Current Genomics (v.11, #6)

Somatic Genome Variations (SGV) are referred to as intercellular variability of genomes in somatic tissues of the same organism. These can manifest as single-nucleotide changes, short DNA sequence changes ( andlt; 1kb), short tandem repeat variations, retrotransposition of mobile genome elements (i.e. SINE and LINE), copy number variations and subchromosomal structural abnormalities (microdeletions, microduplications, inversions; > 1kb), structural chromosome abnormalities observed at microscopic level ( > 2-5 Mb), alterations to chromosome morphology (i.e. fragile sites), aneuploidy (gain/loss of whole chromosomes), polyploidy (gain of haploid chromosome sets). Several lines of evidences have been reported that SGV can play a role in human biodiversity and disease. For instance, it is generally recognized that somatic genome changes produced by genomic and chromosomal instability are cancer-causing. However, related phenomena are rarely addressed in non-malignant tissues. Current genomics essentially uses technologies which operate with DNA isolated from a large pool of cells and analyzes interindividual genomic variations, whereas single-cell genomic approaches are much more rarely applied. This probably explains why SGV are significantly less appreciated. Nevertheless, previous biomedical research does provide initial data that (i) SGV appear to be widespread in human cell populations; (ii) intercellular genomic diversity seems to be associated with a number of neurological, psychiatric and immune diseases, chromosomal syndromes and cancers as well as appear to be involved in critical biological processes (intrauterine development, cell number regulation and aging); (iii) molecular cytogenetics does provide technical solutions for studying single-cell genome variations at molecular resolutions. Therefore, a need appears to exist for additional attention to an underappreciated area of single-cell genomics aimed at studying SGV. The intention of this special issue of Current Genomics (Hot Topic Issue on SGV) is to gather the knowledge about causes and consequences of SGV by addressing the experience of leading experts in fields of human genetics, genomics and molecular cytogenetics. This attempt appears to be successful, inasmuch as the line of reviews has provided for an integrated view of how SGV can be involved in human interindividual diversity, normal prenatal development, aging and pathological changes associated with a number of diseases. The issue begins with theoretical considerations about possible phenotypic effects of SGV and about inevitable changes of current concepts in genomics (epigenomics) resulting from research of SGV. Then, a brief overview of SGV in health and disease is given. The issue continues with two articles dedicated to SGV during human prenatal development. The first one describes recent data on intercellular genomic changes in early human embryos and suggests possible effects at further prenatal developmental stages. The second one gives a timely overview of SGV in extra-embryonic tissues and provides convincing evidence that these do play a significant role in the normal placentation. The next article presents an original hypothesis suggesting one of the most common genetic abnormalities in human newborns (trisomy 21) to be a result of intercellular genomic variations in fetal tissues. Furthermore, an extensive overview of SGV manifesting as aneuploidy involving chromosome 21, which are associated with a broad array of diseases, is given. To end the description of SGV in human embryonic and fetal tissues, a review of ontogenetic genome variations is provided. Surveying data on intercellular genome variability from conception to late ontogeny, it was possible to show that SGV are involved in controlling cell numbers during development and aging. Additionally, a phylogenetic model of and#x201C;dynamic genomeand#x201D; was adapted to cell populations suggesting similar genetic processes to take part as during phylogeny as during ontogeny. Further, the origin of genetic mosaicism produced by SGV manifesting as copy number variations (one of the most common type of genomic variations) is described. According to authors' data and to the literature, this type of SGV is likely to from during embryonic development remaining stable (cell proportions) as long as 20 years. Continuing evaluations of SGV in liveborns, a review of mosaic small supernumerary marker chromosomes, which represent a frequent type of chromosome abnormalities, is presented and the importance of such cases for prenatal diagnosis is underlined. Diagnostic problems related to SGV and possible ways of their solutions are further described in the next review. Here, an overview of genomic and chromosomal instabilities as well as literature data on identification of SGV has allowed to come to an optimistic conclusion that it is possible to propose recommendations on molecular cytogenetic diagnosis and clinical interpretation of SGV. Focusing on medical aspects, it would be interesting to evaluate SGV in a certain disease. This task was successfully completed by a review addressing genomic instabilities in schizophrenia. Finally, a review showing the potential of modeling SGV (somatic copy number variation) and germline genomic variation for biomedical research is presented. All together, the articles in this Hot Topic Issue provide an exciting review of current SGV research that can stimulate readers to pay more attention to single-cell and somatic cell genomics forming a basis for further studies in this area of genomics and epigenomics. This special issue of Current Genomics is dedicated to the memory of our close relative and colleague, Ilia V Soloviev, a talented young researcher and a pioneer of molecular cytogenetics, genome and chromosome research, whose prodigious work has formed our current research directions.

