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DOI: 10.1369/jhc.4A6430.2005
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Journal of Histochemistry and Cytochemistry
Volume 53 (3): 385-390, 2005
Copyright ©The Histochemical Society, Inc.

The Variation of Aneuploidy Frequency in the Developing and Adult Human Brain Revealed by an Interphase FISH Study

Yuri B. Yurov, Ivan Y. Iourov, Viktor V. Monakhov, Ilia V. Soloviev, Viktor M. Vostrikov and Svetlana G. Vorsanova

National Center of Mental Health, Russian Academy of Medical Sciences, Moscow, Russia (YBY,IYI,VVM,IVS,VMV) and Institute of Pediatrics and Children's Surgery, Russian Ministry of Health, Moscow, Russia (SGV)

Correspondence to: Y.B. Yurov, National Center of Mental Health, Russian Academy of Medical Sciences, Zagorodnoe sh.2, 119152, Moscow, Russia. E-mail: y_yurov{at}yahoo.com; i_yurov{at}mail.ru


   Summary
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 Literature Cited
 
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.

(J Histochem Cytochem 53:385–390, 2005)

Key Words: developing and adult human • brain • aneuploidy • DNA probes • FISH


   Introduction
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 Introduction
Materials and Methods
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 Literature Cited
 
THE HUMAN BRAIN is the control center that stores, computes, integrates, and transmits information. It contains ~1012 neurons, each forming as many as a thousand connections with other neurons (Lodish et al. 2000Go). 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. 2001Go). 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. 2002Go). 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 complement in the adult human brain (Yang et al. 2001Go). A significant fraction of the hippocampal pyramidal and basal forebrain neurons in Alzheimer's disease was demonstrated to have fully or partially tetraploid chromosome complement. This imbalance in chromosome complement was proposed to be the direct cause of neuronal loss in Alzheimer's disease. Molecular cytogenetic study of postmortem brain of schizophrenic patients using multicolor FISH (mFISH) has been performed. A statistically significant level of aneuploidy (up to 4% of neurons) was detected in postmortem brain samples of some patients with schizophrenia (prefrontal cortex, Brodmann's area 10). These data have indicated the possibility of a low-level of chromosomal mosaicism being involved in the pathogenesis of schizophrenia (Yurov et al. 2001Go). There is only one preliminary study using mFISH and organotypic cell cultures of the fetal human brain that indicates that the developing human brain contains a large proportion of chromosomally abnormal neuronal cells (Yurov et al. 2003Go). Systematic studies of chromosome variations in non-dividing neuronal cells in the human fetal brain and comparative analysis of the aneuploidy level in adult and developing human brain have not been performed to date.

A resource of human DNA probes for the molecular cytogenetic detection of chromosomal aberrations has been developed. This collection was initially designed for identification of the most common chromosome aberrations in fetal and postnatal uncultured cells as well as metaphase spreads obtained by cell culturing. The DNA probe collection includes the set of centromeric and pericentromeric DNA probes for all human chromosomes, telomeric and subtelomeric probes, and band-specific DNA probes for a large number of human chromosome regions (Yurov et al. 2002Go). The original collection, containing a broad spectrum of DNA probes, was found to be applicable for different chromosome complement studies (Soloviev et al. 1995Go, 1998Go; Vorsanova et al. 1986Go,1994Go; Yurov et al. 1996aGo,bGo, 2002Go). The collection includes more than 800 selected and accurately tested DNA probes as recombinant plasmid, cosmid, YAC, and PAC clones specifically marking different regions of all 24 human chromosomes (Yurov et al. 2002Go). For this pilot FISH study of chromosome variations in the human brain, chromosome-enumerating DNA probes for chromosomes 1, 13, 18, 21, X, and Y from the original collection of probes were selected.

Taking into account that chromosomal complement instability in developing neuronal cells could have substantial effect on normal brain development and functions, direct studies of chromosomal complement in the human brain are of great significance. The aim of the present study was the comparative analysis of chromosomal complement variations in uncultured as well as cultured neuronal cells of developing and adult human brain samples using interphase mFISH.


   Materials and Methods
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Results
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The permission of the Ethics Committee of the Mental Health Research Center of the Russian Academy of Medical Sciences was obtained for the studies of adult and fetal brain. Written informed consent was obtained from the abortion-seeking women and the relatives of men from whom postmortem brain samples were obtained.

