O Gene TP53 e a Revolução na Ciência Moderna: Evidências de um Pico Mutacional Recente e suas Implicações Geocronológicas e Médicas

Sodré GB Neto

 

 

Resumo 

O gene TP53, conhecido como o “guardião do genoma”, desempenha um papel central na manutenção da estabilidade genética e na prevenção da oncogênese. Estudos filogenéticos e arqueogenéticos recentes revelam uma disparidade impressionante entre a diversidade de variantes patogênicas em humanos modernos e hominídeos arcaicos, como Neandertais e Denisovanos. Enquanto tanto o homem moderno, como diversos exemplos de animais e plantas,  apresenta milhares de variações germinativas, evidências de genomas antigos sugerem que muitas dessas mutações surgiram em uma janela temporal extremamente recente, aproximadamente nos últimos 5.000 a 10.000 anos. Este fenômeno, denominado “explosão mutacional”, desafia os modelos uniformitaristas de taxas de mutação constantes e sugere a ocorrência de eventos catastróficos radioativos globais,  que alteraram os relógios moleculares e as premissas de constância de decaimento da geocronologia basada em datações radiométricas de relogios nucleares constantes . Além disso, a compreensão desses padrões paleogenéticos oferece novas fronteiras para a medicina de precisão, permitindo o desenvolvimento de terapias gênicas e proteômicas baseadas em trechos genéticos canônicos e regulação por microRNAs. 

  1. Introdução 

O gene TP53 codifica a proteína p53, um fator de transcrição essencial que regula o ciclo celular, o reparo do DNA e a apoptose [1, 5]. A integridade deste gene é vital para a sobrevivência das espécies, e sua conservação em neandertais com cérebros maiores que os homens modernos reforça a ideia de que antes desta grande catastrofe os homens viviam mais e eram superiores em inteligência confome estudos de Gerald Crabtre [106] [1].

A análise da variação genética humana moderna revela um cenário complexo: milhares de variantes germinativas patogênicas (PVs) e consideradas  “benignas” (BVs)  dentro dos baixos padrões de longevidade atuais, e estão distribuídas nas populações atuais [1, 13]. 

A questão central que emerge da paleogenética moderna é a origem temporal dessas variantes. Estudos recentes utilizando genomas de humanos antigos e hominídeos arcaicos indicam que a vasta maioria das variantes codificadoras de proteínas em humanos modernos surgiu muito recentemente na história da nossa espécie [3, 16]. Este artigo explora como essa “explosão mutacional” revoluciona nossa compreensão da biologia, da história da Terra e da medicina. 

  1. O Pico Mutacional e a Comparação com Hominídeos Arcaicos 

A comparação entre o genoma de humanos modernos e o de Neandertais e Denisovanos revela uma diferença quantitativa e qualitativa marcante nas variações do TP53. Enquanto humanos modernos possuem mais de 2.000 variações documentadas, análises de genomas de Neandertais mostram uma predominância da variação canônica (variação 1) ou um número extremamente reduzido de variantes patogênicas [1, 2]. 

Pesquisas arqueogenéticas em mais de 5.000 genomas antigos datados de até 45.000 anos atrás confirmam que a maioria das variantes patogênicas do TP53 encontradas hoje surgiu nos últimos 8.000 anos [1]. Da mesma forma, a análise de 6.515 exomas modernos estimou que cerca de 73% de todas as variantes de nucleotídeo único (SNVs) codificadoras de proteínas e 86% das variantes deletérias surgiram nos últimos 5.000 a 10.000 anos [3, 43]. Este dado sugere um desvio drástico das taxas de mutação esperadas sob um modelo de equilíbrio de longo prazo. 

  1. Catastrofismo Radioativo e a Queda do Uniformitarismo 

A explicação para uma explosão mutacional tão súbita e global requer mecanismos que transcendam os processos biológicos graduais. Propõe-se que eventos geofísicos extremos, como grandes impactos de asteroides, possam ter induzido fenômenos nucleares globais [4, 18]. Tais impactos geram pressões na escala de Gigapascals e

plasmas de alta temperatura que podem acelerar as taxas de decaimento radioativo e induzir picos de radiação ionizante na superfície terrestre [4, 22, 25]. 

Este “pico radioativo” tem implicações profundas para a geocronologia e os relógios moleculares: 

  1. Geocronologia: A premissa de que as taxas de decaimento radioativo são constantes ao longo de bilhões de anos (uniformitarismo) é desafiada pela evidência de que fatores ambientais extremos (plasma, pressão, campos eletromagnéticos) podem perturbar essas taxas [25, 26, 29]. 
  2. Relógios Moleculares: A calibração dos relógios moleculares baseia-se na acumulação constante de mutações. Um pico mutacional recente traz as linhagens de seres vivos e fósseis para uma janela de tempo muito mais curta do que a prevista pelos modelos tradicionais [33, 34, 50]. 
  3. Implicações para a Medicina Moderna e Paleogenética 

A identificação de padrões genéticos “pré-explosão mutacional” através da paleogenética abre caminhos revolucionários para a medicina: 

Terapia Gênica e Proteômica: O uso de sequências canônicas de TP53 (sem mutações deletérias recentes) como molde para terapias de restauração funcional da p53 em pacientes com câncer [39, 40, 77]. 

