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

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.

[1]  G. Kirov,et al.  Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. , 2010, Archives of general psychiatry.

[2]  J. Soares,et al.  Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology. , 1998, Cancer genetics and cytogenetics.

[3]  P. Visscher,et al.  DNA methylation profiles in monozygotic and dizygotic twins , 2009, Nature Genetics.

[4]  Kenny Q. Ye,et al.  Large-Scale Copy Number Polymorphism in the Human Genome , 2004, Science.

[5]  K. Mrasek,et al.  Early Embryonic Chromosome Instability Results in Stable Mosaic Pattern in Human Tissues , 2010, PloS one.

[6]  K. Chen,et al.  Gene Expression Profile in Interleukin-4-Stimulated Human Vascular Endothelial Cells , 2004, Molecular medicine.

[7]  J. Lupski,et al.  The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans , 2009, Nature Genetics.

[8]  George Kirov,et al.  The role of copy number variation in schizophrenia , 2010, Expert review of neurotherapeutics.

[9]  P. Levitt,et al.  Critical Appraisal of DNA Microarrays in Psychiatric Genomics , 2006, Biological Psychiatry.

[10]  Geert Verbeke,et al.  Chromosome instability is common in human cleavage-stage embryos , 2009, Nature Medicine.

[11]  Jan Komorowski,et al.  Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. , 2008, American journal of human genetics.

[12]  John B Carlin,et al.  DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. , 2010, Human molecular genetics.

[13]  P. Stankiewicz,et al.  Structural variation in the human genome and its role in disease. , 2010, Annual review of medicine.

[14]  W. Orr,et al.  Drosophila peroxiredoxin 5 is the second gene in a dicistronic operon. , 2008, Biochemical and biophysical research communications.

[15]  David B. Goldstein,et al.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia , 2009, PLoS genetics.

[16]  Y. Teo,et al.  Genomic copy number variations in three Southeast Asian populations , 2010, Human mutation.

[17]  J. Komorowski,et al.  Somatic mosaicism for copy number variation in differentiated human tissues , 2008, Human mutation.

[18]  T. Fujiwara,et al.  Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases. , 1998, Biochemical and biophysical research communications.

[19]  R. A. Fisher.  The Genesis of Twins. , 1919, Genetics.

[20]  P. Buckley.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2009 .

[21]  Stephen L. Hauser,et al.  Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis , 2010, Nature.

[22]  Peter Donnelly,et al.  A common sequence motif associated with recombination hot spots and genome instability in humans , 2008, Nature Genetics.

[23]  Matthew E. Ritchie,et al.  High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta , 2010, BMC Genetics.

[24]  P. Holland,et al.  Annotation, nomenclature and evolution of four novel homeobox genes expressed in the human germ line. , 2007, Gene.

[25]  C. Konradi,et al.  Gene expression microarray studies in polygenic psychiatric disorders: Applications and data analysis , 2005, Brain Research Reviews.

[26]  A. Fusco,et al.  A 3.4-kbp transcript of ZNF331 is solely expressed in follicular thyroid adenomas , 2003, Cytogenetic and Genome Research.

[27]  J. Lupski,et al.  Mechanisms of change in gene copy number , 2009, Nature Reviews Genetics.

[28]  C. Castellani,et al.  Copy number variation showers in schizophrenia: an emerging hypothesis , 2009, Molecular Psychiatry.

[29]  Shiva M. Singh,et al.  (Epi)genomics and neurodevelopment in schizophrenia: monozygotic twins discordant for schizophrenia augment the search for disease-related (epi)genomic alterations. , 2009, Genome.

[30]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[31]  A. Farmer,et al.  The Strength of the Genetic Effect , 1994, British Journal of Psychiatry.

[32]  M. Schwartz,et al.  The emergence of a new science of the mind: immunology benefits the mind , 2010, Molecular Psychiatry.

[33]  J. Venter,et al.  Multiple personal genomes await , 2010, Nature.

[34]  G. Zhang,et al.  Isolation, characterization, and mapping of a novel human KRAB zinc finger protein encoding gene ZNF463. , 2001, Biochimica et Biophysica Acta.

[35]  A. Bertelsen,et al.  Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins. , 1989, Archives of general psychiatry.

[36]  Charles Lee,et al.  The clinical context of copy number variation in the human genome , 2010, Expert Reviews in Molecular Medicine.

[37]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[38]  Nicholas J. Schork,et al.  Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. , 2010, Genome research.

[39]  E. Kahana,et al.  Multiple sclerosis: geoepidemiology, genetics and the environment. , 2010, Autoimmunity reviews.

[40]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  L. Feuk,et al.  Detection of large-scale variation in the human genome , 2004, Nature Genetics.

[42]  Junjie Chen,et al.  The DNA damage response pathways: at the crossroad of protein modifications , 2008, Cell Research.