Deciphering Genotype-Phenotype Connections: Leveraging Pangenomes and Comprehensive Genome Variation

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