Theoretical and experimental evidences support the hypothesis that the genomes and the epigenomes may be different in the somatic cells of complex organisms. In the genome, the differences range from single base substitutions to chromosome number; in the epigenome, they entail multiple postsynthetic modifications of the chromatin. Somatic genome variations (SGV) may accumulate during development in response both to genetic programs, which may differ from tissue to tissue, and to environmental stimuli, which are often undetected and generally irreproducible. SGV may jeopardize physiological cellular functions, but also create novel coding and regulatory sequences, to be exposed to intraorganismal Darwinian selection. Genomes acknowledged as comparatively poor in genes, such as humans', could thus increase their pristine informational endowment. A better understanding of SGV will contribute to basic issues such as the and#x201C;nature vs nurtureand#x201D; dualism and the inheritance of acquired characters. On the applied side, they may explain the low yield of cloning via somatic cell nuclear transfer, provide clues to some of the problems associated with transdifferentiation, and interfere with individual DNA analysis. SGV may be unique in the different cells types and in the different developmental stages, and thus explain the several hundred gaps persisting in the human genomes and#x201C;completedand#x201D; so far. They may compound the variations associated to our epigenomes and make of each of us an and#x201C;(epi)genomicand#x201D; mosaic. An ensuing paradigm is the possibility that a single genome (the ephemeral one assembled at fertilization) has the capacity to generate several different brains in response to different environments.

Somatic Genome Variations in Health and Disease by I. Iourov, S. Vorsanova, Y. Yurov (387-396).
It is hard to imagine that all the cells of the human organism (about 1014) share identical genome. Moreover, the number of mitoses (about 1016) required for the organism's development and maturation during ontogeny suggests that at least a proportion of them could be abnormal leading, thereby, to large-scale genomic alterations in somatic cells. Experimental data do demonstrate such genomic variations to exist and to be involved in human development and interindividual genetic variability in health and disease. However, since current genomic technologies are mainly based on methods, which analyze genomes from a large pool of cells, intercellular or somatic genome variations are significantly less appreciated in modern bioscience. Here, a review of somatic genome variations occurring at all levels of genome organization (i.e. DNA sequence, subchromosomal and chromosomal) in health and disease is presented. Looking through the available literature, it was possible to show that the somatic cell genome is extremely variable. Additionally, being mainly associated with chromosome or genome instability (most commonly manifesting as aneuploidy), somatic genome variations are involved in pathogenesis of numerous human diseases. The latter mainly concerns diseases of the brain (i.e. autism, schizophrenia, Alzheimer's disease) and immune system (autoimmune diseases), chromosomal and some monogenic syndromes, cancers, infertility and prenatal mortality. Taking into account data on somatic genome variations and chromosome instability, it becomes possible to show that related processes can underlie non-malignant pathology such as (neuro)degeneration or other local tissue dysfunctions. Together, we suggest that detection and characterization of somatic genome behavior and variations can provide new opportunities for human genome research and genetics.

Somatic Genomic Variations in Early Human Prenatal Development by Caroline Robberecht, Evelyne Vanneste, Anne Pexsters, Thomas D'Hooghe, Thierry Voet, Joris Vermeesch (397-401).
Only 25 to 30and#x25; of conceptions result in a live birth. There is mounting evidence that the cause for this low fecundity is an extremely high incidence of chromosomal rearrangements occurring in the cleavage stage embryo. In this review, we gather all recent evidence for an extraordinary degree of mosaicisms in early embryogenesis. The presence of the rearrangements seen in the cleavage stage embryos can explain the origins of the placental mosaicisms seen during chorion villi sampling as well as the chromosomal anomalies seen in early miscarriages. Whereas these rearrangements often lead to implantation failure and early miscarriages, natural selection of the fittest cells in the embryo is the likely mechanism leading to healthy fetuses.