Six samples (five female and one male) of postmortem adult brain tissues were processed as described previously (Yurov et al. 2001Go). Fifty milligrams of these samples was homogenized in 2 ml of phosphate-buffered saline (PBS), pH 7.3, with 0.1% Nonidet P-40, using a glass-Teflon homogenizer, and centrifuged at 1000 x g for 5 min, followed by fixation of pellets in ice-cold methanol-glacial acetic acid mixture (3:1) three times for 20 min. The resulting suspensions of nuclei were then dropped onto the wet surfaces of microscope slides. The slides were allowed to dry overnight and were dehydrated by ethanol series before being used for FISH experiments. The quality of slides with the fixed nuclei was estimated by the criterion of the absence of surrounding cytoplasm. Another fixation step of cell suspensions was performed, if necessary.

Fetal brain tissue samples were obtained from 12 fetuses (8 female and 4 male) at the time of selective termination of intrauterine pregnancy from healthy females. Six samples (four female and two male) were used for direct preparations of tissue for FISH analysis without cultivation in vitro. Another six samples (four female and two male) were used for preparation of organotypic fetal brain cultures followed by FISH analysis. The criteria of inclusion were age from 25 to 35 years, gestation age 9–11 weeks, negative test for the most common infectious diseases, absence of systemic and genetic diseases in both parents, and absence of treatment by drugs with known teratogenic effects. Gestational age was determined according to a number of parameters (date of last menstrual period, uterine size, and ultrasonography; and after abortion, by measurement of fetal foot length).

The fetal tissue was transferred to a laminar-flow hood. Brain samples were rinsed with Earle's buffered saline solution (EBSS) (No. 24010-035, Gibco Invitrogene, SARL; Cergy Pontois Cedex, France). Medulla oblongata was chosen as a target fetal brain tissue because of its relatively large size to avoid possible contamination by other surrounding embryonic tissues. Medulla oblongata was isolated from the surrounding tissue by a transverse cut through the brain stem at the level of the pons and of the lower medulla using a dissecting microscope (Wild/Leitz M32, Leitz-Wetzlar; Wetzlar, Germany). Meninges and major blood vessels were removed. The isolated medulla was placed in a sterile plastic petri dish with 2 ml EBSS, and transversely cut 300–400-µm slices were made by hand with razor blades. The slices were then divided into ~20 pieces, rinsed in EBSS, and transferred into Pyrex glass bottles containing 10 ml of medium, with rubber silicon stoppers. Some tissue pieces were processed for FISH studies similarly to autopsy samples of the adult brain. Samples were cultivated in a high-speed mini-roller under rotation at 60 rpm. Tissue cultures were maintained for up to 30 days without changing medium according to the protocol previously described for organotypic cultures of postnatal rat hippocampus (Victorov et al. 2001Go). One hundred ml of medium consists of 86.3 ml MEM (Gibco, No. 32260-018); 5 ml fetal bovine serum (Gibco, No.10106-169); 5 ml human umbilical blood serum (Paneco; Moscow, Russia); 2 ml of 40% glucose; 1 ml of 200 mM L-glutamine; 0.5 ml of insulin; and 0.2 ml of antibiotic/antimyotic (Gibco, No.15240-039). Cells in cultures were able to grow, differentiate, and establish histotypical organization and glial–neuronal relationships by the end of 4 weeks in vitro. Nissl staining of tissue culture sections demonstrated good survival of neurons and glial cells. Neurons were immunochemically identified using antibodies against III ß-tubulin; glial fibrillary acidic protein (GFAP) immunostaining identified astrocytes (VM Vostrikov, unpublished data). The cell cultures (ages 3–4 weeks) were processed for FISH studies according to standard cytogenetic fixation procedures using hypotonic treatment and fixation with methanol-acetic acid (3:1).