MicroRNAs e Regulação: MicroRNAs (miRNAs) desempenham um papel crucial na regulação da expressão do TP53 e na resposta ao dano no DNA [84, 85]. Padrões de miRNAs identificados em genomas antigos podem servir como biomarcadores superiores para diagnósticos e tratamentos personalizados, focando em trechos controladores sem defeitos acumulados [36, 37, 102]. 

Diagnóstico de Precisão: A compreensão de que muitas variantes consideradas “normais” em bancos de dados modernos podem ser, na verdade, mutações recentes e deletérias, permite uma reclassificação mais precisa de riscos genéticos [1, 13, 66].

  1. Conclusão 

O estudo do gene TP53 sob uma perspectiva paleogenética e catastrófica revela que a ciência moderna está diante de uma mudança de paradigma. A evidência de um pico mutacional recente não apenas redefine nossa história evolutiva, mas também questiona as bases da datação geológica e oferece ferramentas inéditas para a cura de doenças complexas. A integração da física nuclear, geologia e genética é essencial para decifrar os eventos que moldaram a biodiversidade atual e a saúde humana. Terminamos citando um dos maiores paleontólogos do mundo e de Harvard, que já em 2023, pouco antes de falecer,  observou concordando com seu aluno de doutorado Kurt Patrick Wise e as repetidas reivindicações criacionistas:[107]

“O uniformitarismo é um conceito dual que postula a uniformidade das taxas de mudança geológica e a invariância temporal e espacial das leis naturais. A primeira é falsa e inibe a formação de hipóteses, a segunda pertence à ciência como um todo e não é exclusiva da geologia. O primeiro conceito, intitulado uniformitarismo substantivo, é incorreto e deve ser abandonado; o segundo, intitulado uniformitarismo metodológico, agora é supérfluo e é melhor confiná-lo à história passada da geologia.”

Referências Selecionadas 

(A lista completa de mais de 100 referências está anexada ao documento final) 

  1. Kou, S. H., et al. (2023). TP53 germline pathogenic variants in modern humans were likely originated during recent human history. NAR Cancer. 
  2. Zhao, B., et al. (2024). Pathogenic variants in human DNA damage repair genes mostly arose in recent human history. BMC Cancer. 
  3. Fu, W., et al. (2013). Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 
  4. Sodré Neto, G. B., & Siman, H. L. H. B. (2025). As Contradições Datacionais e Geocronológicas Uniformistas… Jornal da Ciência. 
  5. Levine, A. J. (2020). p53: 800 million years of evolution and 40 years of discovery. Nature Reviews Cancer. … (continua no anexo) 

Lista Completa de Referências Científicas 

  1. Kou, S. H., Li, J., Tam, B., Lei, H., Zhao, B., Xiao, F., … & Wang, S. M. (2023). TP53 germline pathogenic variants in modern humans were likely originated during recent human history. NAR Cancer, 5(3), zcad025. 

https://doi.org/10.1093/narcancer/zcad025 

  1. Zhao, B., Li, J., Sinha, S., Qin, Z., Kou, S. H., Xiao, F., … & Wang, S. M. (2024). Pathogenic variants in human DNA damage repair genes mostly arose in recent

human history. BMC Cancer, 24(1), 415. https://doi.org/10.1186/s12885-024- 12160-6 

  1. Fu, W., O’Connor, T. D., Jun, G., Kang, H. M., Abecasis, G., Leal, S. M., … & Akey, J. M. (2013). Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature, 493(7431), 216-220. 

https://doi.org/10.1038/nature11690 

  1. Sodré Neto, G. B., & Siman, H. L. H. B. (2025). As Contradições Datacionais e Geocronológicas Uniformistas (Baseadas em Constância Quase Eterna de Decaimento) Podem Ser Resolvidas pelos Efeitos Nucleares dos Grandes Impactos. Jornal da Ciência. DOI: 10.13140/RG.2.2.35732.21120 
  2. Levine, A. J. (2020). p53: 800 million years of evolution and 40 years of discovery. Nature Reviews Cancer, 20(8), 471-480. 
  3. Levine, A. J., & Oren, M. (2009). The first 30 years of p53: growing ever more complex. Nature Reviews Cancer, 9(10), 749-758. 
  4. Freed-Pastor, W. A., & Prives, C. (2012). Mutant p53: one name, many proteins. Genes & Development, 26(12), 1268-1286. 
  5. Baugh, E. H., Ke, H., Levine, A. J., Bonneau, R. A., & Chan, C. S. (2018). Why are there hotspot mutations in the TP53 gene in human cancers. Cell Death & Differentiation, 25(1), 154-160. 
  6. Monti, P., Menichini, P., Speciale, A., Cutrona, G., Fais, F., Taiana, E., … & Fronza, G. (2020). Heterogeneity of TP53 mutations and P53 protein residual function in cancer: does it matter?. Frontiers in Oncology, 10, 593383. 
  7. Li, J., Zhao, B., Huang, T., Qin, Z., & Wang, S. M. (2022). Human BRCA pathogenic variants were originated during recent human history. Life Science Alliance, 5(5), e202101263. 
  8. Lei, H., Li, J., Zhao, B., Kou, S. H., Xiao, F., Chen, T., & Wang, S. M. (2024). Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes. Human Genomics, 18(1), 5. 
  9. Greer, C., Bhakta, H., Ghanem, L., Refai, F., Linn, E., & Avella, M. (2021). Deleterious variants in genes regulating mammalian reproduction in Neanderthals, Denisovans and extant humans. Human Reproduction, 36(3), 734- 755. 
  10. Fortuno, C., James, P. A., & Spurdle, A. B. (2018). Current review of TP53 pathogenic germline variants in breast cancer patients outside Li-Fraumeni

syndrome. Human Mutation, 39(12), 1764-1773. 

