A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families - long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements - mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development. © 2010 Elsevier Ltd

LINEs and SINEs of primate evolution

The primate order is a monophyletic group thought to have diverged from the Euarchonta more than 65 mya.1 Recent paleontological and molecular evolution studies place the last common ancestor of primates even earlier (≥ 85 mya).2 More than 300 extant primate species are recognized today,3, 4 clearly emphasizing their diversity and success. Our understanding of the evolution of primates and the composition of their genomes has been revolutionized within the last decade through the increasing availability and analyses of sequenced genomes. However, several aspects of primate evolution have yet to be resolved. DNA sequencing of a wider array of primate species now underway will provide an opportunity to investigate and expand on these questions in great detail. One of the most surprising findings of the human (Homo sapiens) genome project was the high content of repetitive sequences, in particular of mobile DNA.5 This finding has been replicated in all available and analyzed primate draft genome sequences analyzed to date.5-7 In fact, transposable elements (TEs) contribute about 50% of the genome size of humans,5 chimpanzees (Pan troglodytes),6 and rhesus macaques (Macacca mulatta).7 The proportion of TEs among the overall genome content is likely even higher due to the decay of older mobile elements beyond recognition, rearrangements of genomes over the course of evolution, and the challenge of sequencing and assembling repeat-rich regions of the genome.8, 9 Retrotransposons, in particular L1, long interspersed element 1 (LINE1), and Alu, a short interspersed element (SINE), are prominent in primate genomes, and have played a major role in genome evolution and architecture. The evolution and success of the primate-specific LINE and SINE subfamilies (L1 and Alu in particular), their application in phylogenetic studies, and their impact on the architecture of primate genomes will be the focus of this review. In addition, we will briefly cover the emergence and impact of SVA (SINE-R/VNTR/Alu), a composite retrotransposon of relatively recent origin, and of other SINEs that are not common to all primates. © 2010 Wiley Periodicals, Inc

User needs, benefits and integration of robotic systems in a space station laboratory

The methodology, results and conclusions of the User Needs, Benefits, and Integration Study (UNBIS) of Robotic Systems in the Space Station Microgravity and Materials Processing Facility are summarized. Study goals include the determination of user requirements for robotics within the Space Station, United States Laboratory. Three experiments were selected to determine user needs and to allow detailed investigation of microgravity requirements. A NASTRAN analysis of Space Station response to robotic disturbances, and acceleration measurement of a standard industrial robot (Intelledex Model 660) resulted in selection of two ranges of low gravity manipulation: Level 1 (10-3 to 10-5 G at greater than 1 Hz.) and Level 2 (less than = 10-6 G at 0.1 Hz). This included an evaluation of microstepping methods for controlling stepper motors and concluded that an industrial robot actuator can perform milli-G motion without modification. Relative merits of end-effectors and manipulators were studied in order to determine their ability to perform a range of tasks related to the three low gravity experiments. An Effectivity Rating was established for evaluating these robotic system capabilities. Preliminary interface requirements were determined such that definition of requirements for an orbital flight demonstration experiment may be established

Identification and characterization of novel polymorphic LINE-1 insertions through comparison of two human genome sequence assemblies

Mobile elements represent a relatively new class of markers for the study of human evolution. Long interspersed elements (LINEs) belong to a group of retrotransposons comprising approximately 21% of the human genome. Young LINE-1 (L1) elements that have integrated recently into the human genome can be polymorphic for insertion presence/absence in different human populations at particular chromosomal locations. To identify putative novel L1 insertion polymorphisms, we computationally compared two draft assemblies of the whole human genome (Public and Celera Human Genome assemblies). We identified a total of 148 potential polymorphic L1 insertion loci, among which 73 were candidates for novel polymorphic loci. Based on additional analyses we selected 34 loci for further experimental studies. PCR-based assays and DNA sequence analysis were performed for these 34 loci in 80 unrelated individuals from four diverse human populations: African-American, Asian, Caucasian, and South American. All but two of the selected loci were confirmed as polymorphic in our human population panel. Approximately 47% of the analyzed loci integrated into other repetitive elements, most commonly older L1s. One of the insertions was accompanied by a BC200 sequence. Collectively, these mobile elements represent a valuable source of genomic polymorphism for the study of human population genetics. Our results also suggest that the exhaustive identification of L1 insertion polymorphisms is far from complete, and new whole genome sequences are valuable sources for finding novel retrotransposon insertion polymorphisms. © 2006 Elsevier B.V. All rights reserved

