Intercellular differences of chromosomal content in the same individual are defined as chromosomal mosaicism (alias intercellular or somatic genomic variations or, in a number of publications, mosaic aneuploidy). It has long been suggested that this phenomenon poorly contributes both to intercellular (interindividual) diversity and to human disease. However, our views have recently become to change due to a series of communications demonstrated a higher incidence of chromosomal mosaicism in diseased individuals (major psychiatric disorders and autoimmune diseases) as well as depicted chromosomal mosaicism contribution to genetic diversity, the central nervous system development, and aging. The later has been produced by significant achievements in the field of molecular cytogenetics. Recently, Molecular Cytogenetics has published an article by Maj Hulten and colleagues that has provided evidences for chromosomal mosaicism to underlie formation of germline aneuploidy in human female gametes using trisomy 21 (Down syndrome) as a model. Since meiotic aneuploidy is suggested to be the leading genetic cause of human prenatal mortality and postnatal morbidity, these data together with previous findings define chromosomal mosaicism not as a casual finding during cytogenetic analyses but as a more significant biological phenomenon than previously recognized. Finally, the significance of chromosomal mosaicism can be drawn from the fact, that this phenomenon is involved in genetic diversity, normal and abnormal prenatal development, human diseases, aging, and meiotic aneuploidy, the intrinsic cause of which remains, as yet, unknown.

and Institute of Pediatrics and Children's Surgery, Russian Ministry of Health, Moscow, Russia (SGV) S U M M A R Y 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. T he human brain is the control center that stores, computes, integrates, and transmits information. It contains ‫ف‬ 10 12 neurons, each forming as many as a thousand connections with other neurons (Lodish et al. 2000). There have been no direct studies of large-scale genomic variations and chromosomal complement in the human central nervous system. Without experimental proof, the neuronal cells of the normal brain were postulated to contain normal (diploid) chromosome complement. However, indirect evidence for some forms of somatic, genomic, and chromosomal alterations in the neurons of mouse brain has been obtained. By means of fluorescence in situ hybridization (FISH) and spectral karyotype analysis of mouse embryonic cerebral cortical neuroblasts in the developing and adult nervous system, more than 30% of neuroblasts were found to be aneuploid (Rehen et al. 2001). Visualization of metaphase chromosomes by a nuclear transfer technique in mouse cortical neurons has indicated that the majority are characterized by an abnormal karyotype (Osada et al. 2002). Therefore, there is evidence for genomic variation at the level of whole chromosomes in developing and adult mouse neurons.There are only a limited number of molecular cytogenetic studies of the human brain using interphase FISH. The use of FISH was reported for examination of the interphase nuclei chromosomal co...

Molecular cytogenetics is a promising field of biomedical research that has recently revolutionized our thinking on genome structure and behavior. This is in part due to discoveries of human genomic variations and their contribution to biodiversity and disease. Since these studies were primarily targeted at variation of the genome structure, it appears apposite to cover them by molecular cytogenomics. Human brain diseases, which encompass pathogenic conditions from severe neurodegenerative diseases and major psychiatric disorders to brain tumors, are a heavy burden for the patients and their relatives. It has been suggested that most of them, if not all, are of genetic nature and several recent studies have supported the hypothesis assuming them to be associated with genomic instabilities (i.e. single-gene mutations, gross and subtle chromosome imbalances, aneuploidy). The present review is focused on the intriguing relationship between genomic instability and human brain diseases. Looking through the data, we were able to conclude that both interindividual and intercellular genomic variations could be pathogenic representing, therefore, a possible mechanism for human brain malfunctioning. Nevertheless, there are still numerous gaps in our knowledge concerning the link between genomic variations and brain diseases, which, hopefully, will be filled by forthcoming studies. In this light, the present review considers perspectives of this dynamically developing field of neurogenetics and genomics.

Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout the ontogeny, chromosomal mosaicism may mediate genome/chromosome instability and intercellular diversity in health and disease in a bottleneck fashion. However, the ubiquity of negligibly small populations of cells with abnormal karyotypes results in difficulties of the interpretation and detection, which may be nonetheless solved by post-genomic cytogenomic technologies. In the post-genomic era, it has become possible to uncover molecular and cellular pathways to genome/chromosome instability (chromosomal mosaicism or heterogeneity) using advanced whole-genome scanning technologies and bioinformatic tools. Furthermore, the opportunities to determine the effect of chromosomal abnormalities on the cellular phenotype seem to be useful for uncovering the intrinsic consequences of chromosomal mosaicism. Accordingly, a post-genomic review of chromosomal mosaicism in the ontogenetic and pathogenetic contexts appears to be required. Here, we review chromosomal mosaicism in its widest sense and discuss further directions of cyto(post)genomic research dedicated to chromosomal heterogeneity.

Human molecular cytogenetics integrates the knowledge on chromosome and genome organization at the molecular and cellular levels in health and disease. Molecular cytogenetic diagnosis is an integral part of current genomic medicine and is the standard of care in medical genetics and cytogenetics, reproductive medicine, pediatrics, neuropsychiatry and oncology. Regardless numerous advances in this field made throughout the last two decades, researchers and practitioners who apply molecular cytogenetic techniques may encounter several problems that are extremely difficult to solve. One of them is undoubtedly the occurrence of somatic genome and chromosome variations, leading to genomic and chromosomal mosaicism, which are related but not limited to technological and evaluative limitations as well as multiplicity of interpretations. More dramatically, current biomedical literature almost lacks descriptions, guidelines or solutions of these problems. The present article overviews all these problems and gathers those exclusive data acquired from studies of genome and chromosome instability that is relevant to identification and interpretations of this fairly common cause of somatic genomic variations and chromosomal mosaicism. Although the way to define pathogenic value of all the intercellular variations of the human genome is far from being completely understood, it is possible to propose recommendations on molecular cytogenetic diagnosis and management of somatic genome variations in clinical population.

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A rapid fluorescence in-situ hybridization (FISH) technique was used for direct chromosomal analysis on germ cells from an infertile male with large-headed spermatozoa. The interphase chromosomes were fluorescently-labelled using an extremely bright cyanine dye during a 5-15 min FISH procedure. Germ cells were analysed using a battery of chromosome-specific DNA probes in several consecutive rapid FISH experiments. It was found that the majority of large-headed spermatozoa contained a diploid chromosome number probably due to errors in meiosis I or II divisions, whereas the majority of spermatozoa with normal sized heads are haploid and may be utilized for selective in-vitro fertilization procedures. Rapid FISH may be useful for the detection of major chromosomal aneuploidies in germ cells as an alternative technique to standard or multicolour FISH, and may find an additional application for the chromosomal analysis of human preimplantation embryos.