Journal articles: 'Cellular mosaicism'

1

Hagerman, Randi J., and Paul J. Hagerman. "X Inactivation and Cellular Mosaicism." JAMA 296, no. 8 (August 23, 2006): 930. http://dx.doi.org/10.1001/jama.296.8.930-c.

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Sapienza, Carmen. "Genome imprinting, cellular mosaicism and carcinogenesis." Molecular Carcinogenesis 3, no. 3 (1990): 118–21. http://dx.doi.org/10.1002/mc.2940030303.

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Migeon, Barbara R. "X Inactivation and Cellular Mosaicism—Reply." JAMA 296, no. 8 (August 23, 2006): 930. http://dx.doi.org/10.1001/jama.296.8.931-a.

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Iourov, Ivan Y., Svetlana G. Vorsanova, Yuri B. Yurov, and Sergei I. Kutsev. "Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism." Genes 10, no. 5 (May 19, 2019): 379. http://dx.doi.org/10.3390/genes10050379.

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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.

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Hornig, Nadine C., Jeta Demiri, Pascal Rodens, Eva Maria Murga Penas, Almuth Caliebe, Anne Katrin Eckstein, Hans-Udo Schweikert, et al. "Reduced Androgen Receptor Expression in Genital Skin Fibroblasts From Patients With 45,X/46,XY Mosaicism." Journal of Clinical Endocrinology & Metabolism 104, no. 10 (June 10, 2019): 4630–38. http://dx.doi.org/10.1210/jc.2019-00108.

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Abstract Context Molecular mechanisms causing the broad phenotypic diversity of external masculinization in individuals with 45,X/46,XY mosaicism are poorly understood. Objective Analysis of androgen receptor (AR) expression and function as a putative influencing factor for the genital phenotype in patients with 45,X/46,XY mosaicism. Design Measurement of AR mRNA expression levels, AR activity [DHT-mediated APOD (apolipoprotein D) induction] and cellular 45,X/46,XY ratios in genital skin fibroblasts from individuals with 45,X/46,XY mosaicism and male reference individuals, and determination of the external virilization scale from individuals with 45,X/46,XY mosaicism. Setting University hospital endocrine research laboratory. Patients or Other Participants: 30 genital skin fibroblast cultures (GFs) from male reference individuals and 15 GFs from individuals with 45,X/46,XY mosaicism. Intervention None Main Outcome Measures Determination of AR mRNA expression and AR activity in male reference GFs and 45,X/46,XY GFs and correlation of the obtained data with the cellular 45,X/46,XY ratios and the patients’ external virilization scale. Results In 6 of 15 45,X/46,XY GFs, AR mRNA expression and AR activity were significantly lower compared with those in the 46,XY reference GFs. In this subgroup of reduced AR mRNA expression, a positive trend was seen between AR mRNA expression and the percentage of XY-positive cells. Furthermore, we found a positive correlation between AR activity and the external virilization scale in the 15 45,X/46,XY GF samples (P = 0.03). Conclusion Our results suggest that AR expression and AR activity might influence the phenotypic variability seen in patients with 45,X/46,XY mosaicism.

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Katsuda, Tadaaki. "Sub-GOFA: A tool for Sub-Gene Ontology function analysis in clonal mosaicism using semantic (logical) similarity." Bioinformation 18, no. 1 (January 31, 2022): 53–60. http://dx.doi.org/10.6026/97320630018053.

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Clonal mosaicism (a detectable post-zygotic mutational event in cellular subpopulations) is common in cancer patients. Detected segments of clonal mosaicism are usually bundled into large-locus regions for statistical analysis. However, low-frequency genes are overlooked and are not sufficient to elucidate qualitative differences between cancer patients and non-patients. Therefore, it is of interest to develop and describe a tool named Sub-GOFA for Sub-Gene Ontology function analysis in clonal mosaicism using semantic similarity. Sub-GOFA measures the semantic (logical) similarity among patients using the sub-GO network structures of various sizes segmented from the gene ontology (GO) for clustering analysis. The sub-GO’s root-terms with significant differences are extracted as disease-associated genetic functions. Sub-GOFA selected a high ratio of cancer-associated genes under validation with acceptable threshold.

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Lim, Young H., Jonathan M. Fisher, and Keith A. Choate. "Revertant mosaicism in genodermatoses." Cellular and Molecular Life Sciences 74, no. 12 (February 6, 2017): 2229–38. http://dx.doi.org/10.1007/s00018-017-2468-2.

