in ecological and evolutionary research, producing results suggesting that mean d(2) sometimes provides a stronger prediction of fitness than does MLH. In light of the critique, such results are unexpected, but potential explanations for them may exist (at least hypothetically), including scenarios based on close linkage and recent admixture. Nevertheless, a major caveat is that it is very difficult to predict a priori if mean d(2) will improve the genotype-fitness correlation, which in turn makes objective interpretations difficult. Mean d(2)-fitness associations are potentially interesting, but the fact that we cannot easily understand them is problematic and should be thoroughly addressed in each study. Therefore, instead of hastily reached interpretations of mean d(2)-fitness correlations, conclusions need support from complementary analyses, e.g. verifying admixture of genetically structured populations.

Ondine's Curse - Genetic and Iatrogenic Central Hypoventilation as Diagnostic Options in Forensic Medicine.

PubMed

Susło, Robert; Trnka, Jakub; Siewiera, Jacek; Drobnik, Jarosław

2015-01-01

In the Nordic mythology a man lost his ability to breathe without remembering it after he was cursed by water nymph - referred to as 'Ondine's curse' - and then he died as soon as he fell asleep. Family medicine specialists are familiar with many sleeping disorders that their patients commonly call by the term Ondine's Curse. In medical sciences this term is historically related to the group of conditions that have as the common denominator seemingly spontaneous onset of life-threatening hypoventilation. The physiology and genetics specialists focus mainly on congenital central hypoventilation syndrome (CCHS), which was proven to be linked to several genetic mutations. Anesthesiologists tend to be more interested in similarly manifesting iatrogenic condition. Typically, patients that were previously subjected to general anesthesia, after temporarily waking up and regaining the spontaneous respiratory drive, later fall back into unconsciousness and develop hypoventilation. Anesthesiologists also call it Ondine's curse because of the sudden and unexpected sleep onset. The iatrogenic Ondine's curse is proven to be precipitated by delayed anesthetics release from patients' fat tissue - where it was deposited at the time general anesthesia was administered - back into bloodstream. Forensic medicine has to consider the latter form of Ondine's curse called scenario more often, as they investigate sudden deaths related to surgery and general anesthesia in the post-operational care period. These cases may also fall into the category of medical malpractice-related deaths.

Inside ‘Inside View’: reflections on stimulating debate and engagement through a multimedia live theatre production on the dilemmas and issues of pre‐natal screening policy and practice

PubMed Central

Hundt, Gillian Lewando; Bryanston, Claudette; Lowe, Pam; Cross, Saul; Sandall, Jane; Spencer, Kevin

2010-01-01

Abstract Background  The role of applied theatre in engaging both lay and professional publics with debate on health policy and practice is an emergent field. This paper discusses the development, production performance and discussion of ‘Inside View’. 1 Objectives  The objectives were to produce applied theatre from research findings of a completed study on genetic prenatal screening, exploring the dilemmas for women and health professionals of prenatal genetic screening, and to engage audiences in debate and reflection on the dilemmas of prenatal genetic screening. Methods  ‘Inside View’ was developed from a multidisciplinary research study through identification of emergent themes from qualitative interviews, and development of these by the writer, theatre producer and media technologist with input from the researchers. Findings  Inside View was performed in London and the Midlands to varied audiences with a panel discussion and evaluation post performance. The audiences were engaged in debate that was relevant to them professionally and personally. Knowledge translation through applied theatre is an effective tool for engaging the public but the impact subsequently is unclear. There are ethical issues of unexpected disclosure during discussion post performance and the process of transforming research findings into applied theatre requires time and trust within the multidisciplinary team as well as adequate resourcing. PMID:20550593

Pitfalls of the Geographic Population Structure (GPS) Approach Applied to Human Genetic History: A Case Study of Ashkenazi Jews.

PubMed

Flegontov, Pavel; Kassian, Alexei; Thomas, Mark G; Fedchenko, Valentina; Changmai, Piya; Starostin, George

2016-08-16

In a recent interdisciplinary study, Das et al. have attempted to trace the homeland of Ashkenazi Jews and of their historical language, Yiddish (Das et al. 2016 Localizing Ashkenazic Jews to Primeval Villages in the Ancient Iranian Lands of Ashkenaz. Genome Biol Evol. 8:1132-1149). Das et al. applied the geographic population structure (GPS) method to autosomal genotyping data and inferred geographic coordinates of populations supposedly ancestral to Ashkenazi Jews, placing them in Eastern Turkey. They argued that this unexpected genetic result goes against the widely accepted notion of Ashkenazi origin in the Levant, and speculated that Yiddish was originally a Slavic language strongly influenced by Iranian and Turkic languages, and later remodeled completely under Germanic influence. In our view, there are major conceptual problems with both the genetic and linguistic parts of the work. We argue that GPS is a provenancing tool suited to inferring the geographic region where a modern and recently unadmixed genome is most likely to arise, but is hardly suitable for admixed populations and for tracing ancestry up to 1,000 years before present, as its authors have previously claimed. Moreover, all methods of historical linguistics concur that Yiddish is a Germanic language, with no reliable evidence for Slavic, Iranian, or Turkic substrata. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome.

PubMed

Naess, Karin; Freyer, Christoph; Bruhn, Helene; Wibom, Rolf; Malm, Gunilla; Nennesmo, Inger; von Döbeln, Ulrika; Larsson, Nils-Göran

2009-05-01

Leigh syndrome is a common clinical manifestation in children with mitochondrial disease and other types of inborn errors of metabolism. We characterised clinical symptoms, prognosis, respiratory chain function and performed extensive genetic analysis of 25 Swedish children suffering from Leigh syndrome with the aim to obtain insights into the molecular pathophysiology and to provide a rationale for genetic counselling. We reviewed the clinical history of all patients and used muscle biopsies in order to perform molecular, biochemical and genetic investigations, including sequencing the entire mitochondrial DNA (mtDNA), the mitochondrial DNA polymerase (POLGA) gene and the surfeit locus protein 1 (SURF1) gene. Respiratory chain enzyme activity measurements identified five patients with isolated complex I deficiency and five with combined enzyme deficiencies. No patient presented with isolated complex IV deficiency. Seven patients had a decreased ATP production rate. Extensive sequence analysis identified eight patients with pathogenic mtDNA mutations and one patient with mutations in POLGA. Mutations of mtDNA are a common cause of LS and mtDNA analysis should always be included in the diagnosis of LS patients, whereas SURF1 mutations are not a common cause of LS in Sweden. Unexpectedly, age of onset, clinical symptoms and prognosis did not reveal any clear differences in LS patients with mtDNA or nuclear DNA mutations.

Do Viruses Exchange Genes across Superkingdoms of Life?

