Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia

Clinical and Translational Medicine, Nov 2017

Background Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia. Methods We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient. Results We found multiple twin specific sequence differences between co-twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families. Conclusions We have identified genome-wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins.

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Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia

Castellani et al. Clin Trans Med Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia C. A. Castellani 0 2 M. G. Melka 2 J. L. Gui 2 A. J. Gallo 2 R. L. O'Reilly 1 S. M. Singh 1 2 0 Present Address: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA 1 Department of Psychiatry, The University of Western Ontario , London, ON N6A 5B7 , Canada 2 Department of Biology, The University of Western Ontario , London, ON N6A 5B7 , Canada Background: Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia. Methods: We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient. Results: We found multiple twin specific sequence differences between co-twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families. Conclusions: We have identified genome-wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins. Schizophrenia; Whole genome sequencing; Monozygotic twins; Genome variation; Somatic mutation; Threshold model Background Monozygotic (MZ) twins originate from a single fertilized zygote and have been used to study the relative contribution of nature and nurture on a variety of phenotypes and disorders for well over a century. Schizophrenia, which is among the most devastating of the major mental health disorders, is thought to have both genetic and environmental causes [ 1 ]. Results show that although the frequency of schizophrenia is only 1% in the general population, its concordance in MZ twins approximates ~ 50% and not 100% [ 2 ]. Interestingly, recent results have shown that MZ twins may differ for de novo events, that include copy number variations (CNVs) [ 3, 4 ] and DNA methylation [ 5–8 ]. The timing, rate, extent and impact of such de novo events however, is difficult to ascertain. They may occur anytime during development as a normal aspect of development of an organ [ 9 ] and cell type [ 10 ]. Also, depending on the developmental stage at which they arise, will determine their presence in all or almost all cells of an individual or represent mosaicism. The random nature of this variation is expected to differ between MZ twins and contribute to twin differences. Although logical and attractive as a potential hypothesis for the cause of disease discordance in MZ twins, the confirmation of this hypothesis faces two challenges. The first is the identification of all or almost all differences between the genomes of discordant MZ twins and the second is establishing the significance of the observed genomic difference in the disease. Although the former is gradually becoming possible through increased resolution of genomic technologies, the latter remains challenging and will demand diligent efforts [ 11, 12 ]. The challenge of analysis and interpretation of complete genome sequences is attributed to a variety of factors [ 13 ]. First, the sequence coverage is not always 100% and second, the differences between MZ twins are not always easy to confirm due in part to expected mosaicism of unknown frequency and distribution [ 14 ], even though it is possible to differentiate between the pre-zygotic or post-zygotic origin of such twin differences using parental sequences. The next challenge is any involvement of observed differences in the development of schizophrenia. This of course is a much more complicated question. Schizophrenia is highly heterogeneous (...truncated)


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C. A. Castellani, M. G. Melka, J. L. Gui, A. J. Gallo, R. L. O’Reilly, S. M. Singh. Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia, Clinical and Translational Medicine, 2017, pp. 43, Volume 6, Issue 1, DOI: 10.1186/s40169-017-0174-1