Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

Xiao, Fengxia; Zhang, Yingbo; Lagniton, Philip Naderev Panuringan; Kou, Si Hoi; Lei, Huijun; Tam, Benjamin; Wang, San Ming

doi:10.3390/biom13030429

Cited by 9 publications

(4 citation statements)

References 52 publications

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“…Certain computational programs are designed using the concept of evolutionary conservation. However, our studies showed that DDR PVs did not originate from nonhuman species through evolutionary conservation but arose from humans themselves ( Li, et al, 2022 ; Chian, et al, 2023 ; Kou, et al, 2023 ; Xiao, et al, 2023 ), and our current study further reveals that most human DDR PVs arose after the latest human out-of-Africa migration. While evolutionary conservation-based approaches can be powerful in analyzing the benign variants in DDR genes highly conserved between human and nonhuman species, they are not suitable in identifying the PVs in human DDR genes as they are basically absent in non-human species.…”

Section: Discussionsupporting

confidence: 50%

“…Our recent studies in the human DDR genes including BRCA1 , BRCA2 , TP53 , MUTHY , and PALB2 etc. revealed that the DDR PVs were not transmitted from nonhuman species through cross-species conservation but arose in humans themselves ( Li, et al, 2022 ; Chian, et al, 2023 ; Kou, et al, 2023 ; Xiao, et al, 2023 ). The results promoted us to question whether the result observed in these genes could be universal that the PVs in all human DDR genes were originated from humans themselves.…”

Section: Introductionmentioning

confidence: 99%

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

He,

Kou,

et al. 2024

Front. Genet.

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IntroductionThe 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.MethodsWe 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 discussionWe 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.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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

He,

Kou,

et al. 2024

Front. Genet.

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“…This approach largely avoids the uncertainty, complexity, and artefacts in other in silico methods. For example, our study indicates that deleterious variants in human cancer genes did not originate from other species through evolution conservation but arose in recent evolution process of human itself [42][43][44]. This implies that the concept of evolution conservation can't be used to classify deleterious variants in humans; (3) DL-RP-MDS uses MD simulations to monitor the trajectories of structural change caused by VUS variants.…”

Section: Discussionmentioning

confidence: 96%

Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method

Tam,

Qin,

Zhao

et al. 2024

IJMS

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Pathogenic variation in DNA mismatch repair (MMR) gene MLH1 is associated with Lynch syndrome (LS), an autosomal dominant hereditary cancer. Of the 3798 MLH1 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.6% (1199) were classified as Variants of Uncertain Significance (VUS) due to the lack of functional evidence. Further determination of the impact of VUS on MLH1 function is important for the VUS carriers to take preventive action. We recently developed a protein structure-based method named “Deep Learning-Ramachandran Plot-Molecular Dynamics Simulation (DL-RP-MDS)” to evaluate the deleteriousness of MLH1 missense VUS. The method extracts protein structural information by using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, then combines the variation data with an unsupervised learning model composed of auto-encoder and neural network classifier to identify the variants causing significant change in protein structure. In this report, we applied the method to classify 447 MLH1 missense VUS. We predicted 126/447 (28.2%) MLH1 missense VUS were deleterious. Our study demonstrates that DL-RP-MDS is able to classify the missense VUS based solely on their impact on protein structure.

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“…from the common ancestry between human and non-human species through cross-species conservation; 2) from human itself during human evolution process; and 3) from both sources. In our previous study, we observed that the PVs in human DDR genes of BRCA1 and BRCA2, TP53, MUTHY and PALB2 were not inherited from cross-species conservation but originated during recent human evolutionary history (17)(18)(19)(20). The same pattern of PV origin in these DDR genes seems suggesting that the PVs in all human DDR genes favors the 2nd possible origin that they were originated from human itself during human evolution process.…”

Section: Introductionmentioning

confidence: 99%

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

Zhao,

Li,

Sinha

et al. 2023

Preprint

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Background Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of DDR genes. Germline pathogenic variation (PV) damages function of the affected DDR genes, leading to genome instability and high risk of cancer. Knowing evolutionary origin of human DDR PV is essential to understand the etiology of human cancer. However, answer to the issue remains largely elusive. In the study, we analyzed evolutionary origin for the PVs in human DDR genes. Methods We collected 169 DDR genes by referencing various databases, analyzing cross-species genomic data using the phyloFit program of the PHAST package, with visualization using GraphPad Prism software and the ggplot module. Ancient and modern human DDR PV detection and comparison using tools such as SAMtools and variant annotation databases. Evolution selection studies across 20 vertebrates used CodeML in PAML for phylogenetic analysis, and the MEGA were used for sequence alignment. We created an open-access database using a LAMP stack and performed statistical analyses using Pearson correlation and Kruskal-Wallis tests. Results Through phylogenic analysis, we ruled out cross-species conservation as the origin; using archeological approach, we identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 10,000 years. We observed similar pattern of quantitative PV distribution between modern and ancient humans. We also detected a group of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. Conclusions Our study reveals that human DDR pathogenic variation mostly arose in recent human history, and human high cancer risk caused by DDR PVs can be a by-product of human evolution.

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Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

Cited by 9 publications

References 52 publications

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

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

Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method

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

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