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Link to original content: http://pubmed.ncbi.nlm.nih.gov/38948361/
Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration - PubMed Skip to main page content
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. 2024 Jun 14:15:1408952.
doi: 10.3389/fgene.2024.1408952. eCollection 2024.

Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration

Jun He  1 , Si Hoi Kou  1 , Jiaheng Li  1 , Xiaofan Ding  1 , San Ming Wang  1
Affiliations

Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration

Jun He et al. Front Genet. .

Abstract

Introduction: The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans.

Methods: We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African.

Results and discussion: We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.

Keywords: BRCA; DDR genes; TP53; evolution origin; pathogenic variants.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Scheme of the analytic process. See text for detailed explanation.
FIGURE 2
FIGURE 2
Clustering of DDR PVs in different ethnic groups of non-African population. It shows that DDR PVs are clustered following the ethnic relationship between different ethnic groups.
FIGURE 3
FIGURE 3
Direct comparison of DDR PVs between African and non-African. (A). PV-affected DDR genes between African and non-African. It shows that all the PV-affected DDR genes in African were included in the PV-affected DDR genes in non-African; (B). DDR PVs between African and non-African. It shows that most of the DDR PVs in non-African were not present in African.
FIGURE 4
FIGURE 4
Quantitative distribution of DDR PVs, affected DDR genes and pathways between African and non-African. It shows that the patterns of the quantitative distribution of DDR PVs were highly correlated between African and non-African, except for BRCA1 and RAD50. HR, homologous recombination; FA, Fanconi anemia; NER, nucleotide excision repair; MMR, mismatch repair; BER, base excision repair; NHEJ, nonhomologous end joining; DNA rep, DNA replication; DNA res, DNA damage response.
FIGURE 5
FIGURE 5
Comparison of DDR PVs between ancient humans, African, and non-African. It shows that of the shared DDR PVs, those shared between ancient humans and non-African were more common than those shared between ancient humans and African, between African and non-African, and among all the three groups.
FIGURE 6
FIGURE 6
Geographic locations of ancient fossils carrying BRCA and TP53 PVs. It shows the PV carriers distributed across the Eurasia continent. Red: Fossils carrying BRCA1 PVs; yellow: Fossils carrying BRCA2 PVs; blue: Fossils carrying TP53 PVs.
FIGURE 7
FIGURE 7
BRCA PVs between African, non-African and ancient humans. (A). Direct comparison of BRCA PVs between African and non-African. It shows that of the 143 BRCA PVs in non-African, 136 were not shared with African; (B). Comparison of BRCA PVs between African, non-African, and ancient humans. It shows that of the 38 PVs in ancient humans, 30 were not shared with African. The results demonstrated that the BRCA PVs in non-African were largely different from African regardless the absence or presence of ancient BRCA PVs.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was supported by grants from Macau Science and Technology Development Fund [085/2017/A2 (SW), 0077/2019/AMJ (SW), 0032/2022/A1(SW and XD)], University of Macau [(SRG2017-00097-FHS, MYR G2019-00018-FHS, 2020-00094-FHS)](SW), Faculty of Health Sciences, University of Macau [(FHSIG/SW/0007/2020P, MOE Frontiers Science Center for Precision Oncology pilot grants, and a startup fund)] (SW).