Date of Award

4-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Genetics, Genomics and Informatics

Research Advisor

Vincenza Colonna, Ph.D.

Committee

Hao Chen, PhD; Erik Garrison, PhD; Mozhui Kyhobeni, PhD; Robert W. Williams, PhD

Keywords

genomics; pangenomic; genotype-phenotype

Abstract

My thesis explores the application of advanced techniques for discovery of genetic variation and pangenomic approaches to enhance our understanding of genetic variation and genotype-phenotype relationships in two key model organisms: the HXB/BXH recombinant inbred rat family and the BXD mouse family. Through deep sequencing and innovative computational methods, I constructed com- prehensive pangenome graphs that captured genetic diversity beyond what is accessible through conventional single-reference approaches. In the HXB rat family, I identified approximately 200 million base pairs of sequence absent from the reference genome and discovered novel variants associated with glucose metabolism and chromogranin expression through phenome-wide association studies. In the BXD mouse family, I leveraged linked-read sequencing data from 152 strains to create a detailed catalog of genetic variants, improving QTL mapping precision and enabling the identification of regions undergoing parallel evolution across independent populations. By develop- ing new methodologies for mapping reads to pangenome graphs and implementing pangenome-based QTL mapping, I demonstrated that these approaches significantly enhance variant discovery and resolution, particularly in complex genomic regions rich in repetitive elements.I also employed genotype-phenotype mapping to analyze adaptive signatures resulting from laboratory selection pressures. My work shows that even with short linked-reads, pangenomic analyses enable the detection of a truly comprehensive set of variants that would be missed by traditional methods. My research advances our understanding of complex genotype-phenotype relationships, establishes pangenomes as valuable tools for comprehensive genetic analysis in model organisms, and provides a foundation for future applications in precision medicine.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0003-3633-0610

DOI

10.21007/aetd.cghs.2025.0019

Additional Files
2025-003-Villani_AETD-DOA.pdf (182 kB)
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