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UBC Theses and Dissertations
Investigating evolutionary conservation and population specificity of DNA methylation Dong, Zheng
Abstract
Evolutionary processes shape molecular and phenotypic variation and preserve functionally important DNA sequences. Although genomic divergence and conservation have been investigated extensively, epigenomic divergence and conservation remain largely unclear. Particularly, there have been no systematic studies regarding evolutionarily conserved DNA methylation (DNAm), and the population specificity of DNAm has been examined for only ~3.0% of genomic CpGs. To systematically characterize evolutionarily conserved DNAm, I identified methylation-conserved CpGs (MCCs) across great apes and examined their genetic basis, quantitative nature, and potential functional relevance using 202 DNAm array data sets as well as 6 matched genotype and 13 matched transcription data sets. Specifically, I identified 11,500 MCCs genome-wide and separately demonstrated positive relations of CpG methylation conservation with sequence conservation of CpG and DNAm quantitative trait loci. I also determined stable DNAm patterns of MCCs across human individuals and across demographic and environmental factors, tissue types, and noncancer diseases; nonetheless, they varied significantly in multiple cancers. Functional enrichment analysis showed that genes whose expression was associated with MCCs were enriched for cell development and canonical cancer pathways. Furthermore, to obtain a comprehensive picture of population-specific DNAm, I quantified DNAm using whole-genome bisulfite sequencing data from 65 lymphoblastoid B-cell line samples, and analyzed these data together with matched genotype data. Specifically, 101 population-specific co-methylated regions were identified between individuals of European and African ancestry, which were located in genes related to metabolism and infection. Of these, 91 were uniquely identified here compared to previous array-based studies. I also showed that genetic variation played an important role in the population specificity of DNAm and provided a genetic basis for its expansion to East Asian populations and other blood-based samples. Finally, I investigated the impact of the new complete telomere-to-telomere human genome assembly, T2T-CHM13, on genome-wide DNAm analysis, and suggested that it has significant benefits for analyses by including previously unobserved CpGs in short-read sequencing data and by reducing the potential impact of probe cross-reactivity and mismatch for DNAm arrays. Overall, these analyses contributed to the identification and characterization of epigenomic divergence and conservation, especially in terms of their genetic basis and potential functional relevance.
Item Metadata
Title |
Investigating evolutionary conservation and population specificity of DNA methylation
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Creator | |
Supervisor | |
Publisher |
University of British Columbia
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Date Issued |
2024
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Description |
Evolutionary processes shape molecular and phenotypic variation and preserve functionally important DNA sequences. Although genomic divergence and conservation have been investigated extensively, epigenomic divergence and conservation remain largely unclear. Particularly, there have been no systematic studies regarding evolutionarily conserved DNA methylation (DNAm), and the population specificity of DNAm has been examined for only ~3.0% of genomic CpGs. To systematically characterize evolutionarily conserved DNAm, I identified methylation-conserved CpGs (MCCs) across great apes and examined their genetic basis, quantitative nature, and potential functional relevance using 202 DNAm array data sets as well as 6 matched genotype and 13 matched transcription data sets. Specifically, I identified 11,500 MCCs genome-wide and separately demonstrated positive relations of CpG methylation conservation with sequence conservation of CpG and DNAm quantitative trait loci. I also determined stable DNAm patterns of MCCs across human individuals and across demographic and environmental factors, tissue types, and noncancer diseases; nonetheless, they varied significantly in multiple cancers. Functional enrichment analysis showed that genes whose expression was associated with MCCs were enriched for cell development and canonical cancer pathways. Furthermore, to obtain a comprehensive picture of population-specific DNAm, I quantified DNAm using whole-genome bisulfite sequencing data from 65 lymphoblastoid B-cell line samples, and analyzed these data together with matched genotype data. Specifically, 101 population-specific co-methylated regions were identified between individuals of European and African ancestry, which were located in genes related to metabolism and infection. Of these, 91 were uniquely identified here compared to previous array-based studies. I also showed that genetic variation played an important role in the population specificity of DNAm and provided a genetic basis for its expansion to East Asian populations and other blood-based samples. Finally, I investigated the impact of the new complete telomere-to-telomere human genome assembly, T2T-CHM13, on genome-wide DNAm analysis, and suggested that it has significant benefits for analyses by including previously unobserved CpGs in short-read sequencing data and by reducing the potential impact of probe cross-reactivity and mismatch for DNAm arrays. Overall, these analyses contributed to the identification and characterization of epigenomic divergence and conservation, especially in terms of their genetic basis and potential functional relevance.
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Genre | |
Type | |
Language |
eng
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Date Available |
2024-03-28
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0440959
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2024-05
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Campus | |
Scholarly Level |
Graduate
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DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International