Cenário de coocorrência de variantes de nucleotídeo único (SNVs) de diferentes origens evolutivas e consequências funcionais no genoma humano

• Ano de defesa: 2025
• Autor(a) principal: Thais Silva Tavares
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais
• Palavras-chave em Português: Bioinformática; Mutação; Polimorfismo de Nucleotídeo Único; Hotspot de Doença; Mutações humanas; Variantes de nucleotídeo único (SNVs); Hotspots mutacionais; Loci compartilhados germinativo-somático
• Link de acesso: https://hdl.handle.net/1843/83006

The evolution of the genome and the emergence of genetic diseases are driven by mutations, which arise through various mechanisms and shape genetic variability and species adaptation. Despite decades of research on variations in mutation rates and types across genomic regions, few studies have systematically integrated comparative analyses of their spatial distribution in the human genome. In this study, we conducted a large-scale assessment of the distribution and functional characterization of single nucleotide variants (SNVs) across five distinct categories: (i) neutral or nearly neutral polymorphisms, (ii) rare variants, (iii) cancer-associated somatic mutations, (iv) clinically relevant pathogenic germline variants, and (v) benign variants. Using data from public repositories such as COSMIC, ClinVar, and HGDP, we proposed three models to describe the mutational landscape of the human genome. Our findings reveal a significant overlap between different SNV classes, suggesting that certain genomic regions are inherently more prone to accumulating mutations, regardless of their germline or somatic origin. Notably, single nucleotide polymorphisms (SNPs) and recurrent cancer mutations frequently co-occur at the same genomic loci and share identical alleles more often than expected by chance. Five mutational signatures (SBS1, SBS5, SBS6, SBS54, and SBS87) were associated with these shared sites, while CpG islands and microsatellites accounted for only a minor fraction of the observed mutations. Furthermore, functional enrichment analyses identified significant associations between the overlapping regions and key genomic sites, such as 13q12.12 and 19p13.3, as well as pathways involved in cellular signaling and extracellular matrix interactions, including PI3K/AKT/mTOR and ECM-receptor interaction, both of which are crucial for tumor progression. Based on these findings, we propose the existence of critical DNA loci that function as natural mutational hotspots, recurrently affected in both germline and somatic lineages. The identification of these hotspots raises important questions regarding the underlying mechanisms driving their occurrence and their potential role in cancer predisposition.