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Meyer-Mueller, Cameron, Mark J. Osborn, Jakub Tolar, Christina Boull, and Christen L. Ebens. "Revertant Mosaicism in Epidermolysis Bullosa." Biomedicines 10, no. 1 (January 6, 2022): 114. http://dx.doi.org/10.3390/biomedicines10010114.

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Epidermolysis bullosa (EB) is a group of genetic blistering diseases characterized by mechanically fragile skin and mucocutaneous involvement. Historically, disease management has focused on supportive care. The development of new genetic, cellular, and recombinant protein therapies has shown promise, and this review summarizes a unique gene and cell therapy phenomenon termed revertant mosaicism (RM). RM is the spontaneous correction of a disease-causing mutation. It has been reported in most EB subtypes, some with relatively high frequency, and has been observed in both keratinocytes and fibroblasts. RM manifests as identifiable patches of unaffected, blister-resistant skin and can occur through a variety of molecular mechanisms, including true back mutation, intragenic crossover, mitotic gene conversion, and second-site mutation. RM cells represent a powerful autologous platform for therapy, and leveraging RM cells as a therapeutic substrate may avoid the inherent mutational risks of gene therapy/editing. However, further examination of the genomic integrity and long-term functionality of RM-derived cells, as well in vivo testing of systemic therapies with RM cells, is required to realize the full therapeutic promise of naturally occurring RM in EB.

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Giri, Neelam, Ken Matsui, Blanche P. Alter, Sharon A. Savage, Yuanji Pan, and Ligia Pinto. "Bone Marrow Cellular Composition and Inflammatory Cytokine Expression in Patients with Inherited Bone Marrow Failure Syndromes." Blood 120, no. 21 (November 16, 2012): 4401. http://dx.doi.org/10.1182/blood.v120.21.4401.4401.

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Abstract Abstract 4401 Proinflammatory cytokines, TNF-α and IFN-γ, are potent inhibitors of hematopoiesis, and may be relevant in the pathogenesis of bone marrow failure in inherited bone marrow failure syndromes (IBMFS). Increased levels of these cytokines in sera and in bone marrow CD3+ cells have been reported in Fanconi anemia (FA) patients. However, our study did not find increased TNF-α or IFN-γ in sera, or supernatants from phytohemagglutinin-stimulated peripheral blood mononuclear cells from IBMFS patients. To assess whether production of these cytokines is dysregulated in BM of these patients, we examined intracellular expression of TNF-α and IFN-γ in BM mononuclear cells from 16 FA, 20 dyskeratosis congenita (DC), 21 Diamond-Blackfan anemia (DBA) and 7 Shwachman-Diamond syndrome (SDS) patients by flow cytometry; 14 healthy adults were studied as controls. To detect intracellular TNF-α and IFN-γ, BM lymphocytes and monocytes were stimulated with phorbol 12-myristate 13-acetate plus ionomycin (P+I), or lipopolysaccharide (LPS), respectively. Separately, unstimulated cells were stained with antibodies to CD45, CD3, CD19, CD14, and CD34 to determine the proportion of cellular subsets. Percentages of T cells in patients with IBMFS were comparable to the controls, while DC patients had lower proportion of B cells (p=0.02). The percentages of monocytes were lower in FA (p=0.04), DC (p=0.009), and DBA (p<0.001) patients. The proportions of CD34+ cells were also lower in IBMFS patients (≤0.02 for all) except for those with DBA, who had similar proportions as the controls. When we compared the effect of cytopenia (counts below normal for age), only the proportion of CD34+ cells in DC patients was significantly affected. DC patients with cytopenia (n=15) had lower numbers of CD34+ cells (p=0.007) compared with those without (n=5). We also analyzed the effect of somatic mosaicism in FA because it may correct the hematopoietic defect in these patients. FA patients without mosaicism (n=11) had lower proportions of CD19+, CD14+, and CD34+ cells than those with mosaicism (n=5), while the CD3+ cell numbers were unaffected. We detected both intracellular TNF-α and IFN-γ in T cells, but only TNF-α in B cells in response to P+I, while LPS stimulation led to TNF-α production only in monocytes. Percentages of cytokine-producing T and B cells were significantly lower for patients with DBA when compared with healthy adult controls (p<0.006 for T cells and p=0.001 for B cells). There were no significant differences in the other syndromes. Comparison of intracellular cytokines between cytopenic and non-cytopenic patients showed that TNF-α-producing T cells were affected in FA (p=0.03), where the cytopenic patients had a higher proportion of TNF-α-positive T cells. For the LPS-stimulated monocytes, FA (p=0.01) and DBA (p=0.05) patients had significantly lower proportions of TNF-α-producing cells than the controls, and this was independent of cytopenia. There was no effect of mosaicism on cytokine production. Contrary to previous reports, we did not find an increase in intracellular TNF-α or IFN-γ in T cells from FA patients. However, the number of TNF-α-producing monocytes in FA was lower than that in healthy adult controls. This is consistent with reported dysregulation of monocytes in FA patients. We also identified reduced cytokine expression in lymphocytes and monocytes from DBA patients, but not from DC or SDS. As expected, we found reduced proportions of CD34+ cells in FA, DC and SDS, syndromes associated with multilineage cytopenia, and not in DBA which is associated with pure red cell aplasia. And, we ascertained that FA patients with somatic mosaicism had significantly higher percentages of cells including CD34+, suggesting that the corrected stem cell pool in FA mosaics is able to maintain hematopoiesis in contrast to non-mosaic FA patients who develop progressive cytopenia over time. Overall, the effect of cytopenia on cytokine production was mild; however, this may be related to the small sample size. In conclusion, our results suggest that mechanisms other than an excess of inflammatory cytokines may be responsible for bone marrow failure in IBMFS, and this area of research deserves a further attention in larger studies. Disclosures: No relevant conflicts of interest to declare.

