Advanced genome and transcriptome analysis using long-read sequencing technologies

Project Summary As the advancement of long-read sequencing technologies and cutting-edge algorithms, haplotype- resolved telomere-to-telomere (T2T) genome assemblies have almost become available. With more complete genomes and whole-genome long-read sequencing data becoming available, there is an urgent need for comprehensive and personalized analysis of both genomes and transcriptomes. For example, long reads facilitate the discovery of an unprecedented level of structural variations. However, the detailed genome architecture, evolution, and function of multiallelic copy number variations (mCNVs) are unknown, as are nuclear mitochondrial DNA segments (NUMTs). In addition, pan-genome and individualized genome annotation are not yet available, nor are complex rearrangements in the transcriptome, such as V(D)J recombination and gene fusions. Without a comprehensive investigation of individual genomes and transcriptomes, we may miss important information residing at the genome or transcriptome level that may account for various phenotypes and associated diseases. The long-term goal of the laboratory is to comprehensively characterize all forms of genomic and transcriptomic variations and understand their functional consequences and formation mechanisms. While the ESI MIRA has enabled the Principal Investigator to establish a sustainable research program in genomics and bioinformatics with a focus on long- read genomic algorithm development and data analysis, the primary goals for the MIRA Renewal over the next five years include expanding the program to concentrate on both genomic and transcriptomic algorithm development for long-read sequencing, as well as advancing the analysis of sequencing data. The proposed work is innovative as it leverages long-read sequencing technologies combined with advanced bioinformatics tools to enhance the analysis of mCNVs and other genomic variants, offering significant improvements in our understanding of human genome evolution and the potential for novel clinical applications in areas like cancer genomics and precision medicine. The proposed research is significant because it pioneers the application of long-read sequencing to provide a deeper and more accurate understanding of complex genomic and transcriptomic structures, which are critical for unraveling the intricate relationships between genetic variations and phenotypic outcomes in human health and disease.