Chromosome 1 (D1Z1)-, 18 (D18Z1)-, 13/21 (D13Z1/D21Z1)-, X (DXZ1)-, and Y (DYZ3)-specific DNA probes were cloned in the Laboratory of Cytogenetics of the National Center of Mental Health, Moscow, Russia and prepared as described previously (Vorsanova et al. 1986Go,1994Go; Yurov et al. 1996bGo,2002Go; Alexandrov et al. 1988Go; Soloviev et al. 1995Go,1998Go). This set of probe A mixtures of: (a) biotinylated chromosome 1–specific probe, Cy3-labeled chromosome Y–specific probe, fluorescein-labeled chromosome X–specific probe; (b) biotinylated chromosome 1–specific probe, Cy3-labeled chromosome 13/21–specific probe, fluorescein-labeled chromosome X–specific probe; and (c) Cy3-labeled chromosome 18–specific probe, biotinylated chromosome Y–specific probe, fluorescein-labeled chromosome X–specific probe; each at a final concentration of 50 ng/10 µl of hybridizing solution (10% dextran sulfate and 2x SSC in 55% formamide, pH 7) was used. The in situ hybridization and detection protocols were performed as described previously (Soloviev et al. 1994Go,1998Go; Yurov et al. 1996bGo). Aliquots of DNA probe (10 µl per slide) were placed onto the slides, covered by coverslips, and denatured for 5 min at 72C. After 4 hr or overnight hybridization at 37C, the slides were washed for 15 min in 50% formamide, 2x SSC (pH 7) at 42C, followed by two washes for 5 min each in 2x SSC, 0.1% Tween 20 at 37C. The slides were then incubated with 5 µg/ml 7-amino-4-methyl-3-coumarinylacetic acid (AMCA)-avidin (Vector Laboratories, Burlingame, CA) to detect biotin-labeled DNA probes. Finally, interphase nuclei were counterstained with diluted (1:10) 4',6-diamidino-2-phenylindole (DAPI) to allow simultaneous observation of nuclei and hybridized biotin-labeled probe after application of AMCA-avidin.

For epifluorescence microscopy, a Leitz Orthoplan microscope (Leica Mikroskopie und Systeme, Leitz-Wetzlar; Wetzlar, Germany) equipped with a 100 W lamp was used with the following filter sets: A (No. 513,596) for DAPI fluorescence; I3 (No. 513,719) or GR (No. 513,821) for propidium iodide fluorescence and fluorescein isothiocyanate (FITC) signals; GR (No. 513,821) for both fluorescein and cyanine signals; and N2 (No. 513,609) for cyanine signals. All images were observed with the Plan-Neofluar (Leica Mikroskopie und Systeme, Leitz-Wetzlar; Wetzlar, Germany) x40/1.30 or x63/1.30–0.60 oil immersion lenses.

No fewer than 500 nuclei (in a case of adult brain samples) and 1000 nuclei (in a case of embryonic brain samples) were scored for each sample for each probe. Only intact and undamaged nuclei free of cytoplasm were analyzed. Nuclei with low signal intensities, diffuse signals, or absence of signals on both homolog chromosomes were considered to be hybridization failures and were not scored. Two small focal (or paired) signals of the same color and the same intensity, separated by a distance of less than the area of one signal, were considered to be a split signal from one chromosome. Interphase nuclei with one large signal of the same color and increased intensity of fluorescence with the absence of a second hybridization signal in an interphase nucleus were considered to be the over-positioning of two signals and were not scored.


   Results
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Discussion
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Six samples of embryonic human central nervous system, uncultured as well as cultured in vitro were analyzed. Six samples of postmortem adult brains were also analyzed in mFISH experiments. The mFISH studies allowed the multicolor detection of numerous targets in interphase nuclei of neuronal cells obtained from the fetal brain. Examples of FISH application in the study of the chromosome X–specific DNA probe are shown in Figure 1. Variability in the frequencies of aneuploidies between samples of fetal brains and different chromosomes in each sample was observed. The frequencies of chromosomally abnormal nuclei (monosomy, trisomy, and tetrasomy) varied from 0.2% to 4.4% in uncultured fetal brain cells and from 0.4% to 11.0% for different chromosomes in fetal brain cells An example of cell scoring by FISH analysis with a chromosome X–specific DNA probe in fetal uncultured brain samples, fetal cultured brain samples, and adult postmortem brain samples is shown in Table 1. In adult neurons of human brain, the frequencies varied from 0.1% to 1.7%. The incidence of abnormal chromosome complement in adult brain cells (postmortem brain samples) was significantly lower than in fetal brain samples. The mean level of aneuploidy (per individual chromosome) was in the range of 1.3–7.0% in cultured embryonic brain cells, 0.6–4.0% in uncultured embryonic brain cells, and 0.1–0.8% in postmortem brain cells (Table 2).



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  		Figure 1

Examples of interphase mFISH in neuronal cells of adult (postmortem) and embryonic brain. (A) Neuron nucleus of the adult brain after hybridization with chromosome-specific DNA probes for chromosomes 1, 13/21, and X. Biotin-labeled DNA probe for chromosome 1 demonstrates two blue signals (normal disomic pattern of hybridization), Cy3-labeled DNA probe for chromosomes 13/21 shows four red signals (normal disomic pattern of hybridization), and fluorescein-labeled probe for chromosome X shows two green signals (normal disomic pattern of hybridization). (B) Nucleus of aneuploid neuron of the adult brain after hybridization with chromosome-specific DNA probes for chromosomes 1, 13/21, and X. Biotin-labeled DNA probe for chromosome 1 demonstrates two blue signals (normal disomic pattern of hybridization), Cy3-labeled DNA probe for chromosomes 13/21 shows four red signals (normal disomic pattern of hybridization), and fluorescein-labeled probe for chromosome X shows three green signals. Therefore, this nucleus is trisomic for chromosome X. (C) Nuclei of neuronal cells embryonic brain after hybridization with chromosome-specific DNA probes for chromosomes 18 and X. Cy3-labeled chromosome 18–specific probes demonstrates two (normal disomic pattern of hybridization) or three (trisomy 18) red signals and fluorescein-labeled probe for chromosome X shows one (monosomy X) or two (normal disomic pattern of hybridization) green signals.

 

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  		Table 1

Example of cell scoring by FISH analysis with chromosome X–specific DNA probe in fetal uncultured brain samples (uFBS), fetal cultured brain samples (cFBS), and adult postmortem brain samples (APBS)

 

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  		Table 2

Frequencies (%) of chromosomally abnormal nuclei in fetal uncultured fetal brain samples (uFBS), cultured fetal brain samples (cFBS), and adult postmortem brain samples (APBS) for chromosomes 1, 13/21, 18, X, and Y

 

   Discussion
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 Materials and Methods
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Literature Cited
 
mFISH studies with chromosome-enumerating DNA probes for six different chromosomes (1, 13, 18, 21, X, and Y) supply the first evidence for aneuploidy in cells of the developing and adult human brain. Interphase FISH has some limitations in the scoring of low levels of aneuploidy, inasmuch as there are several factors leading to the appearance of an aberrant number of signals. Somatic pairing of homolog chromosomes or over-positioning of signals can produce a "pseudo monosomy." Asynchronously replicating heterochromatic regions containing alphoid (centromeric) DNA can produce additional signals. To avoid technical problems, the use of common criteria developed for FISH signal scoring is strongly recommended for preimplantation as well as for prenatal diagnosis. Interphase nuclei with one large signal of the same color and increased intensity of fluorescence with the absence of the second hybridization signal were considered to be an over-positioning of two signals and were not scored. To avoid the scoring of nuclei with possible DNA loss after nuclei isolation, only intact and undamaged nuclei free of cytoplasm were scored. However, there is still the possibility that some nuclei scored as aneuploid could be the result of FISH artifact. Nevertheless, the scoring of more nuclei (up to 1000) and the simultaneous application of several DNA probes for different chromosomes on the same slide significantly improve the accuracy of the aneuploid cell scoring.

The data obtained provide evidence that a relatively small but significant population of aneuploidy cells is present in fetal as well as in adult human brain in vivo. The number of chromosomally abnormal cells is dramatically increased during the cultivation of human embryonic brain cells in vitro. Therefore, we propose that fetal neuronal cells are characterized by an increased frequency of nonspecific aneuploidy involving different chromosomes. The analysis of one chromosome-specific DNA probe shows that ~95% of neuronal cells could be considered as karyotypically normal. However, multicolor FISH analysis of several chromosomes in one FISH experiment and the application of a probe set for the chromosomes mentioned above strongly indicated that the total number of chromosomally abnormal neuronal cells is higher. We have estimated the total (cumulative) number of aberrant nuclei for chromosomes 1, 13/21, 18, X, and Y to be 22%. One can propose that the number of aneuploidy frequency in fetal human brain cells involving all 23 chromosome pairs is substantially higher. Therefore, our data provide evidence for large-scale genomic (chromosomal) variations in developing neuronal cells. The adult human brain, in contrast, contains significantly lower amounts of aneuploid neuronal cells. The data obtained indicate that fetal and adult brains differ in aneuploidy frequency. Therefore, one can suggest that the selective loss of chromosomally abnormal neuronal cells takes place during ontogenesis. However, a relatively small but significant amount of aneuploid neurons could survive and function in the adult brain. Thus, the high level of chromosomal aneuploidy in embryonic human neuronal cells could be considered to be a cause of genetic mosaicism in fetal brain with conservation of some anueploidy cells during ontogenesis, leading to cryptic chromosomal mosaicism in adult neurons of human brain.

Organotypic cultures of human fetal brain are generally used for the study of human neurodeveloping mechanisms of neurocytotoxicity and neuroprotection. Neuronal embryonic brain cells in cultures are able to grow, differentiate, and establish glial–neuronal relationships. The advantage of this ability is the high survival rate of neurons and glial cells in vitro. Despite the growing number of molecular investigations of human fetal brain organotypic cultures, studies of chromosome variations in the developing human brain have not yet been performed. Our results regarding the dramatic increase of aneuploidy incidence in fetal brain cells cultured in vitro allow us to propose that nondisjunction of chromosomes could also take place in vivo during the differentiation of neuronal cells. The frequency of aneuploidy in uncultured fetal brain cells is lower than in cultured neuronal cells. Therefore, it is reasonable to suggest that conditions of cultivation in vitro probably artificially stimulate division of differentiated neuronal cells and provoke conflict between these two fundamental processes (cell division and cell differentiation). Differentiated neuronal cells could not normally replicate their DNA and pass cell cycles. The high incidence of aneuploidy could also be explained by the inability of partially or fully differentiated neuronal cells to pass correctly a mitotic division. Assuming that the increase of aneuploidy frequency takes place in developing human brain in vivo, one can speculate that the neuronal loss happens during prenatal and neonatal development. Therefore, early childhood is directly related to the phenomenon of increased levels of aneuploidy in differentiated neuronal cells. The dynamic of chromosome variations with a decrease in aneuploidy frequencies in non-cultured embryonic (non-differentiated) brain cells and highly differentiated adult brain cells in comparison to differentiated organotypic brain cell cultures is in agreement with this proposal.

The application of the one-color FISH technique to the study of chromosome complement of interphase nuclei in the adult human brain has demonstrated that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in Alzheimer's disease have tetraploid chromosome complement. This imbalance in chromosome complement has been proposed as one of the causes of neuronal loss in Alzheimer's disease (Yang et al. 2001Go). Molecular cytogenetic study of postmortem brain of schizophrenic patients with mFISH application was performed in our earlier studies. A statistically significant level of aneuploidy (up to 4% of neurons) was detected in the postmortem brain of schizophrenia patients. Low-level chromosomal mosaicism was suggested to be involved in the pathogenesis of schizophrenia (Yurov et al. 2001Go). Regarding previous as well as present studies of chromosome complement in human brain, we have concluded that a low percentage of mosaicism of aneuploidy does exist in the fetal and adult human brain. Recently, central nervous system of mouse, both during development and in adulthood, was proposed to have genetic mosaic features (euploid population intermixed with a smaller genetically diverse aneuploid population) (Rehen et al. 2001Go). The occurrence of this mosaicism may have relevance to stem cell biology, mammalian cloning, genomics, neurogenetics, and neuropsychiatric diseases. These permanent genomic changes may also contribute to physiological and behavioral variations among individuals not accounted for by classical genetics. The presence of chromosomally abnormal neuronal cell populations in the form of extremely low-level mosaicism could significantly affect normal brain development and functions. The real amount of chromosomally abnormal neuronal cells in the normal adult human brain is unknown and should be determined in more-detailed studies with scoring of chromosomes in a larger population of cells. Taking into account that one neuron forms about one thousand connections with other neuronal cells, the presence of a small number of aneuploid neurons could substantially and negatively affect normal development and brain functions. "Cryptic" chromosomal mosaicism in the neurons of brain is not necessarily associated with any specific phenotypic appearance; however, it could have an unfavorable effect on normal brain development and functions as well as relevance to some neuropsychiatric diseases. Therefore, extended studies of chromosomal complement instability in the fetal and adult human brain should be continued.


   Acknowledgments
 
Supported by Copernicus 2 grant no. ICA2-CT-2000-10012 and INTAS grant no. 03-55-4060.


   Footnotes
 
Presented in part at the 14th Workshop on Fetal Cells and Fetal DNA: Recent Progress in Molecular Genetic and Cytogenetic Investigations for Early Prenatal and Postnatal Diagnosis, Friedrich Schiller University, Jena, Germany, April 17–18, 2004.

Received for publication May 31, 2004; accepted September 2, 2004


   Literature Cited
Top
 Summary
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 Materials and Methods
 Results
 Discussion
 Literature Cited
 

Alexandrov IA, Mitkevich SP, Yurov YB (1988) The phylogeny of human chromosome specific alpha satellites. Chromosoma 96:443–453[CrossRef][Medline]

Lodish H, Berk A, Ziputsky L, Matsudaria P, Baltimore D, Darnell J (2000) Molecular Cell Biology, 4th ed. New York, W.H. Freeman Publishers

Osada T, Kusakabe H, Akutsu H, Yagi T, Yamagimachi R (2002) Adult murine neurons: their chromatin and chromosome changes and failure to support embryonic development as revealed by nuclear transfer. Cytogenet Genome Res 97:7–12[CrossRef][Medline]

Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J (2001) Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci U S A 98:13361–13366[Abstract/Free Full Text]

Soloviev IV, Yurov YB, Vorsanova SG, Fayet F, Roizes G, Malet P (1995) Prenatal diagnosis of trisomy 21 using interphase fluorescence in situ hybridization of post-replicated cells with site-specific cosmid and cosmid contig probes. Prenat Diagn 15:237–248[Medline]

Soloviev IV, Yurov YB, Vorsanova SG, Malet P (1994) Microwave activation of fluorescence in situ hybridization: a novel method for rapid chromosome detection and analysis. Focus 16:115–116

Soloviev IV, Yurov YB, Vorsanova SG, Marcais B, Rogaev EI, Kapanadze BI, Brodiansky VM, et al. (1998) Fluorescent in situ hybridization analysis of {alpha}-satellite DNA in cosmid libraries specific for human chromosomes 13, 21 and 22. Rus J Genet 34:1247–1255

Victorov IV, Lyjin AA, Aleksandrove OP (2001) A modified roller method for organotypic brain cultures: free-floating slices of postnatal rat hippocampus. Brain Res Protocols 7:30–37[CrossRef][Medline]

Vorsanova SG, Yurov YB, Alexandrov IA, Demidova IA, Mitkevich SP, Tirskaya AF (1986) 18p-Syndrome: an unusual case and diagnosis by in situ hybridization with chromosome 18-specific alphoid DNA sequence. Hum Genet 72:185–187[CrossRef][Medline]

Vorsanova SG, Yurov YB, Soloviev IV, Demidova IA, Malet P (1994) Rapid identification of marker chromosomes by in situ hybridization under different stringency conditions. Anal Cell Pathol 7:251–259[Medline]

Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 21:2661–2668[Abstract/Free Full Text]

Yurov YB, Saias MJ, Vorsanova SG, Erny R, Soloviev IV, Sharonin VO, Guichaoua MR, et al. (1996a) Rapid chromosomal analysis of germ-line cells by FISH: an investigation of an infertile male with large-headed spermatozoa. Mol Hum Reprod 9:665–668

Yurov YB, Soloviev IV, Vorsanova SG, Marcais B, Roizes G, Lewis R (1996b) High resolution fluorescence in situ hybridization using cyanine and fluorescein dyes: ultra-rapid chromosome detection by directly fluorescently labeled alphoid DNA probes. Hum Genet 97:390–398[Medline]

Yurov YB, Vorsanova SG, Soloviev IV, Demidova IA, Alexandrov IA, Sharonin VO, Beresheva AK (2002) Original collection of DNA probes for preimplantational, fetal prenatal and postnatal diagnosis of chromosomal analysis by FISH. In Macek M Sr, Bianchi D, Cuckle H, eds. Early Prenatal Diagnosis, Fetal Cells and DNA in Mother. Present State and Perspectives. Prague, The Karolinum Press, 275–283

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Yurov YB, Vostrikov VM, Vorsanova SG, Monakhov VV, Iourov IY (2001) Multicolor fluorescent in situ hybridization on post mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. Brain Dev 23(suppl 1):186–190[CrossRef]


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