Nesting Common Eider (Somateria mollissima) Population Quintuples in Northwest Greenland

Common eider (Somateria mollissima) populations in Greenland severely declined throughout the 20th century. As a result, in 2001, harvest regulations were changed and the length of the hunting season was reduced. Recent data suggest that these changes have been successful, and population regrowth is occurring. In the Avanersuaq District, northwest Greenland, only one systematic survey quantifying the number of nesting eiders had previously been conducted, in 1997 and 1998. Although this district had historically been identified as having the largest number of breeding eiders in Greenland, the 1997–98 survey results showed a relatively small estimated population of 5000 pairs. However, it is not known to what extent changes in hunting regulations have affected nesting abundance in this area. Therefore, the Avanersuaq District was systematically resurveyed during the 2009 breeding season, approximately 11 years after the previous survey. These results showed that the population had increased to 5.4 times its 1997–98 size, with an annual compounded growth rate of 15.3%. On a single island, nearly 4500 active nests were observed. Five islands had more than 2600 nests each and comprised 75% of the total nests counted. Along with historical information to account for additional nesting habitat not surveyed, the observed population growth rate from this study suggests that the overall Avanersuaq common eider breeding population size ranges from 25 000 to 30 000 pairs, or roughly half of the total estimated West Greenland breeding population. Despite the significance of the Avanersuaq District as a breeding area for common eiders, we have only limited information about this population. The effects of recent extensions of the hunting season on this population are also unknown, and the only wintering location information is based on a few individuals banded in the 1920s and 1940s. Additional research on migratory movements is suggested before any further changes are made to hunting regulations.Au cours du XXe siècle, les populations d’eiders à duvet (Somateria mollissima) ont connu un déclin considérable au Groenland. C’est pourquoi en 2001, le règlement relatif à la chasse a été modifié et la saison de chasse a été raccourcie. Selon des données récentes, ces changements ont porté fruits en ce sens que la population s’est accrue. Dans le district d’Avanersuaq, dans le nord-ouest du Groenland, seulement un relevé systématique ayant pour but de quantifier le nombre d’eiders nicheurs a été fait, et c’était en 1997-1998. Bien qu’au fil des ans, ce district a compté le plus grand nombre d’eiders reproducteurs du Groenland, le relevé de 1997-1998 avait établi que la population était relativement petite, avec une estimation de 5 000 paires. On ne sait toutefois pas dans quelle mesure la modification du règlement sur la chasse a eu des effets sur l’abondance d’eiders nichant dans la région. Par conséquent, le district d’Avarsuaq a systématiquement fait l’objet d’un autre relevé pendant la saison de reproduction de 2009, soit environ 11 ans après le relevé d’origine. Les résultats ont permis de constater que la population s’était accrue dans une mesure de 5,4 fois par rapport à sa taille de 1997-1998, ce qui correspondait à un taux d’accroissement annuel composé de 15,3 %. Sur une seule île, près de 4 500 nids actifs ont été observés. Cinq îles comptaient plus de 2 600 nids par île, ce qui représentait 75 % du nombre total de nids répertoriés. Jumelé aux données historiques tenant compte de l’habitat de nidification supplémentaire et non relevé, le taux d’accroissement de la population observé à partir de cette étude suggère que la taille de la population globale d’eiders à duvet nicheurs d’Avanersuaq varie de 25 000 à 30 000 paires, ce qui correspond à environ la moitié du total estimé de la population nicheuse de l’ouest du Groenland. Malgré l’importance que revêt le district d’Avanersuaq comme aire de reproduction de l’eider à duvet, nous ne possédons que des renseignements restreints au sujet de cette population. Les effets qu’aura le prolongement récent de la saison de chasse sur cette population sont également inconnus, et la seule information concernant la localisation de l’aire d’hivernage dont nous disposons a trait à quelques individus qui avaient été bagués dans les années 1920 et 1940. Par conséquent, il est suggéré de pousser les recherches relatives aux mouvements migratoires plus loin avant d’apporter d’autres changements au règlement de chasse