  1. Petry, V., Bonadio, R. C., Cagnacci, A. Q. C., Senna, L. A. L., Campos, R. D. N. G., Cotti, G. C., … & Estevez-Diz, M. D. P. (2020). Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome). Family Cancer, 19(1), 47-53. 
  2. Neagu, A. N., Whitham, D., Bruno, P., Arshad, A., Seymour, L., Morrissiey, H., … & Darie, C. C. (2024). Onco-Breastomics: An Eco-Evo-Devo Holistic Approach. International Journal of Molecular Sciences, 25(3), 1628. 
  3. He, J., Kou, S. H., Li, J., Ding, X., & Wang, S. M. (2024). Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of Africa migration. Frontiers in Genetics, 15, 1408952. 
  4. Andaluz, S., Zhao, B., Sinha, S., Lagniton, P. N. P., Costa, D. A., Ding, X., … & Wang, S. M. (2024). Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health. BMC Genomics, 25(1), 416. 
  5. Kring, D. A. (2007). The Chicxulub impact event and its environmental consequences. Chemie der Erde – Geochemistry, 67(1), 1–36. 
  6. Morgan, J. V., et al. (2022). The Chicxulub impact and its environmental consequences. Nature Reviews Earth & Environment, 3(4), 232–246. 
  7. Collins, G. S., et al. (2008). A numerical study of the formation of the Vredefort impact structure. Meteoritics & Planetary Science, 43(12), 1955–1966. 
  8. Navarro, K. F., et al. (2020). Emission spectra of a simulated Chicxulub impact vapor plume. Icarus, 345, 113735. 
  9. Kletetschka, G., et al. (2021). Plasma shielding removes prior magnetization record from impact melt. Scientific Reports, 11(1), 1–10. 
  10. Leckenby, G., et al. (2024). High-temperature 205Tl decay clarifies 205Pb dating in early solar system. Nature Communications, 15(1), 1–11. 
  11. Mishra, B., et al. (2023). Plasma β-Decay Rates in the Framework of PANDORA Project. EPJ Web of Conferences, 288, 02001. 
  12. Emery, G. T. (1972). Perturbation of nuclear decay rates. Annual Review of Nuclear Science, 22(1), 165–202. 
  13. Timashev, S. F. (2015). Radioactive decay as a forced nuclear chemical process: Phenomenology. Russian Journal of Physical Chemistry A, 89(11), 1903–1910.
  14. Fischbach, E., et al. (2009). Time-dependent nuclear decay parameters: new evidence for new forces?. Space Science Reviews, 145(3-4), 285–305. 
  15. Pálffy, A., et al. (2020). Can Extreme Electromagnetic Fields Accelerate the α Decay of Atomic Nuclei?. Physical Review Letters, 124(21), 212505. 
  16. Carpinteri, A., & Manuello, A. (2011). Geomechanical and Geochemical Evidence of Piezonuclear Fission Reactions in the Earth’s Crust. Strain, 47(s2), 267–281. 
  17. Carpinteri, A., Lacidogna, G., & Manuello, A. (2012). Piezonuclear Fission Reactions in Rocks: Evidences from Microchemical Analysis, Neutron Emission, and Geological Transformation. Rock Mechanics and Rock Engineering, 45(4), 621–633. 
  18. Allen, N. H., et al. (2022). A Revision of the Formation Conditions of the Vredefort Crater. Journal of Geophysical Research: Planets, 127(5), e2022JE007186. 
  19. Taleyarkhan, R. P., et al. (2002). Evidence for nuclear emissions during acoustic cavitation. Science, 295(5561), 1868–1873. 
  20. Ho, S. Y. W., Phillips, M. J., Cooper, A., & Drummond, A. J. (2005). Time dependency of molecular rate estimates and systematic overestimation of recent divergence times. Molecular Biology and Evolution, 22(7), 1561-1568. 
  21. Moorjani, P., Amorim, C. E. G., Arndt, P. F., & Przeworski, M. (2016). Variation in the molecular clock of primates. Proceedings of the National Academy of Sciences, 113(38), 10607-10612. 
  22. Bromham, L., & Penny, D. (2003). The modern molecular clock. Nature Reviews Genetics, 4(3), 216-224. 
  23. Patel, V. D., & Capra, J. A. (2017). Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs. BMC Genomics, 18(1), 668. 
  24. Faruq, O., & Vecchione, A. (2015). microRNA: diagnostic perspective. Frontiers in Medicine, 2, 51. 
  25. Ambros, V. (2008). The evolution of our thinking about microRNAs. Nature Medicine, 14(10), 1036-1041. 
  26. Peng, Y., Bai, J., Li, W., Su, Z., & Cheng, X. (2024). Advancements in p53-Based Anti-Tumor Gene Therapy Research. Molecules, 29(22), 5315. 
  27. Valente, J. F. A., Queiroz, J. A., & Sousa, F. (2018). p53 as the focus of gene therapy: past, present and future. Current Drug Targets, 19(15), 1801-1817.
  28. Simons, Y. B., Turchin, M. C., Pritchard, J. K., & Sella, G. (2014). The deleterious mutation load is insensitive to recent population history. Nature Genetics, 46(3), 220-224. 
  29. Gazave, E., Chang, D., Clark, A. G., & Keinan, A. (2013). Population growth inflates the per-individual number of deleterious mutations and reduces their mean effect. Genetics, 195(3), 969-978. 
  30. Keinan, A., & Clark, A. G. (2012). Recent explosive human population growth has resulted in an excess of rare genetic variants. Science, 336(6082), 740-743. 
  31. Tennessen, J. A., Bigham, A. W., O’Connor, T. D., Fu, W., Kenny, E. E., Gravel, S., … & Akey, J. M. (2012). Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science, 337(6090), 64-69. 
