Tracing the origin of disease: studies in thymic epithelial tumors and pandemic SARS-CoV-2

Abstract

Over other genomics techniques, whole-genome sequencing can provide clues to infer major mutagenic processes, timing and order of mutations, and evolutionary characteristics of a given sample. Therefore, this can be used as means of understanding and exploring the characteristics of the disease. This dissertation consists of two major parts. Part 1 describes two apparently distinct cell-of-origins and their clonal evolution toward tumorigenesis through combination analyses of genome and transcriptome profiles of 137 thymic epithelial tumors as well as single-cell transcriptomes of normal thymic tissues. These include (1) thymic progenitor cells evolving into copy-number-stable tumors by a GTF2I gain-of-function point-mutation, and (2) differentiated thymic epithelial cells evolving into tumors by the acquisition of multiple arm-level copy number changes and transcriptional activation of IRS4, a novel oncogene. Mutation-timing analyses on the second group revealed that the progressive copy number gains start from the first decade of the patients’ life. By this stratification, thymomas show substantial differences in transcriptional, metabolic, and immuno-oncologic phenotypes, reflecting the heterogeneity of the cell-of-origin. Part 2 shows an application of the mutational signature analysis to virus evolution to identify its origin and evolutionary characteristics. Through a systematic comparison of 351,525 complete viral genome sequences collected during the recent COVID-19 pandemic, the spectrum of SARS-CoV-2 mutations was investigated. The mutational spectrum of SARS-CoV-2 exhibits extreme asymmetry, with a much higher rate of C>U than U>C substitutions, as well as a higher rate of G>U than U>G substitutions. The substantial asymmetry and directionality of the mutational spectrum enable revealing the Asian origin of SARS-CoV-2 without prior information about the root sequence, collection time, and sampling region. Comparative analysis between relative viruses revealed that the asymmetric spectrum suggests punctuated equilibrium and that the virus is in an accelerated evolutionary phase. These findings provide deep insights into the mutational processes in SARS-CoV-2 viral infection and advance the understanding of the history and future evolution of the virus.