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

A specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischaemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP (cytochrome P450)-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. In the present study we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal mono-oxygenase system that metabolized EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. The main products included 17,18-EEQ (17,18-epoxyeicosatetraenoic acid) from EPA and 14,15-EET (14,15-epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA (polyunsaturated fatty acid)-deficient, Δ-12 and Δ-6 fatty acid desaturase mutants (fat-2 and fat-3 respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolizable AA analogue. Short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. On the basis of these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity under normoxic conditions and was effective not only with C20-PUFA-deficient mutants, but to a lesser extent also with wild-type worms

The Landscape of Reason: A Scheme for Representing Arguments Concerning Environmental, Health and Safety Effects of Chemical Weapons Disposal in the US

To reduce the risk of environmental contamination and honor an international treaty, chemical weapons stored at eight locales around the US are slated for destruction. Incineration is the main choice of a National Research Council committee directed by Congress to weigh the hazards of alternative destruction technologies, but many citizens\u27 groups remain unconvinced. The US Army, which must dispose of the dangerous chemicals, faces decisions about the choice of destruction technologies, as well as more specific questions concerning protection of environment, safety and public health once the technology choices are made. Based on more than 200 individual interviews and 40 focus groups held in communities near where the weapons are stored, this paper illustrates an argumentation scheme for representing the underlying reasons for varying positions in the conflict over technology choices. The argumentation scheme is effective in representing qualitative interview data concerning the complex and dynamic environmental perspectives of diverse regional and national constituencies

Tangram: A comprehensive toolbox for mobile element insertion detection

© 2014 Wu et al.; licensee BioMed Central Ltd. Background: Mobile elements (MEs) constitute greater than 50% of the human genome as a result of repeated insertion events during human genome evolution. Although most of these elements are now fixed in the population, some MEs, including ALU, L1, SVA and HERV-K elements, are still actively duplicating. Mobile element insertions (MEIs) have been associated with human genetic disorders, including Crohn\u27s disease, hemophilia, and various types of cancer, motivating the need for accurate MEI detection methods. To comprehensively identify and accurately characterize these variants in whole genome next-generation sequencing (NGS) data, a computationally efficient detection and genotyping method is required. Current computational tools are unable to call MEI polymorphisms with sufficiently high sensitivity and specificity, or call individual genotypes with sufficiently high accuracy.Results: Here we report Tangram, a computationally efficient MEI detection program that integrates read-pair (RP) and split-read (SR) mapping signals to detect MEI events. By utilizing SR mapping in its primary detection module, a feature unique to this software, Tangram is able to pinpoint MEI breakpoints with single-nucleotide precision. To understand the role of MEI events in disease, it is essential to produce accurate individual genotypes in clinical samples. Tangram is able to determine sample genotypes with very high accuracy. Using simulations and experimental datasets, we demonstrate that Tangram has superior sensitivity, specificity, breakpoint resolution and genotyping accuracy, when compared to other, recently developed MEI detection methods.Conclusions: Tangram serves as the primary MEI detection tool in the 1000 Genomes Project, and is implemented as a highly portable, memory-efficient, easy-to-use C++ computer program, built under an open-source development model