A characterization of postzygotic mutations identified in monozygotic twins

Purpose: There is urgent need for non-invasive diagnostic biomarkers in the preclinical phase of Alzheimer's Disease (AD). Several studies suggest that retinal thickness is reduced in AD. Here, we aim to test the diagnostic value of retinal thickness in preclinical AD, as defined by cognitively normal individuals with amyloid pathology on PET. Methods: One hundred and sixty five cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the European Medical Information Framework for Alzheimer's Disease PreclinAD study. Participants underwent [ 18 F] flutemetamol PET that was visually rated for presence or absence of cortical amyloid beta (Ab). Binding potential (BP ND ) was calculated as continuous measure for Ab. Spectral Domain OCT was used to asses total and individual inner retinal layer thickness in the macular region (ETDRS circles) as well as peripapillary retinal nerve fibre layer (pRNFL) thickness. Differences between Ab+ and AbÀ individuals and associations between BP ND and retinal thickness were analyzed. Results: No differences were found in retinal layer thickness in the macula or pRNFL between Ab+ and AbÀ individuals. A positive associations between BP ND and macular total retinal thickness was observed in the inner ring (p = 0.018), but this was not statistically significant after correction for multiple testing (p = 0.144). Brain/eye parameters had moderate to high intra-twin correlations (p < 0.001) except visual rating score of Ab, which did not correlate (r = 0.21, p = 0.068). Conclusion: Variation in retinal thickness likely reflects genetic differences between individuals, but cannot discriminate between healthy and preclinical AD cases, making its use as biomarker in these early stages limited.

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“…This correlation is high when a trait is mainly determined by genetic factor, as monozygotic twins share their genomic DNA (Ouwens et al. ).…”

Section: Methodsmentioning

confidence: 99%

Retinal layer thickness in preclinical Alzheimer's disease

Kreeke

Nguyen

Haan

et al. 2019

Acta Ophthalmologica

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“…Methylome-wide studies in monozygotic (MZ) and dizygotic (DZ) twins are performed to obtain insight into the extent to which DNA methylation levels are influenced by genetic, environmental and stochastic influences or to identify loci where methylation differences between twins are associated with discordance for traits [ 7 ]. MZ (identical) twins have nearly identical DNA sequences, although they may differ with respect to post-zygotic somatic mutations [ 8 – 10 ]. Their DNA methylation profiles show differences in multiple tissues that are already detectable at birth, and these difference may increase with age [ 11 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs

Dongen

Ehli

Jansen

et al. 2018

Epigenetics & Chromatin

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BackgroundDNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.ResultsGood-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1–10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10−16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10−16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.ConclusionsWe conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0225-x) contains supplementary material, which is available to authorized users.

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“…Bioinformatic Analysis Cases using reference genome GRCh38 2.1.0 (1, 2, 7, 10, 11) were processed with Long Ranger 2.1.6 and GATK HaplotypeCaller 3.8-0. Samples using reference genome b37 2.1.0 (3,4,5,6,8,9,10,12) were processed with Long Ranger 2.1.3 and GATK HaplotypeCaller 3.5-0. The sequencing coverage and fraction of the genome identified by the CNVNATOR [45] calls is recorded in Table S2, and the oncology diagnosis of each case in Table S8.…”

Section: Pediatric Cancermentioning

confidence: 99%

“…The distribution and prevalence of cells with a mosaic mutation depend on a combination of the developmental cell lineage, stage at which the mutation occurred, selection for or against cells with the mutation [3], and cell migration [4]. Somatic mosaicism refers to genetic heterogeneity among non-germ cells, which accrue in normally dividing cells throughout the human lifetime [5,6,7] corroborated by monozygotic twin studies [8]. Mosaicism also plays an important role in many genetic diseases.…”

Section: Introductionmentioning

confidence: 99%

Samovar: Single-sample mosaic SNV calling with linked reads

Darby

Fitch

Brennan

et al. 2019

Preprint

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We present Samovar, a mosaic single-nucleotide variant (SNV) caller for linked-read wholegenome shotgun sequencing data. Samovar scores candidate sites using a random forest model trained using the input dataset that considers read quality, phasing, and linked-read characteristics. We show Samovar calls mosaic SNVs within a single sample with accuracy comparable to what previously required trios or matched tumor/normal pairs and outperform single-sample mosaic variant callers at MAF 5%-50% with at least 30x coverage. Furthermore, we use Samovar to find somatic variants in whole genome sequencing of both tumor and normal from 13 pediatric cancer cases that can be corroborated with high recall with whole exome sequencing. Samovar is available open-source at https://github.com/cdarby/samovar under the MIT license.

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A characterization of postzygotic mutations identified in monozygotic twins

Cited by 13 publications

References 55 publications

Retinal layer thickness in preclinical Alzheimer's disease

Retinal layer thickness in preclinical Alzheimer's disease

Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs

Samovar: Single-sample mosaic SNV calling with linked reads

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