title: INVESTIGATING ORIGIN AND FUNCTIONAL  IMPACT OF GENOMIC STRUCTURAL VARIANTS  WITH NEXT-GENERATION SEQUENCING
creator: Tica, Jelena
subject: 500
subject: 500 Natural sciences and mathematics
description: Genomic variants play an important role in phenotypic variation and have significant impact  on a disease development. Due to the technology limitations, inference of genomic variants and  their potential consequence on phenotype was until recently restricted. Only with the advent  of next-generation sequencing (NGS) approaches, could a vast majority of genomic variants be  successfully identified for the first time. In my PhD Thesis I will present my work on structural  variants (SVs), their formation mechanism and their functional impact.  The first part of my Thesis focuses on structural variants in non-human primates, studies of  which using NGS have not been pursued prior to the research studies we carried out. In order  to inspect the origin and functional impact of SV formation mechanisms, we constructed  a comprehensive SV map based on the fibroblast-derived DNA from three different species:  chimpanzee, orangutan and rhesus macaque. We noted striking differences in the activity of  homology-related SV formation mechanisms between the great apes and rhesus macaques, with  a third of the chimpanzee and orangutan SVs inferred to be formed by non-allelic homologous  recombination compared with only 2% of the macaque SVs. One additional key finding was  the presence of a markedly higher mobile element activity in macaques compared to the other  non-human primates studies. Additionally, we could show that long L1 elements surpassed Alu  activity in chimpanzee and orangutan as opposed to macaque where AluMacYa3 dominates  the genomic landscape causing a burst of relatively short SVs. In addition to inserting into  genome, active L1 elements possess the ability to mobilize 3’ flanking DNA to different genomic  loci as transductions. By combining translocation and L1 discovery pipelines we further developed  a novel computational methodology, termed TIGER, for the discovery of polymorphic  L1-mediated 3’ transductions. We employed TIGER to a deeply sequenced human genome and  to aforementioned non-human primates species to characterize transductions. TIGER enables  studying germline L1-mediated 3’ transductions, making a relevant structural variation class  amenable for population and disease studies for the first time.  In the second part of my Thesis, I discuss the differences in the formation mechanisms of both  germline and somatic SVs in the human genome. Our de novo mechanism classification analyses  performed on four previously published SV datasets revealed that almost half of germline human  SVs are due to mechanisms independent of homology, followed by homology-related DNA repair,  mobile elements and variable number of tandem repeats. We also investigated the formation of  somatic SVs in four medulloblastoma brain tumor patients with a germline TP53 mutation (Li-  Fraumeni syndrome). In contrast to the germline SVs, our analyses of rearrangement breakpoints  in medulloblastoma in the context of mutated TP53, rather support a model of massive DNA  double strand breaks known as chromothripsis, followed by exclusive homology-independent  repair.
date: 2015
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/18769/1/JelenaTica_PhDThesis_Final.pdf
identifier: DOI:10.11588/heidok.00018769
identifier: urn:nbn:de:bsz:16-heidok-187693
identifier:   Tica, Jelena  (2015) INVESTIGATING ORIGIN AND FUNCTIONAL IMPACT OF GENOMIC STRUCTURAL VARIANTS WITH NEXT-GENERATION SEQUENCING.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/18769/
rights: info:eu-repo/semantics/openAccess
rights: Please see front page of the work (Sorry, Dublin Core plugin does not recognise license id)
language: eng