  32. Nelson, J. J., et al. (2012). An abundance of rare functional genetic variation in 202 human genes. Science, 337(6090), 100-104. 
  33. Marth, G. T., Yu, F., Indap, A. R., Garimella, K., Gravel, S., Leong, W. F., … & 1000 Genomes Project. (2011). The functional spectrum of low-frequency coding variation in human populations. Genome Biology, 12(9), R84. 
  34. Coventry, A., et al. (2010). Deep resequencing reveals excess rare variants in genes associated with inflammation. Nature Communications, 1, 131. 
  35. Gravel, S., et al. (2011). Demographic history and rare allele sharing among human populations. Proceedings of the National Academy of Sciences, 108(29), 11983-11988. 
  36. Lohmueller, K. E., et al. (2008). Proportionally more deleterious genetic variation in European than in African populations. Nature, 451(7181), 994-997. 
  37. Subramanian, S. (2016). Evidence for recent, population-specific evolution of the human molecular clock. Proceedings of the National Academy of Sciences, 113(38), 10607-10612. 
  38. Ho, S. Y. W., & Larson, G. (2006). Molecular clocks: when times are a-changin’. Trends in Genetics, 22(2), 79-83. 
  39. Penny, D. (2005). Relativity for molecular clocks. Nature, 436(7048), 183-184. 
  40. Pulit, S. L., et al. (2017). The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives. Current Opinion in Genetics & Development, 41, 150-156.
  41. Henn, B. M., et al. (2016). Distance from Africa predicts mutational load in human populations. Proceedings of the National Academy of Sciences, 113(4), E440- E449. 
  42. Do, R., et al. (2015). No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nature Genetics, 47(2), 126-131. 
  43. Kring, D. A., & Cohen, B. A. (2002). Cataclysmic bombardment throughout the inner solar system 3.9–4.0 Ga. Journal of Geophysical Research: Planets, 107(E2), 4-1. 
  44. Melosh, H. J. (1989). Impact Cratering: A Geologic Process. Oxford University Press. 
  45. Reimold, W. U., & Gibson, R. L. (2010). Meteorite Impact!: The Danger from Space and South Africa’s Mega-Impact The Vredefort Structure. Springer Science & Business Media. 
  46. Gentry, R. V. (1986). Creation’s Tiny Mystery. Earth Science Associates. 
  47. Snelling, A. A. (2005). Radioisotopes and the Age of the Earth: Results of a Young Earth Creationist Research Initiative. Institute for Creation Research. 
  48. Vardiman, L., Snelling, A. A., & Chaffin, E. F. (2000). Radioisotopes and the Age of the Earth: A Young-Earth Creationist Research Initiative. Institute for Creation Research. 
  49. Chaffin, E. F. (2003). Accelerated Decay: Theoretical Considerations. Proceedings of the Fifth International Conference on Creationism. 
  50. Humphreys, D. R. (2003). New evidence for accelerated nuclear decay. Proceedings of the Fifth International Conference on Creationism. 
  51. Austin, S. A. (2005). Do radioisotope clocks need repair? Testing the assumptions of isochron dating using K-Ar, Rb-Sr, Sm-Nd, and Pb-Pb isotopes. Radioisotopes and the Age of the Earth, 2, 325-392. 
  52. Baumgardner, J. R. (2005). Carbon-14 evidence for a recent global flood and a young earth. Radioisotopes and the Age of the Earth, 2, 587-630. 
  53. De Andrade, K. C., et al. (2021). Cancer incidence, patterns, and genotype– phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. The Lancet Oncology, 22(11), 1595-1610.
  54. Khincha, P. P., et al. (2019). Genetic and clinical characteristics of individuals with Li-Fraumeni syndrome. Journal of Clinical Oncology, 37(15), 1500. 
  55. Malkin, D. (2011). Li-Fraumeni syndrome. Genes & Cancer, 2(4), 475-484. 
  56. Olivier, M., et al. (2010). The IARC TP53 database: new features and updates. Human Mutation, 31(6), 631-640. 
  57. Petitjean, A., et al. (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and clinical outcomes: lessons from the IARC TP53 database. Human Mutation, 28(6), 622-629. 
  58. Soussi, T., & Lozano, G. (2005). p53 mutation heterogeneity in cancer: can the immune response provide a clue for personalized medicine? Cancer Cell, 8(5), 349-351. 
  59. Hainaut, P., & Pfeifer, G. P. (2016). Somatic TP53 Mutations as a Signature of Environmental Carcinogens. Seminars in Cancer Biology, 38, 77-87. 
  60. Kandoth, C., et al. (2013). Mutational landscape and significance across 12 major cancer types. Nature, 502(7471), 333-339. 
  61. Lawrence, M. S., et al. (2014). Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 505(7484), 495-501. 
  62. Vogelstein, B., et al. (2013). Cancer genome landscapes. Science, 339(6127), 1546- 1558. 
  63. He, H. (2025). Targeting TP53TG1: A promising prognostic biomarker and therapeutic target for personalized cancer therapy. Discover Oncology, 16(1), 1- 15. 
  64. Xu, B., et al. (2025). The Multifaceted Role of p53 in Cancer Molecular Biology: Insights for Precision Diagnosis and Therapeutic Breakthroughs. Biomolecules, 15(8), 1088. 
