iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/38575974/
Pathogenic variants in human DNA damage repair genes mostly arose in recent human history - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr 4;24(1):415.
doi: 10.1186/s12885-024-12160-6.

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history

Bojin Zhao #  1 , Jiaheng Li #  1 , Siddharth Sinha  1 , Zixin Qin  1 , Si Hoi Kou  1 , Fengxia Xiao  1 , Huijun Lei  1   2 , Tianhui Chen  2   3 , Wenming Cao  4   3 , Xiaofan Ding  1 , San Ming Wang  5
Affiliations

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history

Bojin Zhao et al. BMC Cancer. .

Abstract

Background: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes.

Methods: We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis.

Results: Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals.

Conclusions: Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Keywords: Archaeological; DNA damage repair; Evolutionary origin; Pathogenic variants; Phylogenetic.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Outline of study design. The study included two major parts: Phylogenetic analysis and archeological analysis, with the aim to determine the origin of DDR PVs in modern humans
Fig. 2
Fig. 2
Phylogenetic analysis of human DDR PVs in 100 vertebrate species. The 7432 single nucleotide PVs in 87 DDR genes from ClinVar database were searched in 100 vertebrate species with 8 clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammalia, Aves, Sarcopterygii and Fish. The results showed that the majority of human DDR PVs were not shared, whereas 1497 (20.14%) were shared with non-human vertebrate species mostly distal to human such as the species within Aves and Sarcopterygii, and rarely with species within Primate. Y-axis: species; X-axis: PVs in DDR genes. Red: human PVs shared with other species
Fig. 3
Fig. 3
Timing of DDR PVs of ancient humans shared with modern humans. A Timing distribution of 67 recurrent PVs in 33 DDR genes shared between modern and ancient humans within 10,000 years BP (a few longer than 10,000 years BP were not included due to space limitation). The larger red dot in each PV line represents the earliest identified PV carrier, and the smaller black dot (s) in the same line correspond to the later carriers of the same PV. The line to the left of the larger red dot indicates the presence of PV-free sample(s) older than the first PV carrier, showing that older ancient sample(s) were present for all first identified recurrent PVs carriers, Supplementary Table 7), the line to the right of the last smaller black dot denotes the presence of PV-free sample(s) younger than the last PV carriers. B Different PVs in 73 DDR genes shared between modern and ancient humans within the last 10,000 years (a few longer than 10,000 years BP were not included due to space limitation). Each dot represents a single PV. The larger red dot in each DDR gene line represents the earliest PV identified in the gene, and the smaller black dot (s) in the same line represents different PVs detected later in the same DDR gene. Most of the PVs were present in the carriers dated within the last 5000 year BP. It shows that older ancient samples were present for all firstly identified PVs carriers (Supplementary Table 7)
Fig. 4
Fig. 4
Comparison of DDR PV abundance between ancient humans and modern humans. The comparison was made between the 1781 DDR PVs identified in global modern humans [39] and the 1266 DDR PVs identified in ancient humans in this study. The rate of PVs in each DDR gene in modern or ancient humans was calculated as the number of PVs in each gene / total number of PVs in all DDR genes. Each rectangle in the lower part refers to the PV-containing DDR genes in the affected DDR pathway. It shows that DDR PVs between ancient and modern humans shared similar prevalent distribution, except the PVs of TP53, MLH1 and MSH2 at higher abundance in ancient humans than in modern humans
Fig. 5
Fig. 5
Relationship between evolution selection and DDR genes. It shows the type of evolution selection in the 73 PV-containing DDR genes. The PAML program was used for the test in 21 vertebrate species. A Summary of the DDR genes under positive, negative, and neutral selection. It shows that most of DDR genes were under negative selection. The number in parentheses refers to the PVs identified in ancient humans as list in Table 4. B TP53 under positive selection. It shows that TP53 is under positive selection in all 21 species tested but with different dN/dS ratios in different species. C Number of PV per DDR gene in each type of selection group. It shows that the positive selection group had the highest number, the neutral group had the intermediate number, and the negative group had the lowest number of PVs per gene
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–1078. doi: 10.1038/nature08467. - DOI - PMC - PubMed
    1. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017;58(5):235–263. doi: 10.1002/em.22087. - DOI - PMC - PubMed
    1. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(2):276–292. doi: 10.1200/JCO.2005.10.042. - DOI - PubMed
    1. Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer. 2016;16(1):35–42. doi: 10.1038/nrc.2015.4. - DOI - PubMed
    1. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820–823. doi: 10.1073/pnas.68.4.820. - DOI - PMC - PubMed