Novel retrotransposed imprinted locus identified at human 6p25

Zhang, Aiping; Skaar, David; Li, Yue; Huang, Dale; Price, Thomas M.; Murphy, Susan K.; Jirtle, Randy L.

doi:10.1093/nar/gkr108

Cited by 22 publications

(20 citation statements)

References 57 publications

(58 reference statements)

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“…For the candidate genes investigated in more detail by deep bisulfite sequencing we could not detect allele-specific methylation or imprinting except for the previously described FAM50B [11,25]. Analyses after allele-separation did not reveal significant differences in level or distribution of methylation between the two parental alleles.…”

Section: Resultsmentioning

confidence: 61%

“…NC - normal control; # two CpGs affected - data for the CpG showing a greater difference in methylation are included; * recently shown to be imprinted [11,25]; § methylation level after correction for allelic imbalance in the obtained reads.…”

Section: Resultsmentioning

confidence: 99%

“…FAM50B is a retrotransposed gene located on human chromosome 6p25 and was recently reported to be imprinted [11,25]. They showed that FAM50B is subject to genomic imprinting in various tissues being methylated on the maternal allele and exhibiting expression from the paternal allele only.…”

Section: Resultsmentioning

confidence: 99%

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Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

et al. 2013

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NLRP7 is a maternal effect gene as maternal mutations in this gene cause recurrent hydatidiform moles, spontaneous abortions and stillbirths, whereas live births are very rare. We have studied a patient with multiple anomalies born to a mother with a heterozygous NLRP7 mutation. By array-based CpG methylation analysis of blood DNA from the patient, his parents and 18 normal controls on Illumina Infinium HumanMethylation27 BeadChips we found that the patient had methylation changes (delta ß ≥ 0.3) at many imprinted loci as well as at 87 CpGs associated with 85 genes of unknown imprinting status. Using a pseudoproband (permutation) approach, we found methylation changes at only 7-24 CpGs (mean 15; standard deviation 4.84) in the controls. Thus, the number of abberantly methylated CpGs in the patient is more than 14 standard deviations higher. In order to identify novel imprinted genes among the 85 conspicuous genes in the patient, we selected 19 (mainly hypomethylated) genes for deep bisulfite amplicon sequencing on the ROCHE/454 Genome Sequencer in the patient and at least two additional controls. These controls had not been included in the array analysis and were heterozygous for a single nucleotide polymorphism at the test locus, so that allele-specific DNA methylation patterns could be determined. Apart from FAM50B, which we proved to be imprinted in blood, we did not observe allele-specific DNA methylation at the other 18 loci. We conclude that the patient does not only have methylation defects at imprinted loci but (at least in blood) also an excess of methylation changes at apparently non-imprinted loci.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

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Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

et al. 2013

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“…probes† Lowest p value‡ Probe region* No. probes† Lowest p value‡ Novel candidate DMRs 1 LOC728448/ PPIEL No 40 024 971–40 025 411 3 1.47E−18 40 024 971–40 025 232 2 3.09E−22 4 JAKMIP1 Yes 6 107 021–6 107 339 4 2.48E−16 6 107 021–6 107 339 4 5.83E−36 7 SVOPL Yes 138 348 774–138 349 443 3 6.30E−41 138 348 774–138 349 443 3 7.21E−20 9 FANCC Yes 98 075 481–98 075 492 2 8.29E−58 98 075 481–98 075 492 2 7.28E−55 17 GLP2R No 9 729 250–9 729 424 3 3.33E−16 9 729 250–9 729 422 4 1.81E−23 21 WRB Yes 40 757 691–40 758 208 2 2.51E−20 40 757 691–40 758 208 4 6.71E−29 8 LOC728024/ERLIN2 No 37 605 517–37 605 783 4 3.87E−40 37 605 359–37 605 978 6 2.69E−42 18 LOC100130522/PARD6G-AS1 Yes 77 905 355–77 905 947 3 1.01E−19 77 905 298–77 905 947 9 4.38E−71 22 NHP2L1 Yes 42 078 217–42 078 723 6 4.08E−15 42 078 217–42 078 723 6 4.25E−54 Imprinted—not associated with ID 1 DIRAS343 Yes 68 512 539–68 517 273 21 6.69E−31 68 512 539–68 517 273 20 5.45E−64 6 FAM50B 20 44 Yes 3 849 235–3 849 818 17 1.70E−18 3 849 272–3 849 818 17 1.64E−39 15 IGF1R45 No 99 408 636–99 409 506 5 2.23E−15 99 408 636–99 409 957 …”

Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes

et al. 2014

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BackgroundGenomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome.DesignWe developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith–Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation.ResultsWe detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver–Russell syndrome presentations and one with pseudohypoparathyroidism 1B.ConclusionsThis study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.

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“…[9][10][11] This phenomenon can also be observed in the human genome for a number of genes, e.g., MAGEL2, MKRN3, NDN, and NPAPA1. 9,[12][13][14] In the case of RB1, a differentially methylated CpG island (CpG85), which is part of a retrocopy (PPP1R26P1) and located in intron 2, is responsible for imprinting of the human RB1 gene. Parent-of-origin-specific methylation of CpG85 has been confirmed by other studies.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

et al. 2016

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Gene duplication by retrotransposition, i.e., the reverse transcription of an mRNA and integration of the cDNA into the genome, is an important mechanism in evolution. Based on whole-genome bisulfite sequencing of monocyte DNA, we have investigated the methylation state of all CpG islands (CGIs) associated with a retrocopy (n D 1,319), their genomic environment, as well as the CGIs associated with the ancestral genes. Approximately 10% of retrocopies are associated with a CGI. Whereas almost all CGIs of the human genome are unmethylated, 68% of the CGIs associated with a retrocopy are methylated. In retrocopies resulting from multiple retrotranspositions of the same ancestral gene, the methylation state of the CGI often differs. There is a strong positive correlation between the methylation state of the CGI/ retrocopy and their genomic environment, suggesting that the methylation state of the integration site determined the methylation state of the CGI/retrocopy, or that methylation of the retrocopy by a host defense mechanism has spread into the adjacent regions. Only a minor fraction of CGI/retrocopies (n D 195) has intermediate methylation levels. Among these, the previously reported CGI/retrocopy in intron 2 of the RB1 gene (PPP1R26P1) as well as the CGI associated with the retrocopy RPS2P32 identified in this study carry a maternal methylation imprint. In conclusion, these findings shed light on the evolutionary dynamics and constraints of DNA methylation.

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Novel retrotransposed imprinted locus identified at human 6p25

Cited by 22 publications

References 57 publications

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

Genome-wide DNA methylation analysis of patients with imprinting disorders identifies differentially methylated regions associated with novel candidate imprinted genes

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

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