The schizophrenia brain exhibits low-level aneuploidy involving chromosome 1.

OBJECTIVE: Genetic instability manifested as loss or gain of whole chromosomes (aneuploidy) is a newly described feature of the human brain. Aneuploidy in the brain was hypothesized to be involved in schizophrenia pathogenesis. To gain further insights into the relationship between aneuploidy in the brain and schizophrenia pathogenesis, a molecular-cytogenetic study of chromosome 1 aneuploidy was performed. METHODS: Interphase multiprobe fluorescence in situ hybridization (FISH) with quantitative FISH (QFISH) and interphase chromosome-specific multicolor banding (ICS-MCB) were used to define aneuploidy rate in 12 unaffected and 12 schizophrenia brains. RESULTS: In the unaffected brain (n=12; 22,794 cells analyzed), average frequencies of stochastic chromosome 1 loss and gain were 0.3% (95%CI 0.2-0.4%) and 0.3% (95%CI 0.2-0.4%), respectively. The threshold level for stochastic chromosome gain and loss (the mean+3SD) in the normal brain was 0.7%. Average rate of aneuploidy in the schizophrenia brain (n=12; 28,482 cells analyzed) was 0.9% (95%CI 0.3-1.5%) for chromosome 1 loss and 0.9% (95%CI 0.2-1.7%) for chromosome 1 gain. Significantly increased level of mosaic aneuploidy involving chromosome 1 was revealed in two schizophrenia brains (3.6% and 4.7% of cells with chromosome 1 loss and gain, respectively). Stochastic aneuploidy rate for chromosome 1 in the schizophrenia brain without two outliers (n=10) reached 0.6% (95%CI 0.3-0.9%) for loss and 0.5% (0.2-0.9%) for gain and was higher than in controls (P=0.005 and P=0.001, respectively). CONCLUSIONS: Our findings support the hypothesis suggesting that subtle genomic imbalances manifesting as low-level mosaic aneuploidy may contribute to schizophrenia pathogenesis.

The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study.

Despite the lack of direct cytogenetic studies, the neuronal cells of the normal human brain have been postulated to contain normal (diploid) chromosomal complement. Direct proof of a chromosomal mutation presence leading to large-scale genomic alterations in neuronal cells has been missing in the human brain. Large-scale genomic variations due to chromosomal complement instability in developing neuronal cells may lead to the variable level of chromosomal mosaicism probably having a substantial effect on brain development. The aim of the present study was the pilot assessment of chromosome complement variations in neuronal cells of developing and adult human brain tissues using interphase multicolor fluorescence in situ hybridization (mFISH). Chromosome-enumerating DNA probes from the original collection (chromosomes 1, 13 and 21, 18, X, and Y) were used for the present pilot FISH study. As a source of fetal brain tissue, the medulla oblongata was used. FISH studies were performed using uncultured fetal brain samples as well as organotypic cultures of medulla oblongata tissue. Cortex tissues of postmortem adult brain samples (Brodmann area 10) were also studied. In cultured in vitro embryonic neuronal brain cells, an increased level of aneuploidy was found (mean rate in the range of 1.3-7.0% per individual chromosome, in contrast to 0.6-3.0% and 0.1-0.8% in uncultured fetal and postmortem adult brain cells, respectively). The data obtained support the hypothesis regarding aneuploidy occurrence in normal developing and adult human brain.