  65. Patel, V. D., & Capra, J. A. (2017). Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs. BMC Genomics, 18(1), 668. 
  66. Ambros, V. (2004). The functions of animal microRNAs. Nature, 431(7006), 350- 355. 
  67. Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2), 281-297.
  68. Lu, J., et al. (2005). MicroRNA expression profiles classify human cancers. Nature, 435(7043), 834-838. 
  69. Calin, G. A., & Croce, C. M. (2006). MicroRNA signatures in human cancers. Nature Reviews Cancer, 6(11), 857-866. 
  70. Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs—microRNAs with a role in cancer. Nature Reviews Cancer, 6(4), 259-269. 
  71. He, L., et al. (2007). A microRNA component of the p53 tumour suppressor network. Nature, 447(7148), 1130-1134. 
  72. Raver-Shapira, N., et al. (2007). Transcriptional activation of miR-34a by p53 mediates p53-induced apoptosis. Molecular Cell, 26(5), 731-743. 
  73. Tarasov, V., et al. (2007). Differential regulation of microRNAs by p53 revealed by genome-wide expression profiling: p53-regulated microRNAs can suppress proliferation of colon cancer cells. Cell Cycle, 6(13), 1586-1593. 
  74. Chang, T. C., et al. (2007). Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular Cell, 26(5), 745-752. 
  75. Hermeking, H. (2010). The miR-34 family in cancer and apoptosis. Cell Death & Differentiation, 17(2), 193-199. 
  76. Kim, V. N., Han, J., & Siomi, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology, 10(2), 126-139. 
  77. Friedman, R. C., et al. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Research, 19(1), 92-105. 
  78. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120(1), 15-20. 
  79. Grimson, A., et al. (2007). MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Molecular Cell, 27(1), 91-105. 
  80. Garcia, D. M., et al. (2011). Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nature Structural & Molecular Biology, 18(10), 1139-1146. 
  81. Betel, D., et al. (2010). Comprehensive modeling of microRNA targets predicts functional non-conserved and conserved targets. BMC Bioinformatics, 11(1), 431. 
  82. Agarwal, V., et al. (2015). Predicting effective microRNA target sites in mammalian mRNAs. eLife, 4, e05005.
  83. Krol, J., Loedige, I., & Filipowicz, W. (2010). The widespread regulation of microRNA biogenesis, function and decay. Nature Reviews Genetics, 11(9), 597- 610. 
  84. Pasquinelli, A. E. (2012). MicroRNAs: deviants from the model. Nature Reviews Genetics, 13(4), 273-282. 
  85. Ha, M., & Kim, V. N. (2014). Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology, 15(8), 509-524. 
  86. Jonas, S., & Izaurralde, E. (2015). Towards a molecular understanding of microRNA-mediated gene silencing. Nature Reviews Genetics, 16(7), 421-433. 
  87. Gebert, L. F., & MacRae, I. J. (2019). Regulation of microRNA function in animals. Nature Reviews Molecular Cell Biology, 20(1), 21-37. 
  88. O’Brien, J., et al. (2018). Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Clinical Applications. Frontiers in Endocrinology, 9, 402. 
  89. Rupaimoole, R., & Slack, F. J. (2017). MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery, 16(3), 203-222. 
  90. Ling, H., Fabbri, M., & Calin, G. A. (2013). MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nature Reviews Drug Discovery, 12(11), 847-865. 
  91. Hayes, J., Peruzzi, P. P., & Lawler, S. (2014). MicroRNAs in cancer: biomarkers, functions and therapy. Trends in Molecular Medicine, 20(8), 460-469. 
  92. Hummel, R., et al. (2010). MicroRNAs: precursors and indicators of cancer. Molecular Oncology, 4(2), 137-161.
  93. Crabtree GR. Our fragile intellect. Part I. Trends Genet. 2013 Jan;29(1):1-3. doi: 10.1016/j.tig.2012.10.002. Epub 2012 Nov 12. PMID: 23153596. https://pubmed.ncbi.nlm.nih.gov/23153596/
  94. Gould, S. J. (1 de março de 1965). «Is uniformitarianism necessary?». American Journal of Science (em inglês) (3): 223–228. ISSN 0002-9599. doi:10.2475/ajs.263.3.223. Consultado em 20 de março de 2023
1. Kou, S. H., Li, J., Tam, B., Lei, H., Zhao, B., Xiao, F., ... & Wang, S. M. (2023). TP53 germline pathogenic variants in modern humans were likely originated during recent human history. NAR Cancer, 5(3), zcad025. https://doi.org/10.1093/narcancer/zcad025
2. Zhao, B., Li, J., Sinha, S., Qin, Z., Kou, S. H., Xiao, F., ... & Wang, S. M. (2024). Pathogenic variants in human DNA damage repair genes mostly arose in recent human history. BMC Cancer, 24(1), 415. https://doi.org/10.1186/s12885-024-12160-6
3. Fu, W., O’Connor, T. D., Jun, G., Kang, H. M., Abecasis, G., Leal, S. M., ... & Akey, J. M. (2013). Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature, 493(7431), 216-220. https://doi.org/10.1038/nature11690
4. Sodré Neto, G. B., & Siman, H. L. H. B. (2025). As Contradições Datacionais e Geocronológicas Uniformistas (Baseadas em Constância Quase Eterna de Decaimento) Podem Ser Resolvidas pelos Efeitos Nucleares dos Grandes Impactos. Jornal da Ciência. DOI: 10.13140/RG.2.2.35732.21120
