Confounding by Repetitive Elements and CpG Islands Does Not Explain the Association between Hypomethylation and Genomic Instability

Harris, R. Alan; Shaw, Chad A.; Li, Jian; Cheung, Sau Wai; Coarfa, Cristian; Jeong, Mira; Goodell, Margaret A.; White, Lisa D.; Patel, Ankita; Kang, Sung-Hae L.; Chinault, A. Craig; Gambin, Tomasz; Gambin, Anna; Lupski, James R.; Milosavljevic, Aleksandar

doi:10.1371/journal.pgen.1003333

Cited by 4 publications

(2 citation statements)

References 8 publications

(10 reference statements)

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“…Such mechanisms like non-allelic homologous recombination or break induced replication prevails at regions in the genome exhibiting specific architecture like segmental duplications and common fragile sites, respectively. Moreover, structural mutability is associated with hypomethylation [30, 31] and CpG islands and transcription start and end sites have been shown to be associated with high recombination rates in birds [32].…”

Section: Introductionmentioning

confidence: 99%

CNVs are associated with genomic architecture in a songbird

et al. 2018

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Background: Understanding variation in genome structure is essential to understand phenotypic differences within populations and the evolutionary history of species. A promising form of this structural variation is copy number variation (CNV). CNVs can be generated by different recombination mechanisms, such as non-allelic homologous recombination, that rely on specific characteristics of the genome architecture. These structural variants can therefore be more abundant at particular genes ultimately leading to variation in phenotypes under selection. Detailed characterization of CNVs therefore can reveal evolutionary footprints of selection and provide insight in their contribution to phenotypic variation in wild populations. Results: Here we use genotypic data from a long-term population of great tits (Parus major), a widely studied passerine bird in ecology and evolution, to detect CNVs and identify genomic features prevailing within these regions. We used allele intensities and frequencies from high-density SNP array data from 2,175 birds. We detected 41,029 CNVs concatenated into 8,008 distinct CNV regions (CNVRs). We successfully validated 93.75% of the CNVs tested by qPCR, which were sampled at different frequencies and sizes. A mother-daughter family structure allowed for the evaluation of the inheritance of a number of these CNVs. Thereby, only CNVs with 40 probes or more display segregation in accordance with Mendelian inheritance, suggesting a high rate of false negative calls for smaller CNVs. As CNVRs are a coarse-grained map of CNV loci, we also inferred the frequency of coincident CNV start and end breakpoints. We observed frequency-dependent enrichment of these breakpoints at homologous regions, CpG sites and AT-rich intervals. A gene ontology enrichment analyses showed that CNVs are enriched in genes underpinning neural, cardiac and ion transport pathways. Conclusion: Great tit CNVs are present in almost half of the genes and prominent at repetitive-homologous and regulatory regions. Although overlapping genes under selection, the high number of false negatives make neutrality or association tests on CNVs detected here difficult. Therefore, CNVs should be further addressed in the light of their false negative rate and architecture to improve the comprehension of their association with phenotypes and evolutionary history.

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Section: Introductionmentioning

confidence: 99%

CNVs are associated with genomic architecture in a songbird

et al. 2018

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“…Such mechanisms like non-allelic homologous recombination or break induced replication prevails at regions in the genome exhibiting specific architecture like segmental duplications and common fragile sites, respectively. Moreover, structural mutability is associated with hypomethylation (Li et al, 2012;Harris et al, 2013) and CpG islands and transcription start and end sites have been shown to be associated with high recombination rates in birds (Singhal et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Structural variants in the great tit genome and their effect on seasonal timing

Silva¹,

Henrique²

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Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress

Wang

Song

et al. 2016

Chemosphere

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Microsatellite instability (MSI) analysis, random-amplified polymorphic DNA (RAPD), and methylation-sensitive arbitrarily primed PCR (MSAP-PCR) are methods to evaluate the toxicity of environmental pollutants in stress-treated plants and human cancer cells. Here, we evaluate these techniques to screen for genetic and epigenetic alterations of Arabidopsis plantlets exposed to 0-5.0 mg L(-1) cadmium (Cd) for 15 d. There was a substantial increase in RAPD polymorphism of 24.5, and in genomic methylation polymorphism of 30.5-34.5 at CpG and of 14.5-20 at CHG sites under Cd stress of 5.0 mg L(-1) by RAPD and of 0.25-5.0 mg L(-1) by MSAP-PCR, respectively. However, only a tiny increase of 1.5 loci by RAPD occurred under Cd stress of 4.0 mg L(-1), and an additional high dose (8.0 mg L(-1)) resulted in one repeat by MSI analysis. MSAP-PCR detected the most significant epigenetic modifications in plantlets exposed to Cd stress, and the patterns of hypermethylation and polymorphisms were consistent with inverted U-shaped dose responses. The presence of genomic methylation polymorphism in Cd-treated seedlings, prior to the onset of RAPD polymorphism, MSI and obvious growth effects, suggests that these altered DNA methylation loci are the most sensitive biomarkers for early diagnosis and risk assessment of genotoxic effects of Cd pollution in ecotoxicology.

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Confounding by Repetitive Elements and CpG Islands Does Not Explain the Association between Hypomethylation and Genomic Instability

Cited by 4 publications

References 8 publications

CNVs are associated with genomic architecture in a songbird

CNVs are associated with genomic architecture in a songbird

Structural variants in the great tit genome and their effect on seasonal timing

Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress

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