2024-01-13 07:00:29
Mutations, which constantly occur in every cell in our body, are a key factor contributing to cancer, aging and neurodegeneration. While exposure to mutagenic chemicals or errors in cellular processes during DNA replication contribute to such mutations, the exact distribution and patterns along human chromosomes have been a mystery. Until now.
Dr. Fran Supek, ICREA researcher and head of the Genome Data Science Laboratory at the Barcelona Biomedical Research Institute (IRB Barcelona), and Marina Salvadores, a doctoral student in the same group, have delved into the field of DNA mutations, revealing unexpected patterns that differentiate individuals in terms of mutation risks.
Previous work from the lab identified a type of “genomic spell checker”: a DNA repair mechanism that directs attention to essential parts of human chromosomes, reducing mutation risks. On this basis, the present study aimed to unravel whether individuals present diverse mutation risks and, if so, what mechanisms drive these differences.
“This research not only expands our understanding of the factors that influence mutation rate distribution, but also has important implications for the understanding of cancer evolution, therapeutic strategies, and advances in regenerative medicine,” explains Dr. Supek.
An analysis of genomic “big data”
To address these questions, the researchers performed a comprehensive analysis of the genome sequences of more than 4,000 tumors from various organs. Unlike previous studies, which focused on tissue-specific mutation risks, this research focused specifically on differences between individuals in susceptibility to mutations.
Using a genomic “big data” approach, the team used machine learning algorithms (a form of artificial intelligence) to identify recurring patterns in chromosome segments.
Thus they discovered 13 different patterns, 10 of which correspond to different types of fabric. The remaining three patterns, unexpectedly, were observed in almost all human tissues, revealing that the density of mutations in specific genes varies significantly between individuals.
Connect the dots
To understand the unexpected patterns, the researchers examined additional data, including gene expression and genetic aberrations in cancer cells.
The analysis revealed a striking correlation between increased cell proliferation and alterations in mutation risks. Disruptions in two essential tumor suppressor genes: TP53 and RB1, known to regulate the cell division cycle, were identified as key factors causing changes in mutation risks in chromosomes.
These chromosomal segments not only presented altered mutation risks but also a “remodeling” of large chromosomal regions that are normally inactive. “This remodeling, correlated with greater cell proliferation, reflected changes in mutation risks, which provides a unique insight into the interaction between mutations and epigenetic alterations,” details Marina Salvadores, first author of the study.
In the new study, significant differences in the risks of DNA mutation between different people have been detected. (Illustration: Amazings/NCYT)
Decoding the evolution of cancer
The implications of this study extend beyond fundamental research. By identifying which cancer-causing genes are most affected by changes in mutation risk between individuals, researchers have provided a roadmap for anticipating the trajectory of cancer evolution.
This knowledge is especially relevant for predicting responses to cancer therapies, as it can help predict the development of drug resistance mutations.
The study also provides valuable information on the epigenetics of human cells, highlighting the fact that the epigenome undergoes drastic changes in response to increased or altered cell proliferation. This knowledge has potential implications for cellular reprogramming and regenerative medicine, opening new avenues for future research and therapeutic interventions.
The study is titled “Cell cycle gene alterations associated with a redistribution of mutation risk across chromosomal domains in human cancers.” And it has been published in the academic journal Nature Cancer. (Source: IRB Barcelona)
#detect #differences #risks #DNA #mutation #people