Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the Department Informatics of, Indiana University, August 2003 / Our personal genome, which is the map of our DNA, is our ultimate source of identity, which should be given our highest concern for security. The primary approach used for securing any highly sensitive health care data such as our genome would be to guard against any personal identity information being associated with the data. The belief that nameless data records eliminates risk and would be a benefit to research is the common pretense for how we manage our health data systems. However, the incredible advances that we are seeing with computational power and more affordable and sophisticated DNA sequencing software may be creating a problem greater then the benefit that it is providing. Now we must be concerned about all data in the health care systems that could provide a link to accessible identity free data. Old data records or samples that provide possibilities of DNA sequence matching to existing identity free genomic data presents a whole new problem. How might this change the face of health care? Will further advances in technology make it impossible for us to secure our personal health information? Solutions could lead to restricting our ability to improve health care or it could force us to rely more heavily on ethical judgment to protect the rights of patients. The unprecedented rate of recent advances in information technologies along with improved speed, economy and accuracy of mapping the human genome has created serious concerns about the usage and security of this new highly sensitive genetic data. Our knowledge of DNA has come along way in the 50 years since James Watson and Francis Crick first presented their discovery of the double helix. The discovery timeline has been crowded in recent years starting with the U.S, Department of Energy’s Human Genome Initiative in 1986 and culminating in completion of the Human Genome Project in 2003. The exponential growth of genomic scientific accomplishment now forces us to assume new milestones will arrive sooner then later.

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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 8 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 117-137).

Genome editing mediated by engineered nucleases, including Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) / CRISPR-associated (Cas) systems, holds great potential in a broad range of applications, including biomedical studies and disease treatment. In addition to creating cell lines and disease models, this technology allows generation of well-defined, genetically modified cells and organisms with novel characteristics that can be used to cure diseases, study gene functions, and facilitate drug development. However, achieving both high efficiency and high specificity remains a major challenge in nuclease-based genome editing. The objectives of this thesis were to optimize the design of TALENs to achieve high on-target cleavage activity, and analyze the off-target effect of CRISPR/Cas to help achieve high specificity. Based on experimental evaluation of >200 TALENs, we compared three different TALEN architectures, proposed new TALEN design rules, and developed a Scoring Algorithm for Predicting TALEN Activity (SAPTA) to identify optimal target sites with high activity. We also performed a systematic study to demonstrate the off-target cleavage by CRISPR/Cas9 when DNA sequences contain insertions or deletions compared to the RNA guide strand. Our results strongly indicate the need to perform comprehensive off-target analysis, and suggest specific guidelines for reducing potential off-target cleavage of CRISPR/Cas9 systems. The studies performed in this thesis work provide important insight and powerful tools for the optimization of engineered nucleases in genome editing, thus making a significant contribution to biomedical engineering and medical applications.

Comparisons using cDNA (cloned DNA from expressed genes) from different species greatly increases our understanding and ability to identify the changes in the genetic content of related species through the process of evolution.This research utilized cDNA isolated from developmentally staged female flowers of Tripsacum, a relative of modem maize (corn) with differing modes of reproductive behaviors. The gene expression clone libraries potentially carry the gene(s) responsible for the regulation of fertility, both apomixis and sexual reproduction, in Tripsacum sp. A set of yeast genes with known functions in the reproductive cell division known as meiosis were also investigated, but failed to hybridized to DNA of the maize mapping population.The Tripsacum cDNAs, E2-42 and M2-62, showed monomorphic band patterns, i.e., no differences between individuals. Possibility the quantity of E242 and M2-62 Tripsacum cDNAs for these locus were highly conserved with respect to the fragment lengths generated by restriction digestion of the test individuals. The Tripsacum cDNA sequence L4-14 revealed polymorphic bands patterns when used as a probe for mapping. The L4-14 polymorphisms were scored as both 1:2:1 and 3:1 segregation ratios and mapped to a subset of ordered loci from the Maize Database genome bank, University of Missouri. Two genetic map regions were identified as linked to the L4-14 locus. These regions included bin 6.05-6.08 of chromosome 6 and bin 8.00-.05 of chromosome 8. Linkage to two different chromosomal regions indicated that the L4-14 sequence may be duplicated within the maize genome. Results and discussion of this investigation and analyses are presented. / Department of Biology

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