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Link to original content: http://pubmed.ncbi.nlm.nih.gov/37304756/
TP53 germline pathogenic variants in modern humans were likely originated during recent human history - PubMed Skip to main page content
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. 2023 Jun 9;5(3):zcad025.
doi: 10.1093/narcan/zcad025. eCollection 2023 Sep.

TP53 germline pathogenic variants in modern humans were likely originated during recent human history

Si Hoi Kou  1 , Jiaheng Li  1 , Benjamin Tam  1 , Huijun Lei  1 , Bojin Zhao  1 , Fengxia Xiao  1 , San Ming Wang  1
Affiliations

TP53 germline pathogenic variants in modern humans were likely originated during recent human history

Si Hoi Kou et al. NAR Cancer. .

Abstract

TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Cross-species analysis of TP53 PVs. (A) Distribution of the shared human TP53 PVs in 8 clades. It shows the number of human TP53 PVs shared in eight clades: Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish. The TP53 coding region with functional domain information is at the top. Red cell: the PV shared between humans and other species. c.1010G > A: the TP53 founder PV in the Brazilian population. (B) Distribution of the shared human TP53 PVs in 99 vertebrates. X-axis from left to right: human and 99 vertebrates in 8 clades; Y-axis: number of human TP53 PVs shared with non-human vertebrates.
Figure 2.
Figure 2.
Cross-species analysis of TP53 BVs. (A) Distribution of the shared human TP53 BVs in 8 clades. It shows the number of human TP53 BVs shared in eight clades: Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish. Blue cell: human BVs shared with the species in different clades. (B) Distribution of the shared human TP53 BVs in 99 vertebrates. X-axis from left to right: human and 99 vertebrates in 8 clades; Y-axis: number of human TP53 BVs shared with non-human vertebrates.
Figure 3.
Figure 3.
Temporal and geographic distribution of human TP53 PVs shared in ancient individuals. (A) Temporal distribution of TP53 PVs identified in ancient individuals. X-axis: PVs; Y-axis: Years before present (BP). (B) Geographic distribution of TP53 PVs identified in ancient individuals. Orange dots: ancient human; green triangle: Neanderthals; blue rectangle: Denisovan.
Figure 4.
Figure 4.
Distribution of the shared TP53 PVs and BVs in different functional domains. (A) Domain distribution of 45 PVs shared between modern and ancient humans. (B) Domain distribution of 150 BVs shared between modern and ancient humans. The figure shows that the shared PVs were centered in the DNA-binding domain, whereas the shared BVs were distributed across the entire coding region.
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