<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING"^^ . "Genomic variants play an important role in phenotypic variation and have significant impact\r\non a disease development. Due to the technology limitations, inference of genomic variants and\r\ntheir potential consequence on phenotype was until recently restricted. Only with the advent\r\nof next-generation sequencing (NGS) approaches, could a vast majority of genomic variants be\r\nsuccessfully identified for the first time. In my PhD Thesis I will present my work on structural\r\nvariants (SVs), their formation mechanism and their functional impact.\r\nThe first part of my Thesis focuses on structural variants in non-human primates, studies of\r\nwhich using NGS have not been pursued prior to the research studies we carried out. In order\r\nto inspect the origin and functional impact of SV formation mechanisms, we constructed\r\na comprehensive SV map based on the fibroblast-derived DNA from three different species:\r\nchimpanzee, orangutan and rhesus macaque. We noted striking differences in the activity of\r\nhomology-related SV formation mechanisms between the great apes and rhesus macaques, with\r\na third of the chimpanzee and orangutan SVs inferred to be formed by non-allelic homologous\r\nrecombination compared with only 2% of the macaque SVs. One additional key finding was\r\nthe presence of a markedly higher mobile element activity in macaques compared to the other\r\nnon-human primates studies. Additionally, we could show that long L1 elements surpassed Alu\r\nactivity in chimpanzee and orangutan as opposed to macaque where AluMacYa3 dominates\r\nthe genomic landscape causing a burst of relatively short SVs. In addition to inserting into\r\ngenome, active L1 elements possess the ability to mobilize 3’ flanking DNA to different genomic\r\nloci as transductions. By combining translocation and L1 discovery pipelines we further developed\r\na novel computational methodology, termed TIGER, for the discovery of polymorphic\r\nL1-mediated 3’ transductions. We employed TIGER to a deeply sequenced human genome and\r\nto aforementioned non-human primates species to characterize transductions. TIGER enables\r\nstudying germline L1-mediated 3’ transductions, making a relevant structural variation class\r\namenable for population and disease studies for the first time.\r\nIn the second part of my Thesis, I discuss the differences in the formation mechanisms of both\r\ngermline and somatic SVs in the human genome. Our de novo mechanism classification analyses\r\nperformed on four previously published SV datasets revealed that almost half of germline human\r\nSVs are due to mechanisms independent of homology, followed by homology-related DNA repair,\r\nmobile elements and variable number of tandem repeats. We also investigated the formation of\r\nsomatic SVs in four medulloblastoma brain tumor patients with a germline TP53 mutation (Li-\r\nFraumeni syndrome). In contrast to the germline SVs, our analyses of rearrangement breakpoints\r\nin medulloblastoma in the context of mutated TP53, rather support a model of massive DNA\r\ndouble strand breaks known as chromothripsis, followed by exclusive homology-independent\r\nrepair."^^ . "2015" . . . . . . . "Jelena"^^ . "Tica"^^ . "Jelena Tica"^^ . . . . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (PDF)"^^ . . . "JelenaTica_PhDThesis_Final.pdf"^^ . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (Other)"^^ . . . . . . "preview.jpg"^^ . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (Other)"^^ . . . . . . "medium.jpg"^^ . . . "INVESTIGATING ORIGIN AND FUNCTIONAL\r\nIMPACT OF GENOMIC STRUCTURAL VARIANTS\r\nWITH NEXT-GENERATION SEQUENCING (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #18769 \n\nINVESTIGATING ORIGIN AND FUNCTIONAL \nIMPACT OF GENOMIC STRUCTURAL VARIANTS \nWITH NEXT-GENERATION SEQUENCING\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .