Abstract
Classical genetics describes inheritance in terms of discrete alleles passed from both parents to offspring according to Mendelian inheritance, but many biologically and clinically important genetic phenomena fall outside this framework. This dissertation examines three such phenomena — uniparental disomy, somatic mosaicism, and mitochondrial DNA variation — developing computational and experimental frameworks to detect, benchmark, and interpret each. Unlike typical biparental inheritance, uniparental disomy (UPD) occurs when both chromosomal copies originate from the same parent. I developed Triomix-UPD, an integrated short- and long-read sequencing framework for UPD detection and applied it to 3,740 congenital heart disease (CHD) trios, identifying a 6.57-fold enrichment relative to the general population. Pathogenic variants in PIEZO1 and GLYR1 and a novel candidate gene MESD were functionally validated in zebrafish and human cells, establishing UPD as an underrecognized contributor to CHD. Somatic mosaicism — the presence of genetically distinct cell populations arising from mutations that occur after fertilization — is widespread in human disease, yet robust benchmarks remain scarce. Within the SMaHT Consortium, we mixed six HapMap cell lines to construct a benchmarking resource, enabling systematic evaluation of somatic variant detection technologies. Finally, we characterized mitochondrial DNA (mtDNA) variation across 25 donors and dozens of tissues per donor. Somatic mtDNA burden increased with age in most tissues. Together, these three projects advance our understanding of atypical genetic mechanisms and provide broadly applicable tools for human genomics and disease research.
Committee Chair
Sheng Shih Jin
Committee Members
Dustin Baldridge; Malachi Griffith; Monkol Lek; Patricia Dickson; Ting Wang
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Human & Statistical Genetics)
Document Type
Dissertation
Date of Award
8-13-2026
Language
English (en)
DOI
https://doi.org/10.7936/93py-6b85
Recommended Citation
Kong, Na Hyun, "Atypical Genetic Mechanisms: Uniparental Disomy, Somatic Mosaicism, and Mitochondrial Variation" (2026). Arts & Sciences Graduate Student Theses and Dissertations. 3862.
The definitive version is available at https://doi.org/10.7936/93py-6b85