PubMed

Malik, Shahana S; Azem-E-Zahra, Syeda; Kim, Kyung Mo; Caetano-Anollés, Gustavo; Nasir, Arshan

2017-01-01

Viruses can be classified into archaeoviruses, bacterioviruses, and eukaryoviruses according to the taxonomy of the infected host. The host-constrained perception of viruses implies preference of genetic exchange between viruses and cellular organisms of their host superkingdoms and viral origins from host cells either via escape or reduction. However, viruses frequently establish non-lytic interactions with organisms and endogenize into the genomes of bacterial endosymbionts that reside in eukaryotic cells. Such interactions create opportunities for genetic exchange between viruses and organisms of non-host superkingdoms. Here, we take an atypical approach to revisit virus-cell interactions by first identifying protein fold structures in the proteomes of archaeoviruses, bacterioviruses, and eukaryoviruses and second by tracing their spread in the proteomes of superkingdoms Archaea, Bacteria, and Eukarya. The exercise quantified protein structural homologies between viruses and organisms of their host and non-host superkingdoms and revealed likely candidates for virus-to-cell and cell-to-virus gene transfers. Unexpected lifestyle-driven genetic affiliations between bacterioviruses and Eukarya and eukaryoviruses and Bacteria were also predicted in addition to a large cohort of protein folds that were universally shared by viral and cellular proteomes and virus-specific protein folds not detected in cellular proteomes. These protein folds provide unique insights into viral origins and evolution that are generally difficult to recover with traditional sequence alignment-dependent evolutionary analyses owing to the fast mutation rates of viral gene sequences.

C. elegans STRADalpha and SAD cooperatively regulate neuronal polarity and synaptic organization.

PubMed

Kim, Joanne S M; Hung, Wesley; Narbonne, Patrick; Roy, Richard; Zhen, Mei

2010-01-01

Neurons are polarized cells with morphologically and functionally distinct axons and dendrites. The SAD kinases are crucial for establishing the axon-dendrite identity across species. Previous studies suggest that a tumour suppressor kinase, LKB1, in the presence of a pseudokinase, STRADalpha, initiates axonal differentiation and growth through activating the SAD kinases in vertebrate neurons. STRADalpha was implicated in the localization, stabilization and activation of LKB1 in various cell culture studies. Its in vivo functions, however, have not been examined. In our present study, we analyzed the neuronal phenotypes of the first loss-of-function mutants for STRADalpha and examined their genetic interactions with LKB1 and SAD in C. elegans. Unexpectedly, only the C. elegans STRADalpha, STRD-1, functions exclusively through the SAD kinase, SAD-1, to regulate neuronal polarity and synaptic organization. Moreover, STRD-1 tightly associates with SAD-1 to coordinate its synaptic localizations. By contrast, the C. elegans LKB1, PAR-4, also functions in an additional genetic pathway independently of SAD-1 and STRD-1 to regulate neuronal polarity. We propose that STRD-1 establishes neuronal polarity and organizes synaptic proteins in a complex with the SAD-1 kinase. Our findings suggest that instead of a single, linear genetic pathway, STRADalpha and LKB1 regulate neuronal development through multiple effectors that are shared in some cellular contexts but distinct in others.

Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease

PubMed Central

Paulsson, Kajsa; Cazier, Jean-Baptiste; MacDougall, Finlay; Stevens, Jane; Stasevich, Irina; Vrcelj, Nikoletta; Chaplin, Tracy; Lillington, Debra M.; Lister, T. Andrew; Young, Bryan D.

2008-01-01

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. PMID:18458336

Conflict and cooperation over sex: the consequences of social and genetic polyandry for reproductive success in dunnocks.

PubMed

Santos, Eduardo S A; Santos, Luana L S; Lagisz, Malgorzata; Nakagawa, Shinichi

2015-11-01

Conflict and cooperation within and between the sexes are among the driving forces that lead to the evolution of mating systems. Among mating strategies, female genetic polyandry and male reproductive cooperation pose challenging evolutionary questions regarding the maintenance of systems where one sex suffers from reduced fitness. Here, we investigate the consequences of social and genetic polyandry for reproductive success of females and males in a population of the dunnock, Prunella modularis. We show that female multiple mating ameliorates the negative effects of inbreeding. We, however, found little evidence that females engage in extra-group (pair) mating with less related or more heterozygous males. Breeding in socially polyandrous groups reduced the amount of paternity lost to extra-group males, such that, on average, cobreeding and monogamous males fledged a similar number of young. Importantly, c. 30% of cobreeding male dyads were related, suggesting they could gain indirect fitness benefits. Taken together, cobreeding males achieve equivalent reproductive success to monogamous counterparts under most circumstances. Our study has revealed unexpected complexities in the variable mating system of dunnocks in New Zealand. Our results differ from the well-known Cambridge dunnock study and can help our understanding of the evolution and maintenance of various breeding systems in the animal kingdom. © 2015 The Authors. Journal of Animal Ecology © 2015 British Ecological Society.

A theoretical quantitative genetic study of negative ecological interactions and extinction times in changing environments.

PubMed

Jones, Adam G

2008-04-25

Rapid human-induced changes in the environment at local, regional and global scales appear to be contributing to population declines and extinctions, resulting in an unprecedented biodiversity crisis. Although in the short term populations can respond ecologically to environmental alterations, in the face of persistent change populations must evolve or become extinct. Existing models of evolution and extinction in changing environments focus only on single species, even though the dynamics of extinction almost certainly depend upon the nature of species interactions. Here, I use a model of quantitative trait evolution in a two-species community to show that negative ecological interactions, such as predation and competition, can produce unexpected results regarding time to extinction. Under some circumstances, negative interactions can be expected to hasten the extinction of species declining in numbers. However, under other circumstances, negative interactions can actually increase times to extinction. This effect occurs across a wide range of parameter values and can be substantial, in some cases allowing a population to persist for 40 percent longer than it would in the absence of the species interaction. This theoretical study indicates that negative species interactions can have unexpected positive effects on times to extinction. Consequently, detailed studies of selection and demographics will be necessary to predict the consequences of species interactions in changing environments for any particular ecological community.

Rickets: case series and diagnostic review of hypovitaminosis D in swine.

PubMed

Madson, Darin M; Ensley, Steve M; Gauger, Phil C; Schwartz, Kent J; Stevenson, Greg W; Cooper, Vickie L; Janke, Bruce H; Burrough, Eric R; Goff, Jesse P; Horst, Ronald L

2012-11-01

Rickets can be attributed to nutritional, genetic, hormonal, or toxic disturbances and is classified as a metabolic bone disease. Rickets is most often associated with inappropriate dietary levels of calcium, phosphorus, and/or vitamin D. During a 27-month period (January 2010 through March 2012), the Iowa State University Veterinary Diagnostic Laboratory investigated causes of sudden, unexpected death and lameness in growing pigs throughout the Midwestern United States. Clinical observations from 17 growing pig cases included weakness, lameness, reluctance to move, muscle fasciculations and/or tremors, tetany, and death. Ribs were weak, soft, and bent prior to breaking; rachitic lesions were apparent at costochondral junctions in multiple cases. Acute and/or chronic bone fractures were also noted in multiple bones. Failure of endochondral ossification, expanded physes, infractions, thin trabeculae, and increased osteoclasts were noted microscopically. Decreased bone ash and serum 25(OH)D(3), combined with clinical and microscopic evaluation, confirmed a diagnosis of vitamin D-dependent rickets in all cases. In 3 cases, disease was linked to a specific nutrient supplier that ultimately resulted in a voluntary feed recall; however, most cases in the current investigation were not associated with a particular feed company. The present report describes vitamin D-associated rickets and its importance as a potential cause of weakness, lameness, muscle fasciculations, recumbency or sudden unexpected death in swine, and describes appropriate samples and tests for disease diagnosis.

