Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

Estudo da genitália externa masculina de duas espécies de Opisthacidius Berg, 1879 (Hemiptera, Reduviidae, Reduviinae)

In order to stablish new taxonomic characters for the genus Opisthcidius a detailed comparative study of the male external genitalia was performed in O. rubropictus (H. Shaeffer, 1848), the type species, and O. pertinax (Breddin, 1903), mantioned as predators of triatomines. The most representative phallic structures were: the median process of pygophore, the phallosoma struts and the vesica process.

Marx: From Hegel and Feuerbach to Adam Smith

This paper discusses the development of Marx’s thought over a period of something like fifteen months, between the spring of 1843 and the autumn of 1844. The focus of the paper is Marx’s first encounter with classical political economy as he found it in the Wealth of Nations. The outcome of this encounter was presented by Marx in his Economic and Philosophical Manuscripts of 1844. It is argued here that in the classical theory, with which he had hitherto been largely unfamiliar, Marx found all the elements he needed to synthesise the philosophical standpoint he had developed in the preceding months with political economy. The Manuscripts represent the first crucial stage in the development of this synthesis. This first encounter of Marx with classical political economy, and his first steps in the development of his synthesis, have received hardly any attention in the literature. The present paper seeks to fill this gap.

Marx: From Hegel and Feuerbach to Adam Smith

This paper discusses the development of Marx’s thought over a period of something like fifteen months, between the spring of 1843 and the autumn of 1844. The focus of the paper is Marx’s first encounter with classical political economy as he found it in the Wealth of Nations. The outcome of this encounter was presented by Marx in his Economic and Philosophical Manuscripts of 1844. It is argued here that in the classical theory, with which he had hitherto been largely unfamiliar, Marx found all the elements he needed to synthesise the philosophical standpoint he had developed in the preceding months with political economy. The Manuscripts represent the first crucial stage in the development of this synthesis. This first encounter of Marx with classical political economy, and his first steps in the development of his synthesis, have received hardly any attention in the literature. The present paper seeks to fill this gap.

Nearer to Sraffa than Marx: Adam Smith on Productive and Unproductive Labour

This paper supercedes an earlier attempt I made to pin down the meaning and significance of Adam Smith’s theory of productive and unproductive labour. (Strathclyde Discussion Papers in Economics, No.08-05) My conclusion then was that while Smith’s understanding of what was needed to achieve economic growth was sound, his discussion was marred by apparently conflicting definitions of productive labour. That (essentially conventional) interpretation does not, I now believe, do justice to Smith. Revision is therefore called for: hence the present paper.

Vital Statistics of Panstrongylus geniculatus (Latreille 1811) (Hemiptera: Reduviidae) under Experimental Conditions

A statistical evaluation of the population dynamics of Panstrongylus geniculatus is based on a cohort experiment conducted under controlled laboratory conditions. Animals were fed on hen every 15 days. Egg incubation took 21 days; mean duration of 1st, 2nd, 3rd, 4th, and 5th instar nymphs was 25, 30, 58, 62, and 67 days, respectively; mean nymphal development time was 39 weeks and adult longevity was 72 weeks. Females reproduced during 30 weeks, producing an average of 61.6 eggs for female on its lifetime; the average number of eggs/female/week was 2.1. Total number of eggs produced by the cohort was 1379. Average hatch for the cohort was 88.9%; it was not affected by age of the mother. Age specific survival and reproduction tables were constructed. The following population parameters were evaluated, generation time was 36.1 weeks; net reproduction rate was 89.4; intrinsic rate of natural increase was 0.125; instantaneous birth and death rates were 0.163 and 0.039 respectively; finite rate of increase was 1.13; total reproductive value was 1196 and stable age distribution was 31.2% eggs, 64.7% nymphs and 4.1% adults. Finally the population characteristics of P. geniculatus lead to the conclusion that this species is a K strategist.

Evidence of colonization of man-made ecotopes by Triatoma dimidiata (Latreille, 1811) in Costa Rica

Triatoma dimidiata adults have been frequently found, during the last five years, in a dog kennel and a chicken coop, in the back yard of a well-built house, 15 km from San José, the capital of Costa Rica. In the chicken coop nymphs were also found. Two of the 11 dogs from the kennel were serologically positive for Trypanosoma cruzi infection. The inhabitants of the house, three adults and two children, were negative. This type of colonization by the insect, which is attracted to lights, is becoming common in old and new settlements, with different degrees of success, a fact with epidemiological implications and great relevance in the control strategies that can be applied.

Estudo morfométrico do gênero Panstrongylus Berg, 1879 (Hemiptera, Reduviidae, Triatominae)

The subfamily Triatominae is actually represented by 137 species distributed among 6 tribes and 19 genera. Within this subfamily, the genus Panstrongylus, Berg 1879, is composed by 13 species widespread in sylvatic, peridomestic, and domestic habitats of Neotropical regions. These species are vectors of Chagas disease and consequently are found associated with its main hosts, such as birds and mammals. Interest in species of this genus has been increasing in the last few years. Reports of several authors indicate these Triatominae to invade and colonize houses, increasing their epidemiological significance. Morphometry was used in this study to investigate correlations among possible closely related species. We measured 224 specimens among 13 species through a set of metric variables of the head. The results indicated that the genus Panstrongylus seems to be homogeneous since 10 of the 14 species were shown to be closely related.

