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Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes
Huijun Lei1,2,3, Jiaheng Li1, Bojin Zhao1
1Ministry of Education Frontiers Science Center for Precision Oncology, Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, 999078, China.
Background:
Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs.
Methods:
We retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis.
Results:
Using the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns.
Conclusion:
Our study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.
Insights
Pathogenic variants in mismatch repair (MMR) genes, linked to cancer risk, originated recently in human evolution. These MMR variants were not conserved across species but found in ancient human genomes.
Area of Science:
- Genomics
- Evolutionary Biology
- Cancer Genetics
Background:
- The mismatch repair (MMR) system is crucial for maintaining genome stability.
- Germline pathogenic variants (PVs) in MMR genes cause MMR deficiency, significantly increasing cancer risk.
- Understanding the evolutionary origin of human MMR PVs is vital for comprehending MMR deficiency in cancer.
Purpose of the Study:
- To investigate the evolutionary origin of germline pathogenic variants (PVs) in human mismatch repair (MMR) genes.
- To determine if human MMR PVs originated from cross-species conservation or recent human evolution.
Main Methods:
- Retrieved MMR gene variants from ClinVar and analyzed 100 vertebrate genomes for cross-species conservation using phylogenetic analysis.
- Examined over 5000 ancient human genomes (dated from 45,045 to 100 years before present) for MMR PVs using variant calling on rescaled ancient sequencing data.
Main Results:
- No evidence of cross-species conservation was found for the 3369 MMR PVs identified in modern humans across 99 non-human vertebrate genomes.
- A subset of MMR PVs shared between modern and ancient humans was identified, predominantly within the last 10,000 years, showing similar quantitative patterns.
Conclusions:
- Pathogenic variants in human mismatch repair genes arose within recent human evolutionary history.
- The findings suggest that recent human evolution, rather than ancient cross-species conservation, is the source of common MMR PVs contributing to cancer risk.
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