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Structural Variations in the Human Genome M Structural variations in the human genome The current focus in research on DNA Myrthe Jager July 2011 W.P Kloosterman Department of medical genetics Structural variations in the human genome M. Jager esearch on DNA has evolved from the discovery of the double-helix structure in 1953 to structural variations today. Structural variations are all genomic rearrangements R bigger than one base pair. This definition includes deletions, insertions, translocations, inversions, and duplications. Genomic rearrangements can have an influence on phenotype, and are thus associated with diseases. A Structural variation in a somatic cell might change susceptibility to cancer while a de novo rearrangement in a germ cell might result in congenital defects. Sequencing the break point can aid in relating the variant to a phenotypic effect and may help identifying a mutational mechanism. Three major mechanisms have currently been suggested. NAHR and NHEJ are double strand DNA break repair mechanisms. FoSTeS (or MMBIR) is a replication-based mechanism. Chromothripsis, retrotransposition, alternative FoSTeS and alternative end-joining (MMEJ) are also suggested mechanisms, resulting in structural variations. Finding and defining both pathogenic and non-pathogenic structural variations is important, since we will then be able to establish the cause for some diseases. In the project described in this article, the occurrence of four recurrent non-pathogenic deletions in the population was determined. This experiment shows that non-pathogenic rearrangements are quite common in the population. The deletions in chromosomes 1, 5, 22, and the X-chromosome are present in 35% to 93% of the population. Furthermore, a second experiment was performed in which structural variations of two children with congenital defects were sequenced by capillary sequencing. The goal of this experiment was to identify a possible cause for their abnormalities and to establish which mutational mechanism could have led to the structural variation. No de novo mutations were found in one of the patients. Two mutations that he inherited from his mother were caused by MMEJ and retrotransposition. In the other patient, two de novo rearrangements were found. Sequencing of one of them failed. The other was a 1.4 Mb tandem duplication, containing five genes and two non-processed pseudogenes, of which the coding sequence was still intact. I conclude that this duplication is caused by FoSTeS. Each of the de novo mutations could in theory be the cause for the congenital defects found in the first patient. 2 July 2011 Structural variations in the human genome M. Jager Index Introduction ............................................................................................................................................. 5 Structural variations ............................................................................................................................ 6 Effects of structural variations on phenotype ..................................................................................... 8 Location of mutation ....................................................................................................................... 8 Non-coding DNA .......................................................................................................................... 8 Coding DNA ................................................................................................................................. 9 Structural variations are associated with diseases ....................................................................... 10 De novo ..................................................................................................................................... 10 Cancer ........................................................................................................................................ 12 Population-based differences ....................................................................................................... 12 Detection and identification .............................................................................................................. 13 FISH and Karyotyping .................................................................................................................... 13 Next-generation sequencing ......................................................................................................... 14 Capillary sequencing .................................................................................................................. 15 CNV arrays ..................................................................................................................................... 15 Mutational mechanisms .................................................................................................................... 16 NHEJ ............................................................................................................................................... 17 Alternative EJ pathways ............................................................................................................ 18 HDR ................................................................................................................................................ 18 Replication-based mechanisms ..................................................................................................... 20 MMBIR ....................................................................................................................................... 20 FoSTeS ....................................................................................................................................... 20 Other mechanisms ........................................................................................................................ 21 Retrotransposition..................................................................................................................... 21 Alternative fork stalling ............................................................................................................. 22 Chromothripsis .......................................................................................................................... 22 3 July 2011 Structural variations in the human genome M. Jager Introduction to experiments ................................................................................................................. 23 Materials and methods ......................................................................................................................... 23 PCR and gel electrophoresis analysis ................................................................................................ 23 Significance testing ............................................................................................................................ 23 Primer pairs and DNA-samples.......................................................................................................... 23 Experiment 1 ................................................................................................................................. 23 Experiment 2 ................................................................................................................................. 24 Capillary sequencing of breakpoints and analysis of sequence reads .............................................. 24 Results ................................................................................................................................................... 25 Experiment 1 ..................................................................................................................................... 25 Primer 4 ......................................................................................................................................... 25 Primer 51 ....................................................................................................................................... 25 Primer 71 ....................................................................................................................................... 25 Primer 76 ....................................................................................................................................... 27 Experiment 2 ..................................................................................................................................... 27 Sample 2 ........................................................................................................................................ 27 Sample 3 and 4 .............................................................................................................................. 29 Sample 5 ........................................................................................................................................ 30 Discussion .............................................................................................................................................. 30 Acknowledgements ............................................................................................................................... 33 References ............................................................................................................................................. 33 4 July 2011 Structural variations in the human genome M. Jager Introduction Deoxyribose nucleic acid or
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