5. Levine, A. J. (2020). p53: 800 million years of evolution and 40 years of discovery. Nature Reviews Cancer, 20(8), 471-480.
6. Levine, A. J., & Oren, M. (2009). The first 30 years of p53: growing ever more complex. Nature Reviews Cancer, 9(10), 749-758.
7. Freed-Pastor, W. A., & Prives, C. (2012). Mutant p53: one name, many proteins. Genes & Development, 26(12), 1268-1286.
8. Baugh, E. H., Ke, H., Levine, A. J., Bonneau, R. A., & Chan, C. S. (2018). Why are there hotspot mutations in the TP53 gene in human cancers. Cell Death & Differentiation, 25(1), 154-160.
9. Monti, P., Menichini, P., Speciale, A., Cutrona, G., Fais, F., Taiana, E., ... & Fronza, G. (2020). Heterogeneity of TP53 mutations and P53 protein residual function in cancer: does it matter?. Frontiers in Oncology, 10, 593383.
10. Li, J., Zhao, B., Huang, T., Qin, Z., & Wang, S. M. (2022). Human BRCA pathogenic variants were originated during recent human history. Life Science Alliance, 5(5), e202101263.
11. Lei, H., Li, J., Zhao, B., Kou, S. H., Xiao, F., Chen, T., & Wang, S. M. (2024). Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes. Human Genomics, 18(1), 5.
12. Greer, C., Bhakta, H., Ghanem, L., Refai, F., Linn, E., & Avella, M. (2021). Deleterious variants in genes regulating mammalian reproduction in Neanderthals, Denisovans and extant humans. Human Reproduction, 36(3), 734-755.
13. Fortuno, C., James, P. A., & Spurdle, A. B. (2018). Current review of TP53 pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome. Human Mutation, 39(12), 1764-1773.
14. Petry, V., Bonadio, R. C., Cagnacci, A. Q. C., Senna, L. A. L., Campos, R. D. N. G., Cotti, G. C., ... & Estevez-Diz, M. D. P. (2020). Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome). Family Cancer, 19(1), 47-53.
15. Neagu, A. N., Whitham, D., Bruno, P., Arshad, A., Seymour, L., Morrissiey, H., ... & Darie, C. C. (2024). Onco-Breastomics: An Eco-Evo-Devo Holistic Approach. International Journal of Molecular Sciences, 25(3), 1628.
16. He, J., Kou, S. H., Li, J., Ding, X., & Wang, S. M. (2024). Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration. Frontiers in Genetics, 15, 1408952.
17. Andaluz, S., Zhao, B., Sinha, S., Lagniton, P. N. P., Costa, D. A., Ding, X., ... & Wang, S. M. (2024). Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health. BMC Genomics, 25(1), 416.
18. Kring, D. A. (2007). The Chicxulub impact event and its environmental consequences. Chemie der Erde – Geochemistry, 67(1), 1–36.
19. Morgan, J. V., et al. (2022). The Chicxulub impact and its environmental consequences. Nature Reviews Earth & Environment, 3(4), 232–246.
20. Collins, G. S., et al. (2008). A numerical study of the formation of the Vredefort impact structure. Meteoritics & Planetary Science, 43(12), 1955–1966.
21. Navarro, K. F., et al. (2020). Emission spectra of a simulated Chicxulub impact-vapor plume. Icarus, 345, 113735.
22. Kletetschka, G., et al. (2021). Plasma shielding removes prior magnetization record from impact melt. Scientific Reports, 11(1), 1–10.
23. Leckenby, G., et al. (2024). High-temperature 205Tl decay clarifies 205Pb dating in early solar system. Nature Communications, 15(1), 1–11.
24. Mishra, B., et al. (2023). Plasma β-Decay Rates in the Framework of PANDORA Project. EPJ Web of Conferences, 288, 02001.
25. Emery, G. T. (1972). Perturbation of nuclear decay rates. Annual Review of Nuclear Science, 22(1), 165–202.
26. Timashev, S. F. (2015). Radioactive decay as a forced nuclear chemical process: Phenomenology. Russian Journal of Physical Chemistry A, 89(11), 1903–1910.
27. Fischbach, E., et al. (2009). Time-dependent nuclear decay parameters: new evidence for new forces?. Space Science Reviews, 145(3-4), 285–305.
28. Pálffy, A., et al. (2020). Can Extreme Electromagnetic Fields Accelerate the α Decay of Atomic Nuclei?. Physical Review Letters, 124(21), 212505.
29. Carpinteri, A., & Manuello, A. (2011). Geomechanical and Geochemical Evidence of Piezonuclear Fission Reactions in the Earth’s Crust. Strain, 47(s2), 267–281.
30. Carpinteri, A., Lacidogna, G., & Manuello, A. (2012). Piezonuclear Fission Reactions in Rocks: Evidences from Microchemical Analysis, Neutron Emission, and Geological Transformation. Rock Mechanics and Rock Engineering, 45(4), 621–633.
31. Allen, N. H., et al. (2022). A Revision of the Formation Conditions of the Vredefort Crater. Journal of Geophysical Research: Planets, 127(5), e2022JE007186.
32. Taleyarkhan, R. P., et al. (2002). Evidence for nuclear emissions during acoustic cavitation. Science, 295(5561), 1868–1873.
33. Ho, S. Y. W., Phillips, M. J., Cooper, A., & Drummond, A. J. (2005). Time dependency of molecular rate estimates and systematic overestimation of recent divergence times. Molecular Biology and Evolution, 22(7), 1561-1568.