Genomic and Physiological Characterization of the Chromate-Reducing, Aquifer-Derived Firmicute Pelosinus sp. Strain HCF1

PubMed Central

Han, Ruyang; Karaoz, Ulas; Lim, HsiaoChien; Brodie, Eoin L.

2013-01-01

Pelosinus spp. are fermentative firmicutes that were recently reported to be prominent members of microbial communities at contaminated subsurface sites in multiple locations. Here we report metabolic characteristics and their putative genetic basis in Pelosinus sp. strain HCF1, an isolate that predominated anaerobic, Cr(VI)-reducing columns constructed with aquifer sediment. Strain HCF1 ferments lactate to propionate and acetate (the methylmalonyl-coenzyme A [CoA] pathway was identified in the genome), and its genome encodes two [NiFe]- and four [FeFe]-hydrogenases for H2 cycling. The reduction of Cr(VI) and Fe(III) may be catalyzed by a flavoprotein with 42 to 51% sequence identity to both ChrR and FerB. This bacterium has unexpected capabilities and gene content associated with reduction of nitrogen oxides, including dissimilatory reduction of nitrate to ammonium (two copies of NrfH and NrfA were identified along with NarGHI) and a nitric oxide reductase (NorCB). In this strain, either H2 or lactate can act as a sole electron donor for nitrate, Cr(VI), and Fe(III) reduction. Transcriptional studies demonstrated differential expression of hydrogenases and nitrate and nitrite reductases. Overall, the unexpected metabolic capabilities and gene content reported here broaden our perspective on what biogeochemical and ecological roles this species might play as a prominent member of microbial communities in subsurface environments. PMID:23064329

Three Dimensional Structure of the MqsR:MqsA Complex: A Novel TA Pair Comprised of a Toxin Homologous to RelE and an Antitoxin with Unique Properties

PubMed Central

Kim, Younghoon; Arruda, Jennifer M.; Davenport, Andrew; Wood, Thomas K.; Peti, Wolfgang; Page, Rebecca

2009-01-01

One mechanism by which bacteria survive environmental stress is through the formation of bacterial persisters, a sub-population of genetically identical quiescent cells that exhibit multidrug tolerance and are highly enriched in bacterial toxins. Recently, the Escherichia coli gene mqsR (b3022) was identified as the gene most highly upregulated in persisters. Here, we report multiple individual and complex three-dimensional structures of MqsR and its antitoxin MqsA (B3021), which reveal that MqsR:MqsA form a novel toxin:antitoxin (TA) pair. MqsR adopts an α/β fold that is homologous with the RelE/YoeB family of bacterial ribonuclease toxins. MqsA is an elongated dimer that neutralizes MqsR toxicity. As expected for a TA pair, MqsA binds its own promoter. Unexpectedly, it also binds the promoters of genes important for E. coli physiology (e.g., mcbR, spy). Unlike canonical antitoxins, MqsA is also structured throughout its entire sequence, binds zinc and coordinates DNA via its C- and not N-terminal domain. These studies reveal that TA systems, especially the antitoxins, are significantly more diverse than previously recognized and provide new insights into the role of toxins in maintaining the persister state. PMID:20041169

Transporters, channels, or simple diffusion? Dogmas, atypical roles and complexity in transport systems.

PubMed

Conde, Artur; Diallinas, George; Chaumont, François; Chaves, Manuela; Gerós, Hernâni

2010-06-01

The recent breakthrough discoveries of transport systems assigned with atypical functions provide evidence for complexity in membrane transport biochemistry. Some channels are far from being simple pores creating hydrophilic passages for solutes and can, unexpectedly, act as enzymes, or mediate high-affinity uptake, and some transporters are surprisingly able to function as sensors, channels or even enzymes. Furthermore, numerous transport studies have demonstrated complex multiphasic uptake kinetics for organic and mineral nutrients. The biphasic kinetics of glucose uptake in Saccharomyces cerevisiae, a result of several genetically distinct uptake systems operating simultaneously, is a classical example that is a subject of continuous debate. In contrast, some transporters display biphasic kinetics, being bona fidae dual-affinity transporters, their kinetic properties often modulated by post-translational regulation. Also, aquaporins have recently been reported to exhibit diverse transport properties and can behave as highly adapted, multifunctional channels, transporting solutes such as CO(2), hydrogen peroxide, urea, ammonia, glycerol, polyols, carbamides, purines and pyrimidines, metalloids, glycine, and lactic acid, rather than being simple water pores. The present review provides an overview on some atypical functions displayed by transporter proteins and discusses how this novel knowledge on cellular uptake systems may be related to complex multiphasic uptake kinetics often seen in a wide variety of living organisms and the intriguing diffusive uptake of sugars and other solutes. Copyright 2009 Elsevier Ltd. All rights reserved.

AFM combined to ATR-FTIR reveals Candida cell wall changes under caspofungin treatment.

PubMed

Quilès, Fabienne; Accoceberry, Isabelle; Couzigou, Célia; Francius, Grégory; Noël, Thierry; El-Kirat-Chatel, Sofiane

2017-09-21

Fungal pathogens from Candida genus are responsible for severe life-threatening infections and the antifungal arsenal is still limited. Caspofungin, an antifungal drug used for human therapy, acts as a blocking agent of the cell wall synthesis by inhibiting the β-1,3-glucan-synthase encoded by FKS genes. Despite its efficiency, the number of genetic mutants that are resistant to caspofungin is increasing. An important challenge to improve antifungal therapy is to understand cellular phenomenon that are associated with drug resistance. Here we used atomic force microscopy (AFM) combined to Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR) to decipher the effect of low and high drug concentration on the morphology, mechanics and cell wall composition of two Candida strains, one susceptible and one resistant to caspofungin. Our results confirm that caspofungin induces a dramatic cell wall remodelling via activation of stress responses, even at high drug concentration. Additionally, we highlighted unexpected changes related to drug resistance, suggesting that caspofungin resistance associated with FKS gene mutations comes from a combination of effects: (i) an overall remodelling of yeast cell wall composition; and (ii) cell wall stiffening through chitin synthesis. This work demonstrates that AFM combined to ATR-FTIR is a valuable approach to understand at the molecular scale the biological mechanisms associated with drug resistance.

Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy.

PubMed

Roncarati, Roberta; Latronico, Michael V G; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

2011-11-01

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. Copyright © 2011 Wiley-Liss, Inc.

Role of housing modalities on management and surveillance strategies for adventitious agents of rodents.