Environmental management for the control of Triatoma dimidiata (Latreille, 1811), (Hemiptera: Reduviidae) in Costa Rica: a pilot project

An ecological control method, using environmental management operations, based on biological and behavioral characteristics of Triatoma dimidiata (Latreille, 1811), was implemented as a pilot project in an area of Costa Rica where the bug is prevalent. The sample was represented by 20 houses with peridomestic colonies (two also had indoor infestation), divided in two equivalent groups of 10 each. In one group we intervened the houses, i.e. all objects or materials that were serving as artificial ecotopes for the bugs were removed, and the second group was used as control houses. After a year of periodic follow up, it became evident that in those houses with a modified environment the number of insects had decreased notoriously even after the first visits and this was more evident after a period of 12.5 to 13.5 months in which no insects were detected in eight of the houses. It also became clear that in this group of houses, recolonization by wild bugs from the surrounding areas, became more difficult, probably due to the absence of protection from bug predators. In the control houses, with the exception of three in which the inhabitants decided to intervene on their own, and another house with a peculiar situation, the insect populations remained the same or even showed a tendency to increase, as confirmed at the end of the experiment. We believe that the method is feasible, low costing and non contaminating. It could be used successfully in other places where T. dimidiata is common and also in countries where other species colonize peridomestic areas of homes. Environmental management of this kind should seek the participation of the members of the communities, in order to make it a more permanent control measure.

Copy number variation and chromatin structure

The functional consequences of structural variation in the human genome range from adaptation, to phenotypic variation, to predisposition to diseases. Copy number variation (CNV) was shown to influence the phenotype by modifying, in a somewhat dose-dependent manner, the expression of genes that map within them, as well as that of genes located on their flanks. To assess the possible mechanism(s) behind this neighboring effect, we compared histone modification status of cell lines from patients affected by Williams-Beuren, Williams-Beuren region duplication, Smith-Magenis or DiGeorge Syndrome and control individuals using a high-throughput version of chromatin immuno-precipitation method (ChIP), called ChlP-seq. We monitored monomethylation of lysine K20 on histone H4 and trimethylation of lysine K27 on histone H3, as proxies for open and condensed chromatin, respectively. Consistent with the changes in expression levels observed for multiple genes mapping on the entire length of chromosomes affected by structural variants, we also detected regions with modified histone status between samples, up- and downstream from the critical regions, up to the end of the rearranged chromosome. We also gauged the intrachromosomal interactions of these cell lines utilizing chromosome conformation capture (4C-seq) technique. We observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together, possibly forming an interacting cluster with each other and the WBSCR. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We conclude, that large genomic rearrangements can lead to changes in the state of the chromatin spreading far away from the critical region, thus possibly affecting expression globally and as a result modifying the phenotype of the patients. - Les conséquences fonctionnelles des variations structurelles dans le génome humain sont vastes, allant de l'adaptation, en passant par les variations phénotypiques, aux prédispositions à certaines maladies. Il a été démontré que les variations du nombre de copies (CNV) influencent le phénotype en modifiant, d'une manière plus ou moins dose-dépendante, l'expression des gènes se situant à l'intérieur de ces régions, mais également celle des gènes se trouvant dans les régions flanquantes. Afin d'étudier les mécanismes possibles sous-jacents à cet effet de voisinage, nous avons comparé les états de modification des histones dans des lignées cellulaires dérivées de patients atteints du syndrome de Williams-Beuren, de la duplication de la région Williams-Beuren, du syndrome de Smith-Magenis ou du syndrome de Di- George et d'individus contrôles en utilisant une version haut-débit de la méthode d'immunoprécipitation de la chromatine (ChIP), appelée ChIP-seq. Nous avons suivi la mono-méthylation de la lysine K20 sur l'histone H4 et la tri-méthylation de la lysine K27 sur l'histone H3, marqueurs respectifs de la chromatine ouverte et fermée. En accord avec les changements de niveaux d'expression observés pour de multiples gènes tout le long des chromosomes affectés par les CNVs, nous avons aussi détecté des régions présentant des modifications d'histones entre les échantillons, situées de part et d'autre des régions critiques, jusqu'aux extrémités du chromosome réarrangé. Nous avons aussi évalué les interactions intra-chromosomiques ayant lieu dans ces cellules par l'utilisation de la technique de capture de conformation des chromosomes (4C-seq). Nous avons observé qu'un groupe de gènes flanquants la région critique du syndrome de Williams-Beuren (WBSCR) forment souvent une boucle, constituant un groupe d'interactions privilégiées entre ces gènes et la WBSCR. La délétion de la WBSCR perturbe l'expression de ce groupe de gènes flanquants, mais également les interactions à grande échelle entre eux et la région réarrangée. Nous en concluons que les larges réarrangements génomiques peuvent aboutir à des changements de l'état de la chromatine pouvant s'étendre bien plus loin que la région critique, affectant donc potentiellement l'expression de manière globale et ainsi modifiant le phénotype des patients.