34. Moorjani, P., Amorim, C. E. G., Arndt, P. F., & Przeworski, M. (2016). Variation in the molecular clock of primates. Proceedings of the National Academy of Sciences, 113(38), 10607-10612.
35. Bromham, L., & Penny, D. (2003). The modern molecular clock. Nature Reviews Genetics, 4(3), 216-224.
36. Patel, V. D., & Capra, J. A. (2017). Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs. BMC Genomics, 18(1), 668.
37. Faruq, O., & Vecchione, A. (2015). microRNA: diagnostic perspective. Frontiers in Medicine, 2, 51.
38. Ambros, V. (2008). The evolution of our thinking about microRNAs. Nature Medicine, 14(10), 1036-1041.
39. Peng, Y., Bai, J., Li, W., Su, Z., & Cheng, X. (2024). Advancements in p53-Based Anti-Tumor Gene Therapy Research. Molecules, 29(22), 5315.
40. Valente, J. F. A., Queiroz, J. A., & Sousa, F. (2018). p53 as the focus of gene therapy: past, present and future. Current Drug Targets, 19(15), 1801-1817.
41. Simons, Y. B., Turchin, M. C., Pritchard, J. K., & Sella, G. (2014). The deleterious mutation load is insensitive to recent population history. Nature Genetics, 46(3), 220-224.
42. Gazave, E., Chang, D., Clark, A. G., & Keinan, A. (2013). Population growth inflates the per-individual number of deleterious mutations and reduces their mean effect. Genetics, 195(3), 969-978.
43. Keinan, A., & Clark, A. G. (2012). Recent explosive human population growth has resulted in an excess of rare genetic variants. Science, 336(6082), 740-743.
44. Tennessen, J. A., Bigham, A. W., O'Connor, T. D., Fu, W., Kenny, E. E., Gravel, S., ... & Akey, J. M. (2012). Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science, 337(6090), 64-69.
45. Nelson, J. J., et al. (2012). An abundance of rare functional genetic variation in 202 human genes. Science, 337(6090), 100-104.
46. Marth, G. T., Yu, F., Indap, A. R., Garimella, K., Gravel, S., Leong, W. F., ... & 1000 Genomes Project. (2011). The functional spectrum of low-frequency coding variation in human populations. Genome Biology, 12(9), R84.
47. Coventry, A., et al. (2010). Deep resequencing reveals excess rare variants in genes associated with inflammation. Nature Communications, 1, 131.
48. Gravel, S., et al. (2011). Demographic history and rare allele sharing among human populations. Proceedings of the National Academy of Sciences, 108(29), 11983-11988.
49. Lohmueller, K. E., et al. (2008). Proportionally more deleterious genetic variation in European than in African populations. Nature, 451(7181), 994-997.
50. Subramanian, S. (2016). Evidence for recent, population-specific evolution of the human molecular clock. Proceedings of the National Academy of Sciences, 113(38), 10607-10612.
51. Ho, S. Y. W., & Larson, G. (2006). Molecular clocks: when times are a-changin'. Trends in Genetics, 22(2), 79-83.
52. Penny, D. (2005). Relativity for molecular clocks. Nature, 436(7048), 183-184.
53. Pulit, S. L., et al. (2017). The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives. Current Opinion in Genetics & Development, 41, 150-156.
54. Henn, B. M., et al. (2016). Distance from Africa predicts mutational load in human populations. Proceedings of the National Academy of Sciences, 113(4), E440-E449.
55. Do, R., et al. (2015). No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nature Genetics, 47(2), 126-131.
56. Kring, D. A., & Cohen, B. A. (2002). Cataclysmic bombardment throughout the inner solar system 3.9–4.0 Ga. Journal of Geophysical Research: Planets, 107(E2), 4-1.
57. Melosh, H. J. (1989). Impact Cratering: A Geologic Process. Oxford University Press.
58. Reimold, W. U., & Gibson, R. L. (2010). Meteorite Impact!: The Danger from Space and South Africa’s Mega-Impact The Vredefort Structure. Springer Science & Business Media.
59. Gentry, R. V. (1986). Creation's Tiny Mystery. Earth Science Associates.
60. Snelling, A. A. (2005). Radioisotopes and the Age of the Earth: Results of a Young-Earth Creationist Research Initiative. Institute for Creation Research.
61. Vardiman, L., Snelling, A. A., & Chaffin, E. F. (2000). Radioisotopes and the Age of the Earth: A Young-Earth Creationist Research Initiative. Institute for Creation Research.
62. Chaffin, E. F. (2003). Accelerated Decay: Theoretical Considerations. Proceedings of the Fifth International Conference on Creationism.
63. Humphreys, D. R. (2003). New evidence for accelerated nuclear decay. Proceedings of the Fifth International Conference on Creationism.
64. Austin, S. A. (2005). Do radioisotope clocks need repair? Testing the assumptions of isochron dating using K-Ar, Rb-Sr, Sm-Nd, and Pb-Pb isotopes. Radioisotopes and the Age of the Earth, 2, 325-392.
65. Baumgardner, J. R. (2005). Carbon-14 evidence for a recent global flood and a young earth. Radioisotopes and the Age of the Earth, 2, 587-630.
66. De Andrade, K. C., et al. (2021). Cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. The Lancet Oncology, 22(11), 1595-1610.