PubMed

Shek, William R

2008-01-01

Specific pathogen-free (SPF) rodents for modern biomedical research need to be free of pathogens and other infectious agents that may not produce disease but nevertheless cause research interference. To meet this need, rodents have been rederived to eliminate adventitious agents and then housed in room- to cage-level barrier systems to exclude microbial contaminants. Because barriers can and do fail, routine health monitoring (HM) is necessary to verify the SPF status of colonies. Testing without strict adherence to biosecurity practices, however, can lead to the inadvertent transfer of unrecognized, inapparent agents among institutions and colonies. Microisolation caging systems have become popular for housing SPF rodents because they are versatile and provide a highly effective cage-level barrier to the entry and spread of adventitious agents. But when a microisolation-caged colony is contaminated, the cage-level barrier impedes the spread of infection and so the prevalence of infection is often low, which increases the chance of missing a contamination and complicates the corroboration of unexpected positive findings. The expanding production of genetically engineered mutant (GEM) rodent strains at research institutions, where biosecurity practices vary and the risk of microbial contamination can be high, underscores the importance of accurate HM results in mitigating the risk of the introduction and spread of microbial contaminants with the exchange of mutant rodent strains among investigators and institutions.

Female social preference for males that have evolved via monogamy: evidence of a trade-off between pre- and post-copulatory sexually selected traits?

PubMed

Firman, Renée C

2014-10-01

When females mate with multiple males both pre- and post-copulatory sexual selections occur. It has been suggested that females benefit from polyandry when better-quality males are successful in sperm competition and sire high-quality offspring. Indeed, studies of experimental evolution have confirmed that sperm competition selects for both increased ejaculate quality and elevated offspring viability. Fewer investigations have explored whether these fitness benefits are evident beyond early life-history stages. Here, I used house mice (Mus domesticus) from selection lines that had been evolving for 25 generations under either polygamy or monogamy to test whether females preferred males from lines that had evolved with sperm competition. Males from the polygamous lines had previously been shown to achieve a fitness advantage under semi-natural conditions, deeming them to be of high genetic quality and leading to the a priori expectation that females would prefer males that had evolved with sperm competition compared with males that had not. Contrary to expectation, the data showed that sexually receptive females spent more time associating with males from the monogamous lines. This unexpected but interesting result is discussed in relation to sperm competition theory that predicts a trade-off between male investment in pre- and post-copulatory sexually selected traits. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

An examination of sudden acceleration

DOT National Transportation Integrated Search

1989-01-01

This report describes the results of a study to identify and evaluate factors which could potentially cause or contribute to the occurrence of "Sudden Acceleration Incidents" (SAI). SAI are defined in this report as unintended, unexpected, high-power...

Myelin-reactive “type B” T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice

PubMed Central

Kawamura, Kazuyuki; McLaughlin, Katherine A.; Weissert, Robert; Forsthuber, Thomas G.

2009-01-01

Genes of the major histocompatibility complex (MHC) show the strongest genetic association with multiple sclerosis (MS) but the underlying mechanisms have remained unresolved. Here, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401 contribute to autoimmune central nervous system (CNS) demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon backcrossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific “type B” T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific “type B” T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and “type B” T cells can escape the induction of T cell tolerance and may promote MS. PMID:18713991

Anxiety and the Processing of Emotionally Threatening Stimuli: Distinctive Patterns of Selective Attention among High- and Low-Test-Anxious Children.

ERIC Educational Resources Information Center

Vasey, Michael W.; And Others

1996-01-01

Tested for bias toward shifting attention toward threatening stimuli among high-anxious children and away from such stimuli among low-anxious children, ages 11-14. Results supported the predicted attentional bias toward threat cues among high-test-anxious children. Unexpectedly, the predicted attentional bias away from threat cues among…

Problems due to superheating of cryogenic liquids

NASA Astrophysics Data System (ADS)

Hands, B. A.

1988-12-01

Superheating can cause several problems in the storage of cryogenic liquids: stratification can cause unexpectedly high tank pressures or, in multicomponent liquids, rollover with its consequential high vaporization rate; geysering causes the rapid expulsion of static liquid from a vertical tube; chugging is a similar phenomenon observed when liquid flows through a reasonably well-insulated pipe.

Preparing to "Not" Be a Footballer: Higher Education and Professional Sport

ERIC Educational Resources Information Center

Hickey, Christopher; Kelly, Peter

2008-01-01

In the commercialised and professionalised world of elite sport, issues associated with career pathways and post sporting career options have a particular resonance. In various football codes, an unexpected knock, twist, bend or break can profoundly impact a player's career. In this high risk and high consequence environment, a number of sports…

Searching for hidden unexpected features in the SnIa data

NASA Astrophysics Data System (ADS)

Shafieloo, A.; Perivolaropoulos, L.

2010-06-01

It is known that κ2 statistic and likelihood analysis may not be sensitive to the all features of the data. Despite of the fact that by using κ2 statistic we can measure the overall goodness of fit for a model confronted to a data set, some specific features of the data can stay undetectable. For instance, it has been pointed out that there is an unexpected brightness of the SnIa data at z > 1 in the Union compilation. We quantify this statement by constructing a new statistic, called Binned Normalized Difference (BND) statistic, which is applicable directly on the Type Ia Supernova (SnIa) distance moduli. This statistic is designed to pick up systematic brightness trends of SnIa data points with respect to a best fit cosmological model at high redshifts. According to this statistic there are 2.2%, 5.3% and 12.6% consistency between the Gold06, Union08 and Constitution09 data and spatially flat ΛCDM model when the real data is compared with many realizations of the simulated monte carlo datasets. The corresponding realization probability in the context of a (w0,w1) = (-1.4,2) model is more than 30% for all mentioned datasets indicating a much better consistency for this model with respect to the BND statistic. The unexpected high z brightness of SnIa can be interpreted either as a trend towards more deceleration at high z than expected in the context of ΛCDM or as a statistical fluctuation or finally as a systematic effect perhaps due to a mild SnIa evolution at high z.

Social evolution and genetic interactions in the short and long term.

PubMed

Van Cleve, Jeremy

2015-08-01

The evolution of social traits remains one of the most fascinating and feisty topics in evolutionary biology even after half a century of theoretical research. W.D. Hamilton shaped much of the field initially with his 1964 papers that laid out the foundation for understanding the effect of genetic relatedness on the evolution of social behavior. Early theoretical investigations revealed two critical assumptions required for Hamilton's rule to hold in dynamical models: weak selection and additive genetic interactions. However, only recently have analytical approaches from population genetics and evolutionary game theory developed sufficiently so that social evolution can be studied under the joint action of selection, mutation, and genetic drift. We review how these approaches suggest two timescales for evolution under weak mutation: (i) a short-term timescale where evolution occurs between a finite set of alleles, and (ii) a long-term timescale where a continuum of alleles are possible and populations evolve continuously from one monomorphic trait to another. We show how Hamilton's rule emerges from the short-term analysis under additivity and how non-additive genetic interactions can be accounted for more generally. This short-term approach reproduces, synthesizes, and generalizes many previous results including the one-third law from evolutionary game theory and risk dominance from economic game theory. Using the long-term approach, we illustrate how trait evolution can be described with a diffusion equation that is a stochastic analogue of the canonical equation of adaptive dynamics. Peaks in the stationary distribution of the diffusion capture classic notions of convergence stability from evolutionary game theory and generally depend on the additive genetic interactions inherent in Hamilton's rule. Surprisingly, the peaks of the long-term stationary distribution can predict the effects of simple kinds of non-additive interactions. Additionally, the peaks capture both weak and strong effects of social payoffs in a manner difficult to replicate with the short-term approach. Together, the results from the short and long-term approaches suggest both how Hamilton's insight may be robust in unexpected ways and how current analytical approaches can expand our understanding of social evolution far beyond Hamilton's original work. Copyright © 2015 Elsevier Inc. All rights reserved.

