De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on Attention Problems

1] Avera Institute for Human Genetics, Avera Behavioral Health Center, Sioux Falls, SD, USA [2] Department of Psychiatry, University of South Dakota, Sioux Falls, SD, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 04/2012; 20(10):1037-43. DOI: 10.1038/ejhg.2012.49
Source: PubMed


Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of ∼3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical.

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    • "All the miRNA-CNVs clustered based on the point and type of origin showed biased contributions of miRNA-CNVs from mother compared to father. Though, earlier studies have reported diverse CNV transmission and de novo event rates in probands with several neurodevelopmental phenotypes and monozygotic twin studies [51]–[54], however, no such inheritance rate on the miRNA-CNVs has been performed before. miRNA-CNV frequency bias was observed on the CNV transmissions from maternal genome only, showing major contributions from deletion CNVs than duplications. "
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    ABSTRACT: MicroRNAs are involved in post-transcriptional down-regulation of gene expression. Variations in miRNA genes can severely affect downstream-regulated genes and their pathways. However, population-specific burden of CNVs on miRNA genes and the complexities created towards the phenotype is not known. From a total of 44109 CNVs investigated from 1715 individuals across 12 populations using high-throughput arrays, 4007 miRNA-CNVs (∼9%) consisting 6542 (∼5%) miRNA genes with a total of 333 (∼5%) singleton miRNA genes were identified. We found miRNA-CNVs across the genomes of individuals showing multiple hits in many targets, co-regulated under the same pathway. This study proposes four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity.
    PLoS ONE 02/2014; 9(2):e90391. DOI:10.1371/journal.pone.0090391 · 3.23 Impact Factor
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    • "Using monozygotic twins, three somatic CNV events were found to be associated with discordance for congenital heart defects (Breckpot et al., 2012). Similarly, two de novo CNVs — a pre-twinning duplication and a post-twinning deletion were found to be associated with attention problems (Ehli et al., 2012). Another study looking at Rett syndrome in discordant monozygotic twins found differences in deoxyribonucleic acid (DNA) methylation between twins detected in fibroblasts in the upstream region of genes involved in brain function to be associated with the disease (Miyake et al., 2013). "
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    ABSTRACT: We have evaluated copy number variants (CNVs) in six monozygotic twin pairs discordant for schizophrenia. The data from Affymetrix® Human SNP 6.0 arrays™ were analyzed using Affymetrix® Genotyping Console™, Partek® Genomics Suite™, PennCNV, and Golden Helix SVS™. This yielded both program-specific and overlapping results. Only CNVs called by Affymetrix Genotyping Console, Partek Genomics Suite, and PennCNV were used in further analysis. This analysis included an assessment of calls in each of the six twin pairs towards identification of unique CNVs in affected and unaffected co-twins. Real time polymerase chain reaction (PCR) experiments confirmed one CNV loss at 7q11.21 that was found in the affected patient but not in the unaffected twin. The results identified CNVs and genes that were previously implicated in mental abnormalities in four of the six twin pairs. It included PYY (twin pairs 1 and 5), EPHA3 (twin pair 3), KIAA1211L (twin pair 4), and GPR139 (twin pair 5). They represent likely candidate genes and CNVs for the discordance of four of the six monozygotic twin pairs for this heterogeneous neurodevelopmental disorder. An explanation for these differences is ontogenetic de novo events that differentiate in the monozygotic twins during development.
    Twin Research and Human Genetics 02/2014; 17(02):1-13. DOI:10.1017/thg.2014.6 · 2.30 Impact Factor
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    • "If 1–1.4% of these calls were somatic events, the observed rate per individual would approximate the predicted error rate. A recent study reported an intratwin pair difference in monozygotic twins suggesting a posttwinning de novo copy number variant event (Ehli et al. 2012). Several other studies have reported CNVs in twin studies (Bruder et al. 2008; Maiti et al. 2011; Sasaki et al. 2011; Breckpot et al. 2012), and so there may be differences in somatic Copy Number Variant and SNP occurrence. "
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    ABSTRACT: When applying genome-wide sequencing technologies to disease investigation, it is increasingly important to resolve sequence variation in regions of the genome that may have homologous sequences. The human mitochondrial genome challenges interpretation given the potential for heteroplasmy, somatic variation, and homologous nuclear mitochondrial sequences (numts). Identical twins share the same mitochondrial DNA (mtDNA) from early life, but whether the mitochondrial sequence remains similar is unclear. We compared an adult monozygotic twin pair using high throughput-sequencing and evaluated variants with primer extension and mitochondrial pre-enrichment. Thirty-seven variants were shared between the twin individuals, and the variants were verified on the original genomic DNA. These studies support highly identical genetic sequence in this case. Certain low-level variant calls were of high quality and homology to the mitochondrial DNA, and they were further evaluated. When we assessed calls in pre-enriched mitochondrial DNA templates, we found that these may represent numts, which can be differentiated from mtDNA variation. We conclude that twin identity extends to mitochondrial DNA, and it is critical to differentiate between numts and mtDNA in genome sequencing, particularly since significant heteroplasmy could influence genome interpretation. Further studies on mtDNA and numts will aid in understanding how variation occurs and persists.
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