67. Khincha, P. P., et al. (2019). Genetic and clinical characteristics of individuals with Li-Fraumeni syndrome. Journal of Clinical Oncology, 37(15), 1500.
68. Malkin, D. (2011). Li-Fraumeni syndrome. Genes & Cancer, 2(4), 475-484.
69. Olivier, M., et al. (2010). The IARC TP53 database: new features and updates. Human Mutation, 31(6), 631-640.
70. Petitjean, A., et al. (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and clinical outcomes: lessons from the IARC TP53 database. Human Mutation, 28(6), 622-629.
71. Soussi, T., & Lozano, G. (2005). p53 mutation heterogeneity in cancer: can the immune response provide a clue for personalized medicine? Cancer Cell, 8(5), 349-351.
72. Hainaut, P., & Pfeifer, G. P. (2016). Somatic TP53 Mutations as a Signature of Environmental Carcinogens. Seminars in Cancer Biology, 38, 77-87.
73. Kandoth, C., et al. (2013). Mutational landscape and significance across 12 major cancer types. Nature, 502(7471), 333-339.
74. Lawrence, M. S., et al. (2014). Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 505(7484), 495-501.
75. Vogelstein, B., et al. (2013). Cancer genome landscapes. Science, 339(6127), 1546-1558.
76. He, H. (2025). Targeting TP53TG1: A promising prognostic biomarker and therapeutic target for personalized cancer therapy. Discover Oncology, 16(1), 1-15.
77. Xu, B., et al. (2025). The Multifaceted Role of p53 in Cancer Molecular Biology: Insights for Precision Diagnosis and Therapeutic Breakthroughs. Biomolecules, 15(8), 1088.
78. Patel, V. D., & Capra, J. A. (2017). Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs. BMC Genomics, 18(1), 668.
79. Ambros, V. (2004). The functions of animal microRNAs. Nature, 431(7006), 350-355.
80. Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2), 281-297.
81. Lu, J., et al. (2005). MicroRNA expression profiles classify human cancers. Nature, 435(7043), 834-838.
82. Calin, G. A., & Croce, C. M. (2006). MicroRNA signatures in human cancers. Nature Reviews Cancer, 6(11), 857-866.
83. Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs—microRNAs with a role in cancer. Nature Reviews Cancer, 6(4), 259-269.
84. He, L., et al. (2007). A microRNA component of the p53 tumour suppressor network. Nature, 447(7148), 1130-1134.
85. Raver-Shapira, N., et al. (2007). Transcriptional activation of miR-34a by p53 mediates p53-induced apoptosis. Molecular Cell, 26(5), 731-743.
86. Tarasov, V., et al. (2007). Differential regulation of microRNAs by p53 revealed by genome-wide expression profiling: p53-regulated microRNAs can suppress proliferation of colon cancer cells. Cell Cycle, 6(13), 1586-1593.
87. Chang, T. C., et al. (2007). Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular Cell, 26(5), 745-752.
88. Hermeking, H. (2010). The miR-34 family in cancer and apoptosis. Cell Death & Differentiation, 17(2), 193-199.
89. Kim, V. N., Han, J., & Siomi, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology, 10(2), 126-139.
90. Friedman, R. C., et al. (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Research, 19(1), 92-105.
91. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120(1), 15-20.
92. Grimson, A., et al. (2007). MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Molecular Cell, 27(1), 91-105.
93. Garcia, D. M., et al. (2011). Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nature Structural & Molecular Biology, 18(10), 1139-1146.
94. Betel, D., et al. (2010). Comprehensive modeling of microRNA targets predicts functional non-conserved and conserved targets. BMC Bioinformatics, 11(1), 431.
95. Agarwal, V., et al. (2015). Predicting effective microRNA target sites in mammalian mRNAs. eLife, 4, e05005.
96. Krol, J., Loedige, I., & Filipowicz, W. (2010). The widespread regulation of microRNA biogenesis, function and decay. Nature Reviews Genetics, 11(9), 597-610.
97. Pasquinelli, A. E. (2012). MicroRNAs: deviants from the model. Nature Reviews Genetics, 13(4), 273-282.
98. Ha, M., & Kim, V. N. (2014). Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology, 15(8), 509-524.
99. Jonas, S., & Izaurralde, E. (2015). Towards a molecular understanding of microRNA-mediated gene silencing. Nature Reviews Genetics, 16(7), 421-433.
100. Gebert, L. F., & MacRae, I. J. (2019). Regulation of microRNA function in animals. Nature Reviews Molecular Cell Biology, 20(1), 21-37.
101. O'Brien, J., et al. (2018). Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Clinical Applications. Frontiers in Endocrinology, 9, 402.
102. Rupaimoole, R., & Slack, F. J. (2017). MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery, 16(3), 203-222.
103. Ling, H., Fabbri, M., & Calin, G. A. (2013). MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nature Reviews Drug Discovery, 12(11), 847-865.
104. Hayes, J., Peruzzi, P. P., & Lawler, S. (2014). MicroRNAs in cancer: biomarkers, functions and therapy. Trends in Molecular Medicine, 20(8), 460-469.

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