Driving performance changes of middle-aged experienced taxi drivers due to distraction tasks during unexpected situations.

PubMed

Kim, Hyung-Sik; Choi, Mi-Hyun; Choi, Jin-Seung; Kim, Hyun-Joo; Hong, Sang-Pyo; Jun, Jae-Hoon; Tack, Gye-Rae; Kim, Boseong; Min, Ung-Chan; Lim, Dae-Woon; Chung, Soon-Cheol

2013-10-01

This study investigated the effects of distraction taskssuch as sending a text message with a cellphone and searching navigation with car navigation system-on the driving performance of 29 highly experienced taxi drivers in their 50s. All participants were instructed to drive using a driving simulator for 2 min. while maintaining a constant distance from the vehicle in front and a constant speed. Participants drove without any distractions for the first minute. For an additional minute, they performed Driving Only or performed a task while driving (Driving + Sending Text Message or Driving + Searching Navigation). An unexpected situation, in which the participant had to stop abruptly due to a sudden stop of the preceding vehicle, occurred during this period. Driving performance during the unexpected situation was evaluated by car control variables, medial-lateral coefficient of variation and brake time, and by motion variables such as the jerk-cost function. Compared to Driving Only, jerk-cost function, medial-lateral coefficient of variation, and brake time increased during Driving + Sending Text Message or Driving + Searching Navigation.

Unexpected inhibition of CO 2 gas hydrate formation in dilute TBAB solutions and the critical role of interfacial water structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Ngoc N.; Nguyen, Anh V.; Nguyen, Khoi T.

Gas hydrates formed under moderated conditions open up novel approaches to tackling issues related to energy supply, gas separation, and CO 2 sequestration. Several additives like tetra-n-butylammonium bromide (TBAB) have been empirically developed and used to promote gas hydrate formation. Here we report unexpected experimental results which show that TBAB inhibits CO 2 gas hydrate formation when used at minuscule concentration. We also used spectroscopic techniques and molecular dynamics simulation to gain further insights and explain the experimental results. They have revealed the critical role of water alignment at the gas-water interface induced by surface adsorption of tetra-n-butylammonium cation (TBAmore » +) which gives rise to the unexpected inhibition of dilute TBAB solution. The water perturbation by TBA + in the bulk is attributed to the promotion effect of high TBAB concentration on gas hydrate formation. We explain our finding using the concept of activation energy of gas hydrate formation. Our results provide a step toward to mastering the control of gas hydrate formation.« less

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

PubMed

van de Kamp, J M; Betsalel, O T; Mercimek-Mahmutoglu, S; Abulhoul, L; Grünewald, S; Anselm, I; Azzouz, H; Bratkovic, D; de Brouwer, A; Hamel, B; Kleefstra, T; Yntema, H; Campistol, J; Vilaseca, M A; Cheillan, D; D'Hooghe, M; Diogo, L; Garcia, P; Valongo, C; Fonseca, M; Frints, S; Wilcken, B; von der Haar, S; Meijers-Heijboer, H E; Hofstede, F; Johnson, D; Kant, S G; Lion-Francois, L; Pitelet, G; Longo, N; Maat-Kievit, J A; Monteiro, J P; Munnich, A; Muntau, A C; Nassogne, M C; Osaka, H; Ounap, K; Pinard, J M; Quijano-Roy, S; Poggenburg, I; Poplawski, N; Abdul-Rahman, O; Ribes, A; Arias, A; Yaplito-Lee, J; Schulze, A; Schwartz, C E; Schwenger, S; Soares, G; Sznajer, Y; Valayannopoulos, V; Van Esch, H; Waltz, S; Wamelink, M M C; Pouwels, P J W; Errami, A; van der Knaap, M S; Jakobs, C; Mancini, G M; Salomons, G S

2013-07-01

Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Community-acquired methicillin-resistant Staphylococcus aureus: community transmission, pathogenesis, and drug resistance.

PubMed

Yamamoto, Tatsuo; Nishiyama, Akihito; Takano, Tomomi; Yabe, Shizuka; Higuchi, Wataru; Razvina, Olga; Shi, Da

2010-08-01

Methicillin-resistant Staphylococcus aureus (MRSA) is able to persist not only in hospitals (with a high level of antimicrobial agent use) but also in the community (with a low level of antimicrobial agent use). The former is called hospital-acquired MRSA (HA-MRSA) and the latter community-acquired MRSA (CA-MRSA). It is believed MRSA clones are generated from S. aureus through insertion of the staphylococcal cassette chromosome mec (SCCmec), and outbreaks occur as they spread. Several worldwide and regional clones have been identified, and their epidemiological, clinical, and genetic characteristics have been described. CA-MRSA is likely able to survive in the community because of suitable SCCmec types (type IV or V), a clone-specific colonization/infection nature, toxin profiles (including Pantone-Valentine leucocidin, PVL), and narrow drug resistance patterns. CA-MRSA infections are generally seen in healthy children or young athletes, with unexpected cases of diseases, and also in elderly inpatients, occasionally surprising clinicians used to HA-MRSA infections. CA-MRSA spreads within families and close-contact groups or even through public transport, demonstrating transmission cores. Re-infection (including multifocal infection) frequently occurs, if the cores are not sought out and properly eradicated. Recently, attention has been given to CA-MRSA (USA300), which originated in the US, and is growing as HA-MRSA and also as a worldwide clone. CA-MRSA infection in influenza season has increasingly been noted as well. MRSA is also found in farm and companion animals, and has occasionally transferred to humans. As such, the epidemiological, clinical, and genetic behavior of CA-MRSA, a growing threat, is focused on in this study.

Comparative Transcriptomic Approaches Exploring Contamination Stress Tolerance in Salix sp. Reveal the Importance for a Metaorganismal de Novo Assembly Approach for Nonmodel Plants1[OPEN

PubMed Central

Brereton, Nicholas J. B.; Marleau, Julie; Nissim, Werther Guidi; Labrecque, Michel; Joly, Simon; Pitre, Frederic E.

2016-01-01

Metatranscriptomic study of nonmodel organisms requires strategies that retain the highly resolved genetic information generated from model organisms while allowing for identification of the unexpected. A real-world biological application of phytoremediation, the field growth of 10 Salix cultivars on polluted soils, was used as an exemplar nonmodel and multifaceted crop response well-disposed to the study of gene expression. Sequence reads were assembled de novo to create 10 independent transcriptomes, a global transcriptome, and were mapped against the Salix purpurea 94006 reference genome. Annotation of assembled contigs was performed without a priori assumption of the originating organism. Global transcriptome construction from 3.03 billion paired-end reads revealed 606,880 unique contigs annotated from 1588 species, often common in all 10 cultivars. Comparisons between transcriptomic and metatranscriptomic methodologies provide clear evidence that nonnative RNA can mistakenly map to reference genomes, especially to conserved regions of common housekeeping genes, such as actin, α/β-tubulin, and elongation factor 1-α. In Salix, Rubisco activase transcripts were down-regulated in contaminated trees across all 10 cultivars, whereas thiamine thizole synthase and CP12, a Calvin Cycle master regulator, were uniformly up-regulated. De novo assembly approaches, with unconstrained annotation, can improve data quality; care should be taken when exploring such plant genetics to reduce de facto data exclusion by mapping to a single reference genome alone. Salix gene expression patterns strongly suggest cultivar-wide alteration of specific photosynthetic apparatus and protection of the antenna complexes from oxidation damage in contaminated trees, providing an insight into common stress tolerance strategies in a real-world phytoremediation system. PMID:27002060

Genetic insights into Graminella nigrifrons Competence for maize fine streak virus infection and transmission.

