The discovery of copy number variations (CNV) in the human genome opened new perspectives on the study of the genetic causes of inherited disorders and the aetiology of common diseases. Here, a single-cell-level investigation of CNV in different human tissues led us to uncover the phenomenon of mitotically derived genomic mosaicism, which is stable in different cell types of one individual. The CNV mosaic ratios were different between the 10 individuals studied. However, they were stable in the T lymphocytes, immortalized B lymphoblastoid cells, and skin fibroblasts analyzed in each individual. Because these cell types have a common origin in the connective tissues, we suggest that mitotic changes in CNV regions may happen early during embryonic development and occur only once, after which the stable mosaic ratio is maintained throughout the differentiated tissues. This concept is further supported by a unique study of immortalized B lymphoblastoid cell lines obtained with 20 year difference from two subjects. We provide the first evidence of somatic mosaicism for CNV, with stable variation ratios in different cell types of one individual leading to the hypothesis of early embryonic chromosome instability resulting in stable mosaic pattern in human tissues. This concept has the potential to open new perspectives in personalized genetic diagnostics and can explain genetic phenomena like diminished penetrance in autosomal dominant diseases. We propose that further genomic studies should focus on the single-cell level, to better understand the aetiology of aging and diseases mediated by somatic mutations.
Small supernumerary marker chromosomes (sSMC) can appear in a numerically normal ‘basic karyotype’, but also in a numerically abnormal one like a Turner syndrome karyotype (= sSMCT). Here we present 17 new cases with such a mos 45,X/46,X,+mar karyotype. Moreover we reviewed all 512 cytogenetically similar cases available from the literature and supply for the first time data on occurrence, shapes and subgroups of this rare cytogenetic entity. sSMCT are very rare in the common population (1:100,000) – however, they can be observed with a 45- and even 60-times higher frequency in infertile and (develop)mentally retarded patients, respectively. Even though sSMCT derive from one of the gonosomes in >99% of the cases, there are also exceptional reports on sSMCT derived from one of the autosomes. The majority of sSMCT(X) form ring chromosomes, while most sSMCT(Y) are inverted duplicated/isodicentric chromosomes. Although >500 sSMCT are reported, a detailed characterization of the chromosomal breakpoints is only given for a minority. Thus, more cases with detailed (molecular) cytogenetic marker chromosome characterization are needed to provide information on formation and effects of an sSMCT.
Abstract. The differentiation of homologous chromosomes as well as their parental origin can presently be conducted and determined exclusively by molecular genetic methods using microsatellite or SNP analysis. Only in exceptional cases is a distinction on a single-cell level possible, e.g. due to variations within the heterochromatic regions of chromosomes 1, 9, 16 and Y or the p-arms of the acrocentric chromosomes. In the absence of such polymorphisms, an individual distinction of the homologous chromosomes is not currently possible. Consequently, various questions of scientific and diagnostic relevance are unable to be answered. Based on the recently detected large-scale copy-number variations (LCV) or copynumber polymorphisms (CNP) spanning up to several megabase pairs of DNA, in this study, a molecular cytogenetic technique for the inter-individual differentiation of homologous chromosomes called parental-origin-determination fluorescence in situ hybridization (pod-FISH) is presented. All human chromosomes were covered with 225 LCVand/or CNP-specific BAC probes, and one-to five-color chromosome-specific pod-FISH sets were created, evaluated and optimized. We demonstrated that pod-FISH is suitable for single-cell analysis of uniparental disomy (UDP) in clinical cases such as Prader-Willi syndrome caused by maternal UPD. A rare clinical case with a mosaic form of a genome-wide isodisomy was used to determine the detection limits of pod-FISH. Additionally we analyzed the informativeness of conventional microsatellite analysis for the first time and compared the results to pod-FISH. With this new possibility to study the parental origin of individual human chromosomes on a single-cell level, new doors for diagnostic and basic research are opened.
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 B-lymphoblastoid 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.
Directly transmitted unbalanced chromosomal abnormalities (UBCA) or euchromatic variants (EV) were recently reported for >50 euchromatic regions of almost all human autosomes. UBCA and EV are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on partial trisomies of chromosome 10 within the pericentromeric region which were detected by standard G banding. Those were referred for further delineation of the size of these duplicated regions for molecular cytogenetics and/or array-CGH. Partial trisomies of chromosome 10 in the pericentromeric region were identified prenatally in seven cases. A maximum of three copies of the region from 10p12.1 to 10q11.22 was observed in all cases without apparent clinical abnormalities. The imbalances were either caused by a direct duplication in one familial case or by de novo small supernumerary marker chromosomes (sSMC). Thus, we report a yet unrecognized chromosomal region subject to UBCA detected in seven unrelated cases. To the best of our knowledge, this is the first report of a UBCA in the pericentromeric region of chromosome 10 that is not correlated with any clinical consequences.
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