Dal, Gülşah Merve2016-01-082016-01-082014http://hdl.handle.net/11693/16882Ankara : Department of Molecular Biology and Genetics and the Graduate School Engineering and Science of Bilkent University, 2014.Thesis (Ph. D.) -- Bilkent University, 2014.Includes bibliographical references leaves 106-118.Characterizing the patterns and rate of de novo mutations is crucial for our perception of evolution and genetic basis of human disease. Direct observation of de novo single nucleotide variation (SNV) rate in healthy individuals revealed a rate in a range of 0.82 – 1.70 ×10-8 base pair per generation. However, the developmental timing of the de novo mutations is unknown and thus, contribution of the early post-zygotic mutations to the human de novo SNV rate remained unknown. In an attempt to estimate the rate of de novo mutations regarding the developmental timing of mutagenesis, we sequenced the whole genomes of a healthy monozygotic twin pair and their parents with a total of 170 fold coverage. We identified the de novo SNVs through examination of the genotypes of each individual for each of the variants in a synchronous manner. Subsequent to the Sanger sequencing based validation, we conservatively characterized a total of 32 de novo SNVs. Of these 23 were shared by the twin pair, 8 were specific to twin I, and 1 was specific to twin II. We estimated the overall de novo SNV rate of 1.31 × 10-8 for twin I and 1.01 × 10-8 for twin II. The rate of the early post-zygotic de novo SNVs was calculated to be 0.34 × 10-8 and 0.04 × 10-8 for twin I and twin II, respectively. These data indicate the growing importance of genome mosaicism which might be resulted from de novo mutations of early post-zygotic origin in disease pathogenesis.xvvi, 199, [5] leaves, graphics, tablesEnglishinfo:eu-repo/semantics/openAccessMutation ratede novo SNVmonozygotic twinssomatic mosaicismearly post-zygoticnext generation sequencingQZ50 .D35 2014Genetic disorders.Human chromosome abnormalities.Genomics.Genetic disorders--Epidemiology.Single nucleotide polymorphisms.Genetics--Research.Thesis