PubMed

Cassone, Bryan J; Cisneros Carter, Fiorella M; Michel, Andrew P; Stewart, Lucy R; Redinbaugh, Margaret G

2014-01-01

Most plant-infecting rhabdoviruses are transmitted by one or a few closely related insect species. Additionally, intraspecific differences in transmission efficacy often exist among races/biotypes within vector species and among strains within a virus species. The black-faced leafhopper, Graminella nigrifrons, is the only known vector of the persistent propagative rhabdovirus Maize fine streak virus (MFSV). Only a small percentage of leafhoppers are capable of transmitting the virus, although the mechanisms underlying vector competence are not well understood. RNA-Seq was carried out to explore transcript expression changes and sequence variation in G. nigrifrons and MFSV that may be associated with the ability of the vector to acquire and transmit the virus. RT-qPCR assays were used to validate differential transcript accumulation. Feeding on MFSV-infected maize elicited a considerable transcriptional response in G. nigrifrons, with increased expression of cytoskeleton organization and immunity transcripts in infected leafhoppers. Differences between leafhoppers capable of transmitting MFSV, relative to non-transmitting but infected leafhoppers were more limited, which may reflect difficulties discerning between the two groups and/or the likelihood that the transmitter phenotype results from one or a few genetic differences. The ability of infected leafhoppers to transmit MFSV did not appear associated with virus transcript accumulation in the infected leafhoppers or sequence polymorphisms in the viral genome. However, the non-structural MFSV 3 gene was expressed at unexpectedly high levels in infected leafhoppers, suggesting it plays an active role in the infection of the insect host. The results of this study begin to define the functional roles of specific G. nigrifrons and MFSV genes in the viral transmission process.

Genetic Insights into Graminella nigrifrons Competence for Maize fine streak virus Infection and Transmission

PubMed Central

Michel, Andrew P.; Stewart, Lucy R.; Redinbaugh, Margaret G.

2014-01-01

Background Most plant-infecting rhabdoviruses are transmitted by one or a few closely related insect species. Additionally, intraspecific differences in transmission efficacy often exist among races/biotypes within vector species and among strains within a virus species. The black-faced leafhopper, Graminella nigrifrons, is the only known vector of the persistent propagative rhabdovirus Maize fine streak virus (MFSV). Only a small percentage of leafhoppers are capable of transmitting the virus, although the mechanisms underlying vector competence are not well understood. Methodology RNA-Seq was carried out to explore transcript expression changes and sequence variation in G. nigrifrons and MFSV that may be associated with the ability of the vector to acquire and transmit the virus. RT-qPCR assays were used to validate differential transcript accumulation. Results/Significance Feeding on MFSV-infected maize elicited a considerable transcriptional response in G. nigrifrons, with increased expression of cytoskeleton organization and immunity transcripts in infected leafhoppers. Differences between leafhoppers capable of transmitting MFSV, relative to non-transmitting but infected leafhoppers were more limited, which may reflect difficulties discerning between the two groups and/or the likelihood that the transmitter phenotype results from one or a few genetic differences. The ability of infected leafhoppers to transmit MFSV did not appear associated with virus transcript accumulation in the infected leafhoppers or sequence polymorphisms in the viral genome. However, the non-structural MFSV 3 gene was expressed at unexpectedly high levels in infected leafhoppers, suggesting it plays an active role in the infection of the insect host. The results of this study begin to define the functional roles of specific G. nigrifrons and MFSV genes in the viral transmission process. PMID:25420026

Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

PubMed

Hammer, C; Stepniak, B; Schneider, A; Papiol, S; Tantra, M; Begemann, M; Sirén, A-L; Pardo, L A; Sperling, S; Mohd Jofrry, S; Gurvich, A; Jensen, N; Ostmeier, K; Lühder, F; Probst, C; Martens, H; Gillis, M; Saher, G; Assogna, F; Spalletta, G; Stöcker, W; Schulz, T F; Nave, K-A; Ehrenreich, H

2014-10-01

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.

Autosomal Genes of Autosomal/X-Linked Duplicated Gene Pairs and Germ-Line Proliferation in Caenorhabditis elegans

PubMed Central

Maciejowski, John; Ahn, James Hyungsoo; Cipriani, Patricia Giselle; Killian, Darrell J.; Chaudhary, Aisha L.; Lee, Ji Inn; Voutev, Roumen; Johnsen, Robert C.; Baillie, David L.; Gunsalus, Kristin C.; Fitch, David H. A.; Hubbard, E. Jane Albert

2005-01-01

We report molecular genetic studies of three genes involved in early germ-line proliferation in Caenorhabditis elegans that lend unexpected insight into a germ-line/soma functional separation of autosomal/X-linked duplicated gene pairs. In a genetic screen for germ-line proliferation-defective mutants, we identified mutations in rpl-11.1 (L11 protein of the large ribosomal subunit), pab-1 [a poly(A)-binding protein], and glp-3/eft-3 (an elongation factor 1-α homolog). All three are members of autosome/X gene pairs. Consistent with a germ-line-restricted function of rpl-11.1 and pab-1, mutations in these genes extend life span and cause gigantism. We further examined the RNAi phenotypes of the three sets of rpl genes (rpl-11, rpl-24, and rpl-25) and found that for the two rpl genes with autosomal/X-linked pairs (rpl-11 and rpl-25), zygotic germ-line function is carried by the autosomal copy. Available RNAi results for highly conserved autosomal/X-linked gene pairs suggest that other duplicated genes may follow a similar trend. The three rpl and the pab-1/2 duplications predate the divergence between C. elegans and C. briggsae, while the eft-3/4 duplication appears to have occurred in the lineage to C. elegans after it diverged from C. briggsae. The duplicated C. briggsae orthologs of the three C. elegans autosomal/X-linked gene pairs also display functional differences between paralogs. We present hypotheses for evolutionary mechanisms that may underlie germ-line/soma subfunctionalization of duplicated genes, taking into account the role of X chromosome silencing in the germ line and analogous mammalian phenomena. PMID:15687263

Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion

PubMed Central

Saitta, Sulagna C.; Harris, Stacy E.; Gaeth, Ann P.; Driscoll, Deborah A.; McDonald-McGinn, Donna M.; Maisenbacher, Melissa K.; Yersak, Jill M.; Chakraborty, Prabir K.; Hacker, April M.; Zackai, Elaine H.; Ashley, Terry; Emanuel, Beverly S.

