Article thumbnail

Ontogenetic De Novo Copy Number Variations (CNVs) as a Source of Genetic Individuality: Studies on Two Families with MZD Twins for Schizophrenia

By Sujit Maiti, Kiran Halagur Bhoge Gowda Kumar, Christina A. Castellani, Richard O'Reilly and Shiva M. Singh

Abstract

Genetic individuality is the foundation of personalized medicine, yet its determinants are currently poorly understood. One issue is the difference between monozygotic twins that are assumed identical and have been extensively used in genetic studies for decades [1]. Here, we report genome-wide alterations in two nuclear families each with a pair of monozygotic twins discordant for schizophrenia evaluated by the Affymetrix 6.0 human SNP array. The data analysis includes characterization of copy number variations (CNVs) and single nucleotide polymorphism (SNPs). The results have identified genomic differences between twin pairs and a set of new provisional schizophrenia genes. Samples were found to have between 35 and 65 CNVs per individual. The majority of CNVs (∼80%) represented gains. In addition, ∼10% of the CNVs were de novo (not present in parents), of these, 30% arose during parental meiosis and 70% arose during developmental mitosis. We also observed SNPs in the twins that were absent from both parents. These constituted 0.12% of all SNPs seen in the twins. In 65% of cases these SNPs arose during meiosis compared to 35% during mitosis. The developmental mitotic origin of most CNVs that may lead to MZ twin discordance may also cause tissue differences within individuals during a single pregnancy and generate a high frequency of mosaics in the population. The results argue for enduring genome-wide changes during cellular transmission, often ignored in most genetic analyses

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3047561
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2009). (Epi)genomics and neurodevelopment in schizophrenia: monozygotic twins discordant for schizophrenia augment the search for disease-related (epi)genomic alterations.
  2. (1989). A
  3. (2003). A 3.4-kbp transcript of ZNF331 is solely expressed in follicular thyroid adenomas.
  4. (2008). A common sequence motif associated with recombination hot spots and genome instability in humans.
  5. (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia.
  6. (2007). Annotation, nomenclature and evolution of four novel homeobox genes expressed in the human germ line.
  7. (1998). Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases.
  8. (2009). Chromosome instability is common in human cleavage-stage embryos.
  9. (2010). Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia.
  10. (2009). Copy number variation showers in schizophrenia: an emerging hypothesis.
  11. (2006). Critical appraisal of DNA microarrays in psychiatric genomics.
  12. (1998). Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology.
  13. (2004). Detection of large-scale variation in the human genome.
  14. (2010). DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet.
  15. (2009). DNA methylation profiles in monozygotic and dizygotic twins.
  16. (2008). Drosophila peroxiredoxin 5 is the second gene in a dicistronic operon.
  17. (2010). Early embryonic chromosome instability results in stable mosaic pattern in human tissues.
  18. (2005). Epigenetic differences arise during the lifetime of monozygotic twins.
  19. (1994). Farmer A
  20. (2005). Gene expression microarray studies in polygenic psychiatric disorders: applications and data analysis.
  21. (2004). Gene expression profile in interleukin-4-stimulated human vascular endothelial cells.
  22. (2010). Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
  23. (2010). Genomic copy number variations in three Southeast Asian populations.
  24. (1996). Genomic organization and mapping of the mouse P26s4 ATPase gene: a member of the remarkably conserved AAA gene family.
  25. (2010). High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta.
  26. (2001). Isolation, characterization, and mapping of a novel human KRAB zinc finger protein encoding gene ZNF463.
  27. (2004). Large-scale copy number polymorphism in the human genome.
  28. (2009). Mechanisms of change in gene copy number.
  29. (2010). Multiple personal genomes await.
  30. (2010). Multiple sclerosis: geoepidemiology, genetics and the environment.
  31. (2008). Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles.
  32. (2010). Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia.
  33. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
  34. (2008). Somatic mosaicism for copy number variation in differentiated human tissues.
  35. (2010). Structural variation in the human genome and its role in disease.
  36. (2010). The clinical context of copy number variation in the human genome.
  37. (2007). The diploid genome sequence of an individual human.
  38. (2008). The DNA damage response pathways: at the crossroad of protein modifications.
  39. (2009). The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans.
  40. (2010). The emergence of a new science of the mind: immunology benefits the mind.
  41. (1919). The Genesis of Twins.
  42. (2010). The role of copy number variation in schizophrenia.