Somatic Genomic Variations in Extra-Embryonic Tissues by Jingly Weier, Christy Ferlatte, Heinz-Ulli Weier (402-408).
In the mature chorion, one of the membranes that exist during pregnancy between the developing fetus and mother, human placental cells form highly specialized tissues composed of mesenchyme and floating or anchoring villi. Using fluorescence in situ hybridization, we found that human invasive cytotrophoblasts isolated from anchoring villi or the uterine wall had gained individual chromosomes; however, chromosome losses were detected infrequently. With chromosomes gained in what appeared to be a chromosome-specific manner, more than half of the invasive cytotrophoblasts in normal pregnancies were found to be hyperdiploid. Interestingly, the rates of hyperdiploid cells depended not only on gestational age, but were strongly associated with the extraembryonic compartment at the fetal-maternal interface from which they were isolated. Since hyperdiploid cells showed drastically reduced DNA replication as measured by bromodeoxyuridine incorporation, we conclude that aneuploidy is a part of the normal process of placentation potentially limiting the proliferative capabilities of invasive cytotrophoblasts. Thus, under the special circumstances of human reproduction, somatic genomic variations may exert a beneficial, anti-neoplastic effect on the organism.

It is well known that varying degrees of mosaicism for Trisomy 21, primarily a combination of normal and Trisomy 21 cells within individual tissues, may exist in the human population. This involves both Trisomy 21 mosaicism occurring in the germ line and Trisomy 21 mosaicism documented in different somatic tissues, or indeed a combination of both in the same subjects. Information on the incidence of Trisomy 21 mosaicism in different tissue samples from people with clinical features of Down syndrome as well as in the general population is, however, still limited. One of the main reasons for this lack of detailed knowledge is the technological problem of its identification, where in particular low grade/cryptic Trisomy 21 mosaicism, i.e. occurring in less than 3-5and#x25; of the respective tissues, can only be ascertained by fluorescence in situ hybridization (FISH) methods on large cell populations from the different tissue samples. In this review we summarize current knowledge in this field with special reference to the question on the likely incidence of germinal and somatic Trisomy 21 mosaicism in the general population and its mechanisms of origin. We also highlight the reproductive and clinical implications of this type of aneuploidy mosaicism for individual carriers. We conclude that the risk of begetting a child with Trisomy 21 Down syndrome most likely is related to the incidence of Trisomy 21 cells in the germ line of any carrier parent. The clinical implications for individual carriers may likewise be dependent on the incidence of Trisomy 21 in the relevant somatic tissues. Remarkably, for example, there are indications that Trisomy 21 mosaicism will predispose carriers to conditions such as childhood leukemia and Alzheimer's Disease but there is on the other hand a possibility that the risk of solid cancers may be substantially reduced.

Ontogenetic Variation of the Human Genome by Y. Yurov, S. Vorsanova, I. Iourov (420-425).
The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new and#x201C;dynamic genomeand#x201D; model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.

The Human Genome Puzzle — the Role of Copy Number Variation in Somatic Mosaicism by Hasmik Mkrtchyan, Madeleine Gross, Sophie Hinreiner, Anna Polytiko, Marina Manvelyan, Kristin Mrasek, Nadezda Kosyakova, Elisabeth Ewers, Heike Nelle, Thomas Liehr, Samarth Bhatt, Karen Thoma, Erich Gebhart, Sylvia Wilhelm, Raimund Fahsold, Marianne Volleth, Anja Weise (426-431).
The discovery of copy number variations (CNV) in the human genome opened new perspectives in the study of the genetic causes of inherited disorders and the etiology of common diseases. Differently patterned instances of somatic mosaicism in CNV regions have been shown to be present in monozygotic twins and throughout different tissues within an individual. A single-cell-level investigation of CNV in different human cell types led us to uncover mitotically derived genomic mosaicism, which is stable in different cell types of one individual. A unique study of immortalized Blymphoblastoid cell lines obtained with 20 year interval from the same two subjects shows that mitotic changes in CNV regions may happen early during embryonic development and seem to occur only once, as levels of mosaicism remained stable. This finding has the potential to change our concept of dynamic human genome variation. We propose that further genomic studies should focus on the single-cell level, to understand better the etiology and physiology of aging and diseases mediated by somatic variations.

