Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2019, Biomedical Sciences (Bioinformatics and Proteomics/Genomics)

Every human has about 100 novel mutations that are absent in the genomes of his/her parents. This intense influx of mutations degrades information that is stored in the DNA sequences and, at the same time, provides an opportunity for creation of new genetic messages. Currently, over one hundred million mutations have been characterized in the public databases. The dynamics of mutation have been investigated for decades in both experiments and sophisticated mathematical models, yet our understanding of genome evolution is still ambiguous. In this project, we computationally processed eighty million human mutations to get clear answers to basic questions about DNA evolution. Specifically, how is the non-randomness in nucleotide composition in vast genomic regions maintained? What biological forces preserve sequence non-randomness from being degraded by novel mutations? Our goal was to uncover peculiarities in dynamics of G+C nucleotide content and evaluate the equilibrium of GC-percentage in the human genome. We found that novel mutations that convert G:C pairs into A:T pairs are 1.39 times more frequent than opposite mutations that change A:T → G:C. This effect is more striking if we take into account the fact that the total number of G:C pairs (42%) is significantly less than the number of A:T pairs (58%). Hence, calculating per nucleotide pair, the mutations of G:C → A:T is 1.93 times more frequent than A:T → G:C mutations. Such bias should create fewer and fewer G:C pairs in the genomes from generation to generation, until it reaches equilibrium at 34% of GC-composition. However, the GC-percentage of the human genome is stable at 42%. There are two possible biological processes that may be responsible for preserving GC-composition from degradation: i) natural selection or ii) biased gene conversion. However, estimated parameters for both processes are unable to explain the maintenance of CG-percentage. We re-evaluated the biased gene conversion paramete (open full item for complete abstract)

Committee: Alexei Fedorov (Committee Chair); Robert Blumenthal (Committee Member); Sadik Khuder (Committee Member) Subjects: Bioinformatics; Biology

Doctor of Philosophy, Case Western Reserve University, 2004, Genetics

The human genome is comprised of a wide spectrum of repetitive sequences. Segmental duplications are a class of repetitive sequence that has been independently associated with human genomic disease and evolutionary rearrangements. I have undertaken a study to test the hypothesis that evolutionary rearrangements and rearrangements within the human genome are linked by genomic instability at sites of segmental duplication. This study has focused on the 15q11-q13 region of the human genome due to the presence of several large clusters of segmental duplications that have been associated with the common deletion breakpoints of Prader-Willi and Angelman syndromes. Using both computational and experimental techniques I have constructed sequence assemblies within these complex regions that provide a substrate for comparative primate studies. Extensive evolutionary variation at sites of segmental duplication, in both the pericentromeric region of 15q11 and within the 15q11-q13 common deletion breakpoints was observed. The scope of variation detected included both large-scale chromosome restructuring events and local re-patterning within clusters of segmental duplications. Sequence analysis of the 15q11-q13 common deletion breakpoint clusters revealed a complex evolutionary history associated with extensive segmental duplication. In addition, I describe a mechanism in which recurrent homogenization of a particular component of the 15q11-q13 breakpoints, the HERC2 duplicon, suggests dynamic restructuring of these regions occurred recently in multiple independent primate lineages. The abundant plasticity observed in the 15q11-q13 region in primates indicates genomic instability is a general property of segmental duplications that is not bound by the barrier of speciation. Also, through the use of the array comparative genomic hybridization technique I have demonstrated the efficacy of the method for detecting genomic imbalance across a wide range of 15q11-q13 genomic rearrangem (open full item for complete abstract)

Committee: Evan Eichler (Advisor) Subjects: Biology, Genetics