2010-01-01

Chromosome 22q11.2 deletions are found in almost 90% of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). Large, chromosome-specific low copy repeats (LCRs), flanking and within the deletion interval, are presumed to lead to misalignment and aberrant recombination in meiosis resulting in this frequent microdeletion syndrome. We traced the grandparental origin of regions flanking de novo 3 Mb deletions in 20 informative three-generation families. Haplotype reconstruction showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19/20 families. Instead, the normal chromosome 22 in these probands showed interchromosomal exchanges in 2/15 informative meioses, a rate consistent with the genetic distance. Meiotic exchanges, visualized as MLH1 foci, localize to the distal long arm of chromosome 22 in 75% of human spermatocytes tested, also reflecting the genetic map. Additionally, we found no effect of proband gender or parental age on the crossover frequency. Parental origin studies in 65 de novo 3 Mb deletions (including these 20 patients) demonstrated no bias. Unlike Williams syndrome, we found no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11 deleted patients, or in eight non-deleted patients with a DGS/VCFS phenotype using FISH. Our data are consistent with significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 as the likely etiology for the deletion. This type of exchange occurs more often than is described for deletions of chromosomes 7q11, 15q11, 17p11 and 17q11, implying a difference in the meiotic behavior of chromosome 22. PMID:14681306

A Genetic Variant in Vitamin B12 Metabolic Genes That Reduces the Risk of Congenital Heart Disease in Han Chinese Populations

PubMed Central

Wang, Feng; Peng, Qian-Qian; Hou, Jia; Sun, Shu-Na; Gui, Yong-Hao; Duan, Wen-Yuan; Qiao, Bin; Wang, Hong-Yan

2014-01-01

Background Genome-wide association studies on components of the one-carbon metabolic pathway revealed that human vitamin B12 levels could be significantly influenced by variationsinthefucosyltransferase 2 (FUT2), cubilin (CUBN), and transcobalamin-I (TCN1) genes. An altered vitamin B12 level is an important factor that disturbs the homeostasis of the folate metabolism pathway, which in turn can potentially lead to the development of congenital heart disease (CHD). Therefore, we investigated the association between the variants of vitamin B12-related genes and CHD in Han Chinese populations. Methods and Results Six variants of the vitamin B12-related genes were selected for analysis in two independent case-control studies, with a total of 868 CHD patients and 931 controls. The variant rs11254363 of the CUBN gene was associated with a decreased risk of developing CHD in both the separate and combined case-control studies. Combined samples from the two cohorts had a significant decrease in CHD risk for the G allele (OR = 0.48, P = 1.7×10−5) and AG+GG genotypes (OR = 0.49, P = 4×10−5), compared with the wild-type A allele and AA genotype, respectively. Conclusions Considering the G allele of variant rs11254363 of the CUBN gene was associated with an increased level of circulating vitamin B12. This result suggested that the carriers of the G allele would benefit from the protection offered by the high vitamin B12 concentration during critical heart development stages. This finding shed light on the unexpected role of CUBN in CHD development and highlighted the interplay of diet, genetics, and human birth defects. PMID:24533076

An outbreak of respiratory tularemia caused by diverse clones of Francisella tularensis.

PubMed

Johansson, Anders; Lärkeryd, Adrian; Widerström, Micael; Mörtberg, Sara; Myrtännäs, Kerstin; Ohrman, Caroline; Birdsell, Dawn; Keim, Paul; Wagner, David M; Forsman, Mats; Larsson, Pär

2014-12-01

The bacterium Francisella tularensis is recognized for its virulence, infectivity, genetic homogeneity, and potential as a bioterrorism agent. Outbreaks of respiratory tularemia, caused by inhalation of this bacterium, are poorly understood. Such outbreaks are exceedingly rare, and F. tularensis is seldom recovered from clinical specimens. A localized outbreak of tularemia in Sweden was investigated. Sixty-seven humans contracted laboratory-verified respiratory tularemia. F. tularensis subspecies holarctica was isolated from the blood or pleural fluid of 10 individuals from July to September 2010. Using whole-genome sequencing and analysis of single-nucleotide polymorphisms (SNPs), outbreak isolates were compared with 110 archived global isolates. There were 757 SNPs among the genomes of the 10 outbreak isolates and the 25 most closely related archival isolates (all from Sweden/Finland). Whole genomes of outbreak isolates were >99.9% similar at the nucleotide level and clustered into 3 distinct genetic clades. Unexpectedly, high-sequence similarity grouped some outbreak and archival isolates that originated from patients from different geographic regions and up to 10 years apart. Outbreak and archival genomes frequently differed by only 1-3 of 1 585 229 examined nucleotides. The outbreak was caused by diverse clones of F. tularensis that occurred concomitantly, were widespread, and apparently persisted in the environment. Multiple independent acquisitions of F. tularensis from the environment over a short time period suggest that natural outbreaks of respiratory tularemia are triggered by environmental cues. The findings additionally caution against interpreting genome sequence identity for this pathogen as proof of a direct epidemiological link. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Decoupling of Host–Symbiont–Phage Coadaptations Following Transfer Between Insect Species

PubMed Central

Chafee, Meghan E.; Zecher, Courtney N.; Gourley, Michelle L.; Schmidt, Victor T.; Chen, John H.; Bordenstein, Sarah R.; Clark, Michael E.; Bordenstein, Seth R.

2011-01-01

Transferring endosymbiotic bacteria between different host species can perturb the coordinated regulation of the host and bacterial genomes. Here we use the most common maternally transmitted bacteria, Wolbachia pipientis, to test the consequences of host genetic background on infection densities and the processes underlying those changes in the parasitoid wasp genus Nasonia. Introgressing the genome of Nasonia giraulti into the infected cytoplasm of N. vitripennis causes a two-order-of-magnitude increase in bacterial loads in adults and a proliferation of the infection to somatic tissues. The host effect on W. pipientis distribution and densities is associated with a twofold decrease in densities of the temperate phage WO-B. Returning the bacteria from the new host species back to the resident host species restores the bacteria and phage to their native densities. To our knowledge, this is the first study to report a host–microbe genetic interaction that affects the densities of both W. pipientis and bacteriophage WO-B. The consequences of the increased bacterial density include a reduction in fecundity, an increase in levels of cytoplasmic incompatibility (CI), and unexpectedly, male-to-female transfer of the bacteria to uninfected females and an increased acceptance of densely infected females to interspecific mates. While paternal inheritance of the W. pipientis was not observed, the high incidence of male-to-female transfer in the introgressed background raises the possibility that paternal transmission could be more likely in hybrids where paternal leakage of other cytoplasmic elements is also known to occur. Taken together, these results establish a major change in W. pipientis densities and tissue tropism between closely related species and support a model in which phage WO, Wolbachia, and arthropods form a tripartite symbiotic association in which all three are integral to understanding the biology of this widespread endosymbiosis. PMID:20944019