Somatic Mosaicism in Cases with Small Supernumerary Marker Chromosomes by Thomas Liehr, Tatyana Karamysheva, Martina Merkas, Lukrecija Brecevic, Ahmed Hamid, Elisabeth Ewers, Kristin Mrasek, Nadezda Kosyakova, Anja Weise (432-439).
Somatic mosaicism is something that is observed in everyday lives of cytogeneticists. Chromosome instability is one of the leading causes of large-scale genome variation analyzable since the correct human chromosome number was established in 1956. Somatic mosaicism is also a well-known fact to be present in cases with small supernumerary marker chromosomes (sSMC), i.e. karyotypes of 47,+mar/46. In this study, the data available in the literature were collected concerning the frequency mosaicism in different subgroups of patients with sSMC. Of 3124 cases with sSMC 1626 (52and#x25;) present with somatic mosaicism. Some groups like patients with Emanuel-, cat-eye- or i(18p)- syndrome only tend rarely to develop mosaicism, while in Pallister-Killian syndrome every patient is mosaic. In general, acrocentric and nonacrocentric derived sSMCs are differently susceptible to mosaicism; non-acrocentric derived ones are hereby the less stable ones. Even though, in the overwhelming majority of the cases, somatic mosaicism does not have any detectable clinical effects, there are rare cases with altered clinical outcomes due to mosaicism. This is extremely important for prenatal genetic counseling. Overall, as mosaicism is something to be considered in at least every second sSMC case, array-CGH studies cannot be offered as a screening test to reliably detect this kind of chromosomal aberration, as low level mosaic cases and cryptic mosaics are missed by that.

Molecular Cytogenetic Diagnosis and Somatic Genome Variations by S. Vorsanova, Y. Yurov, I. Soloviev, I. Iourov (440-446).
Human molecular cytogenetics integrates the knowledge on chromosome and genome organization at the molecularand cellular levels in health and disease. Molecular cytogenetic diagnosis is an integral part of current genomicmedicine and is the standard of care in medical genetics and cytogenetics, reproductive medicine, pediatrics, neuropsychiatryand oncology. Regardless numerous advances in this field made throughout the last two decades, researchers andpractitioners who apply molecular cytogenetic techniques may encounter several problems that are extremely difficult tosolve. One of them is undoubtedly the occurrence of somatic genome and chromosome variations, leading to genomic andchromosomal mosaicism, which are related but not limited to technological and evaluative limitations as well as multiplicityof interpretations. More dramatically, current biomedical literature almost lacks descriptions, guidelines or solutions ofthese problems. The present article overviews all these problems and gathers those exclusive data acquired from studies ofgenome and chromosome instability that is relevant to identification and interpretations of this fairly common cause ofsomatic genomic variations and chromosomal mosaicism. Although the way to define pathogenic value of all the intercellularvariations of the human genome is far from being completely understood, it is possible to propose recommendationson molecular cytogenetic diagnosis and management of somatic genome variations in clinical population.

Genomic and Epigenomic Instability, Fragile Sites, Schizophrenia and Autism by Cassandra Smith, Andrew Bolton, Giang Nguyen (447-469).
Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methioninetransulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.

Controlled Somatic and Germline Copy Number Variation in the Mouse Model by Yann Herault, Arnaud Duchon, Damien Marechal, Matthieu Raveau, Patricia Pereira, Emilie Dalloneau, Veronique Brault (470-480).
Changes in the number of chromosomes, but also variations in the copy number of chromosomal regions have been described in various pathological conditions, such as cancer and aneuploidy, but also in normal physiological condition. Our classical view of DNA replication and mitotic preservation of the chromosomal integrity is now challenged as new technologies allow us to observe such mosaic somatic changes in copy number affecting regions of chromosomes with various sizes. In order to go further in the understanding of copy number influence in normal condition we could take advantage of the novel strategy called Targeted Asymmetric Sister Chromatin Event of Recombination (TASCER) to induce recombination during the G2 phase so that we can generate deletions and duplications of regions of interest prior to mitosis. Using this approach in the mouse we could address the effects of copy number variation and segmental aneuploidy in daughter cells and allow us to explore somatic mosaics for large region of interest in the mouse.

Erratum by Bentham Science Publishers (481-481).
Due to an oversight on the part of the author, unfortunately the manuscript entitled and#x201C;The Origin of Amerindians and the Peopling of the Americas According to HLA Genes: Admixture with Asian and Pacific Peopleand#x201D; submitted for publication in the journal Current Genomics- Volume 11, Issue 2 (pg. 103-114) has been published with one word missing: Abstract 2nd line from botton: It reads and#x201C;......6) HLA variability is more common.......and#x201D;, and it should read and#x201C;.......6) HLA haplotype variability is more common......and#x201D;.