Structure and function of the human genome.
ABSTRACT The human genome project has had an impact on both biological research and its political organization; this review focuses primarily on the scientific novelty that has emerged from the project but also touches on its political dimensions. The project has generated both anticipated and novel information; in the later category are the description of the unusual distribution of genes, the prevalence of non-protein-coding genes, and the extraordinary evolutionary conservation of some regions of the genome. The applications of the sequence data are just starting to be felt in basic, rather than therapeutic, biomedical research and in the vibrant human origins and variation debates. The political impact of the project is in the unprecedented extent to which directed funding programs have emerged as drivers of basic research and the organization of the multidisciplinary groups that are needed to utilize the human DNA sequence.
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ABSTRACT: Shotgun sequencing is the most powerful strategy for large scale sequencing. Two main approaches exist: clone-by-clone and whole genome shotgun (WGS). In the clone-by-clone strategy, overlapping clones are amplified and then sheared in a random fashion. In the WGS approach, a sufficient amount of cells from the target organism are obtained, and the random shearing is performed on extracted DNA. In both approaches, the resulting fragments are cloned and the fragment ends are subsequently sequenced, producing sequence reads. If a sufficient amount of sequence has been obtained, the reads will overlap in a way that makes it possible to deduce their correct order. A number of computer programs have been developed for this task. However, none of these programs are capable of producing correct assemblies if the target sequence contains repeats. This is because assembly algorithms in general are greedy, which means that when faced with different alternatives for the positioning of a read, the algorithm will fit the read at the first available position meeting the criteria for inclusion into the assembly. The resulting assemblies typically have the repeat regions degenerated, truncating the regions into a few copies with abnormally high shotgun coverage. This phenomenon occurs even when the repeat copies differ from each other, since the assembly programs are unable to distinguish the subtle differences between repeat elements from the sequencing errors produced by the sequencing apparatus . The work presented here is aimed at solving the repeat problem by detecting and utilizing single base differences between nearly identical repeats. In paper I, a statistical method for detecting repeat differences in the presence of sequencing errors was developed, implemented, and tested on simulated data. We showed that it is possible to obtain high specificity as well as sensitivity compared to other methods, by evaluating coinciding deviations from consensus in pairs of columns in multiple alignments. In paper II, a finishing tool (DNPTrapper) that visualizes the differences and enables manual and semi-automatic resolution of repeat regions was constructed and tested with simulated data as well as real data from the Trypanosoma cruzi WGS project. Results showed that using DNPTrapper, it is possible to resolve and analyze complicated repeat regions previously considered difficult or even impossible to resolve. Finally in paper III, five repeated genes in T. cruzi were analyzed using DNPTrapper. Different repeat characteristics in the parasite were described, and it was shown that thorough analysis of repeat regions is required for correcting erroneous consensus sequences of repeated genes in the assembly.
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ABSTRACT: This paper describes PDB4DNA, a new Geant4 user application, based on an independent, cross-platform, free and open source C library, so-called PDBlib, which enables use of atomic level description of DNA molecule in Geant4 Monte Carlo particle transport simulations. For the evaluation of direct damage induced on the DNA molecule by ionizing particles, the application makes use of an algorithm able to determine the closest atom in the DNA molecule to energy depositions. Both the PDB4DNA application and the PDBlib library are available as free and open source under the Geant4 license.Computer Physics Communications 03/2015; DOI:10.1016/j.cpc.2015.02.026 · 2.41 Impact Factor
Article: Postmarketing Analysis of Medicines[Show abstract] [Hide abstract]
ABSTRACT: There are many surveillance systems of congenital defects all over the world; several of them have developed specific approaches to generate and test selected hypotheses regarding human teratogens. However, to the best of our knowledge, none of them have a permanent and systematised programme for the study of the risk and safety of drugs. The aim of this article is to describe the research programme on the potential effects of drugs in pregnancy followed by the Spanish Collaborative Study of Congenital Malformations (ECEMC), which is a permanent ongoing case-control study and surveillance system. The programme to analyse drugs includes a continuous and systematic study on the potential effects of medicines used during pregnancy. This programme has several characteristics that make it different from other current systems: (i) the collection of numerous datapoints (up to 312 per infant) in a case-control design; (ii) the use of a versatile and specific coding of birth defects; (iii) a specific programme for the continuous analysis of the potential effects of each type of drugs used during pregnancy that has been developed specifically for the ECEMC methodology, including its dysmorphological coding system. The description of the ECEMC’s approach to surveillance of the effects of drug use during pregnancy may help researches in this area, particularly those using data from birth defects registries.Drug Safety 30(4). DOI:10.2165/00002018-200730040-00003 · 2.62 Impact Factor