Decoding the genome beyond sequencing: The new phase of genomic research

Abstract

While our understanding of gene-based biology has greatly improved, it is clear that the function of the genome and most diseases cannot be fully explained by genes and other regulatory elements. Genes and the genome represent distinct levels of genetic organization with their own coding systems; Genes code parts like protein and RNA, but the genome codes the structure of genetic networks, which are defined by the whole set of genes, chromosomes and their topological interactions within a cell. Accordingly, the genetic code of DNA offers limited understanding of genome functions. In this perspective, we introduce the genome theory which calls for the departure of gene-centric genomic research. To make this transition for the next phase of genomic research, it is essential to acknowledge the importance of new genome-based biological concepts and to establish new technology platforms to decode the genome beyond sequencing.

Evolutionary mechanism unifies the hallmarks of cancer

“…While most of the molecular targets are well-characterized, in real tumors, they quickly become moving targets under medical treatments, especially when the treatment pressure is high, rapid and massive genome reorganization (termed genome chaos) occurs, which can drastically change dominating pathways. [24][25][26] Interestingly, mathematical and evolutionary modeling have supported that therapeutic intervention can provide selective pressure for the expansion of resistant variants, 27,28 and treatment has been proposed to accelerate cancer genome evolution and tumor progression. 29 This would suggest that, regardless of which hallmark is targeted, the cancer adapts and persists.…”

“…1). 24,25 The transition of two phases of somatic cell evolution is linked to stress response, system instability, genome-mediated system replacement coupled with diverse phenotypes and how evolution occurs. Together with the evolutionary mechanism of cancer, it offers explanations to many previous puzzling issues, such as (i) why there is elevated genome alteration in the first place.…”

“…42 key transitions of cancer. 24 Recently, cancer genome sequencing has forcefully confirmed both the concept of punctuated cancer evolution and the importance of genome chaos. [37][38][39]51,52 In order to apply the genome theory to unify the hallmarks of cancer, one needs to understand more about the hallmarks.…”

“…Multiple level landscape models illustrate this principle well, where there are so many pathways that can achieve fitness, and it is therefore challenging to predict specific pathways. 9,24,58 Paradoxically, the seemingly complex relationship between hallmarks can be easily unified or understood by using the evolutionary framework of cancer. First, such framework is based on the cancer evolution principle, the most fundamental understanding of cancer.…”

“…It takes chromosomal instability (CIN) into serious consideration, as the genome carried inheritance (or system inheritance) is a key component for somatic cell evolution. 24,42,47 Despite that CIN has received less attention in the hallmark papers, cancer cell phenotypic variation, tumor heterogeneity, and cancer evolution have been attributed to CIN, [59][60][61][62] and this key feature can be linked to all of the hallmarks. We have shown that elevated levels of genome alterations are common in preneoplastic stages both in vitro and in vivo 63 and highly associated with key stages of cancer stage transition (immortalization, transformation, metastasis, and drug resistance).…”