Bioinformatics investigation of biological characteristics of cell-free DNA to enhance non-invasive prenatal testing and cancer detection

Ph.D. ; There is increasing research interest in studying the biological characteristics of circulating cell-free DNA (cfDNA) as well as its clinical applications. The discoveries of circulating fetal DNA in the plasma of pregnant women, of donor-specific DNA in patients who have undergone an organ transplantation, and tumor-derived DNA in cancer patients have opened up numerous new possibilities for noninvasive prenatal testing (NIPT), transplant monitoring, and cancer liquid biopsy. In this thesis, I have developed novel bioinformatics approaches with which to assiduously study the biological properties of cell-free DNA. I have then incorporated these novel findings into refined bioinformatics platforms to enhance noninvasive prenatal testing and cancer detection. I have performed detailed investigations of plasma DNA fragment sizes, of preferential cleavage sites of plasma DNA derived from different tissues (i.e., plasma DNA preferred ends), and the relationship between fragment end points and nucleosome structures. ; In the first section, I have briefly summarized the biology of cfDNA and its current clinical applications. ; In the second section, I described my work on the development of a novel bioinformatics algorithm with which to determine the genomic locations that are preferentially cleaved in fetal and maternal DNA genomes, referred to as the fetal-preferred and maternal-preferred ends. I have also studied the relationship between plasma DNA preferred ends and nucleosome structures. It was found that fetal DNA was frequently cut within the nucleosomal cores, whereas maternal DNA was cut mostly within the nucleosomal linker regions—discoveries that offered new insights into the mechanism of plasma DNA generation whereby fetal DNA molecules are shorter than maternal DNA molecules. Determination of these preferred ends also allowed us to noninvasively predict fetal DNA fraction while improving the overall performance of NIPT. Fetal DNA fraction is one of the important parameters governing the overall ...