Willingness and ability to pay for unexpected dental expenses by Finnish adults

PubMed Central

2012-01-01

Background Since 2002, adults have been able to choose oral health care services in the public sector or in the private sector in Finland. Though various subsidies for care exist in both sectors, the Public Dental Service (PDS) is a cheaper option for the patient but, on the other hand, there are no waiting lists for private care. The aim of this study was to assess middle-aged adults' use of dental services, willingness to pay (WTP) and ability to pay (ATP) for unexpected, urgent dental treatment. Methods Postal questionnaires on use of dental services were sent to a random sample of 1500 47-59 year old adults living in three large municipalities in the Helsinki region. The initial response rate was 65.8%. Two hypothetical scenarios were presented: "What would be the highest price you would be prepared to pay to have a lost filling replaced immediately, or, at the latest, the day after losing the filling?" and " How much could you pay for unexpected dental expenses at two weeks notice, if you suddenly needed more comprehensive treatment?" Logistic regression analysis was used to analyse factors related to WTP and ATP. Results Most respondents (89.6%) had visited a dentist recently and a majority (76.1%) had used private services. For immediate replacement of a lost filling, almost all respondents (93.2%) were willing to pay the lower price charged in the PDS and 46.2% were willing to pay the private fee. High income and no subjective need for dental treatment were positively associated with the probability of paying a higher price. Most respondents (93.0%) were able to pay a low fee, EUR 50 and almost half (41.6%) at least EUR 300 for unexpected treatment at short notice. High income and male sex were associated with high ATP. Conclusion There was a strong and statistically significant relationship between income and WTP and ATP for urgent dental care, indicating that access to publicly provided services improved equity for persons with low income. PMID:22935077

Insights From Genomics Into Spatial and Temporal Variation in Batrachochytrium dendrobatidis.

PubMed

Byrne, A Q; Voyles, J; Rios-Sotelo, G; Rosenblum, E B

2016-01-01

Advances in genetics and genomics have provided new tools for the study of emerging infectious diseases. Researchers can now move quickly from simple hypotheses to complex explanations for pathogen origin, spread, and mechanisms of virulence. Here we focus on the application of genomics to understanding the biology of the fungal pathogen Batrachochytrium dendrobatidis (Bd), a novel and deadly pathogen of amphibians. We provide a brief history of the system, then focus on key insights into Bd variation garnered from genomics approaches, and finally, highlight new frontiers for future discoveries. Genomic tools have revealed unexpected complexity and variation in the Bd system suggesting that the history and biology of emerging pathogens may not be as simple as they initially seem. Copyright © 2016 Elsevier Inc. All rights reserved.

Deconstructing Pancreas Developmental Biology

PubMed Central

Benitez, Cecil M.; Goodyer, William R.

2012-01-01

The relentless nature and increasing prevalence of human pancreatic diseases, in particular, diabetes mellitus and adenocarcinoma, has motivated further understanding of pancreas organogenesis. The pancreas is a multifunctional organ whose epithelial cells govern a diversity of physiologically vital endocrine and exocrine functions. The mechanisms governing the birth, differentiation, morphogenesis, growth, maturation, and maintenance of the endocrine and exocrine components in the pancreas have been discovered recently with increasing tempo. This includes recent studies unveiling mechanisms permitting unexpected flexibility in the developmental potential of immature and mature pancreatic cell subsets, including the ability to interconvert fates. In this article, we describe how classical cell biology, genetic analysis, lineage tracing, and embryological investigations are being complemented by powerful modern methods including epigenetic analysis, time-lapse imaging, and flow cytometry-based cell purification to dissect fundamental processes of pancreas development. PMID:22587935

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

PubMed Central

Ssentongo, Paddy; Robuccio, Anna E.; Thuku, Godfrey; Sim, Derek G.; Nabi, Ali; Bahari, Fatemeh; Shanmugasundaram, Balaji; Billard, Myles W.; Geronimo, Andrew; Short, Kurt W.; Drew, Patrick J.; Baccon, Jennifer; Weinstein, Steven L.; Gilliam, Frank G.; Stoute, José A.; Chinchilli, Vernon M.; Read, Andrew F.; Gluckman, Bruce J.; Schiff, Steven J.

2017-01-01

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP. PMID:28272506

Unexpected angular or rotational deformity after corrective osteotomy

PubMed Central

2014-01-01

Background Codman’s paradox reveals a misunderstanding of geometry in orthopedic practice. Physicians often encounter situations that cannot be understood intuitively during orthopedic interventions such as corrective osteotomy. Occasionally, unexpected angular or rotational deformity occurs during surgery. This study aimed to draw the attention of orthopedic surgeons toward the concepts of orientation and rotation and demonstrate the potential for unexpected deformity after orthopedic interventions. This study focused on three situations: shoulder arthrodesis, femoral varization derotational osteotomy, and femoral derotation osteotomy. Methods First, a shoulder model was generated to calculate unexpected rotational deformity to demonstrate Codman’s paradox. Second, femoral varization derotational osteotomy was simulated using a cylinder model. Third, a reconstructed femoral model was used to calculate unexpected angular or rotational deformity during femoral derotation osteotomy. Results Unexpected external rotation was found after forward elevation and abduction of the shoulder joint. In the varization and derotation model, closed-wedge osteotomy and additional derotation resulted in an unexpected extension and valgus deformity, namely, under-correction of coxa valga. After femoral derotational osteotomy, varization and extension of the distal fragment occurred, although the extension was negligible. Conclusions Surgeons should be aware of unexpected angular deformity after surgical procedure involving bony areas. The degree of deformity differs depending on the context of the surgical procedure. However, this study reveals that notable deformities can be expected during orthopedic procedures such as femoral varization derotational osteotomy. PMID:24886469

High-throughput sequencing of the chloroplast and mitochondrion of Chlamydomonas reinhardtii to generate improved de novo assemblies, analyze expression patterns and transcript speciation, and evaluate diversity among laboratory strains and wild isolates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallaher, Sean D.; Fitz-Gibbon, Sorel T.; Strenkert, Daniela

Chlamydomonas reinhardtii is a unicellular chlorophyte alga that is widely studied as a reference organism for understanding photosynthesis, sensory and motile cilia, and for development of an algal-based platform for producing biofuels and bio-products. Its highly repetitive, ~205-kbp circular chloroplast genome and ~15.8-kbp linear mitochondrial genome were sequenced prior to the advent of high-throughput sequencing technologies. Here, high coverage shotgun sequencing was used to assemble both organellar genomes de novo. These new genomes correct dozens of errors in the prior genome sequences and annotations. Gen-ome sequencing coverage indicates that each cell contains on average 83 copies of the chloroplast genomemore » and 130 copies of the mitochondrial genome. Using protocols and analyses optimized for organellar tran-scripts, RNA-Seq was used to quantify their relative abundances across 12 different growth conditions. Forty-six percent of total cellular mRNA is attributable to high expression from a few dozen chloroplast genes. RNA-Seq data were used to guide gene annotation, to demonstrate polycistronic gene expression, and to quantify splicing of psaA and psbA introns. In contrast to a conclusion from a recent study, we found that chloroplast transcripts are not edited. Unexpectedly, cytosine-rich polynucleotide tails were observed at the 3’-end of all mitochondrial transcripts. A comparative genomics analysis of eight laboratory strains and 11 wild isolates of C. reinhardtii identified 2658 variants in the organellargenomes, which is 1/10th as much genetic diversity as is found in the nucleus.« less