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      Aneuploidy and Confined Chromosomal Mosaicism in the Developing Human Brain

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          Understanding the mechanisms underlying generation of neuronal variability and complexity remains the central challenge for neuroscience. Structural variation in the neuronal genome is likely to be one important mechanism for neuronal diversity and brain diseases. Large-scale genomic variations due to loss or gain of whole chromosomes (aneuploidy) have been described in cells of the normal and diseased human brain, which are generated from neural stem cells during intrauterine period of life. However, the incidence of aneuploidy in the developing human brain and its impact on the brain development and function are obscure.

          Methodology/Principal Findings

          To address genomic variation during development we surveyed aneuploidy/polyploidy in the human fetal tissues by advanced molecular-cytogenetic techniques at the single-cell level. Here we show that the human developing brain has mosaic nature, being composed of euploid and aneuploid neural cells. Studying over 600,000 neural cells, we have determined the average aneuploidy frequency as 1.25–1.45% per chromosome, with the overall percentage of aneuploidy tending to approach 30–35%. Furthermore, we found that mosaic aneuploidy can be exclusively confined to the brain.


          Our data indicates aneuploidization to be an additional pathological mechanism for neuronal genome diversification. These findings highlight the involvement of aneuploidy in the human brain development and suggest an unexpected link between developmental chromosomal instability, intercellural/intertissular genome diversity and human brain diseases.

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          Most cited references 31

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          Genetic instabilities in human cancers.

          Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
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            Structural variation in the human genome.

            The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term 'structural variation' in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants - collectively termed copy-number variants or copy-number polymorphisms - as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.
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              To err (meiotically) is human: the genesis of human aneuploidy.

              Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

                Author and article information

                Role: Academic Editor
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                27 June 2007
                : 2
                : 6
                [1 ]National Research Center of Mental Health, Russian Academy of Medical Sciences, Moscow, Russia
                [2 ]Institute of Pediatrics and Children Surgery, Roszdrav, Moscow, Russia
                [3 ]Institute of Human Genetics and Anthropology, Jena, Germany
                [4 ]Rostov State Medical University, Roszdrav, Rostov-on-Don, Russia
                [5 ]Institute of Human Genetics, Montpellier, France
                Centre de Regulacio Genomica - Barcelona Biomedical Research Park, Spain
                Author notes
                * To whom correspondence should be addressed. E-mail: y_yurov@

                Conceived and designed the experiments: YY II SV. Performed the experiments: II TL AK. Analyzed the data: YY II SV AK AB ID VK VK. Contributed reagents/materials/analysis tools: TL SK FP VM IS. Wrote the paper: YY II SV.

                Yurov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 6
                Research Article
                Developmental Biology/Neurodevelopment
                Genetics and Genomics/Chromosome Biology
                Neuroscience/Neurobiology of Disease and Regeneration
                Neurological Disorders/Developmental and Pediatric Neurology



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