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Kim, Han-Joon, and Beom S. Jeon. "Hypothesis: Somatic Mosaicism and Parkinson Disease." Experimental Neurobiology 23, no. 4 (December 31, 2014): 271–76. http://dx.doi.org/10.5607/en.2014.23.4.271.

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C, Perandones, Pellene LA, Giugni JC, Calvo DS, RainaGB, Cuevas SM, Mata IF, et al. "Hypothesis: Somatic Mosaicism and Parkinson Disease." Experimental Neurobiology 24, no. 2 (June 30, 2015): 173–75. http://dx.doi.org/10.5607/en.2015.24.2.173.

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Kothary, R. K., N. D. Allen, S. C. Barton, M. L. Norris, and M. A. H. Surani. "Factors affecting cellular mosaicism in the expression of a lacZ transgene in two-cell stage mouse embryos." Biochemistry and Cell Biology 70, no. 10-11 (October 1, 1992): 1097–104. http://dx.doi.org/10.1139/o92-155.

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In the present study, we have analysed the expression pattern of a lacZ transgene (CMZ12) in preimplantation stage mouse embryos. The transgene is expressed at the two-cell stage, where it shows cellular mosaicism due to variable expressivity. The variable gene expression indicates a partial penetrance of the transgene. The extent of variation in expression is influenced by the genetic background of the oocyte. DBA/2 and CFLP genetic backgrounds promote high expression of the transgene, while Balb/c, C57BL/6, DDK, and F1(C57BL/6 × CBA) genetic backgrounds give none or very little lacZ activity. In vitro culture of one-cell embryos to the two-cell stage induces the expression of lacZ in all strain backgrounds tested. The variation in CMZ12 expression is a transient phenomenon and does not affect later stage activity of the transgene. Nuclear transfer experiments and DNA methylation analysis suggests that a heritable modification of the transgene locus has not occurred.Key words: cellular mosaicism, lacZ transgene, mouse embryos, variable expressivity.

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Tolar, Jakub, Margaret L. MacMillan, Sat Dev Batish, Cindy Eide, Yeva Flit, Stella M. Davies, Bruce R. Blazar, Arleen D. Auerbach, and John E. Wagner. "High Incidence of Hematopoietic Stem Cell Mosaicism in Fanconi Anemia." Blood 108, no. 11 (November 16, 2006): 993. http://dx.doi.org/10.1182/blood.v108.11.993.993.

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Abstract Determination of the degree of somatic mosaicism providing functional correction of Fanconi anemia (FA) hematopoiesis has direct implications for gene therapy for FA: it may help assess the percentage of FA hematopoietic cells corrected by gene therapy approaches that are needed to achieve clinically meaningful effects. Hypersensitivity to DNA interstrand cross-linking agents, such as diepoxybutane (DEB) and mitomycin C (MMC), is a cellular marker for diagnosis of FA. However, in some FA patients a population of DEB-resistant PHA-stimulated lymphoblasts (PHA-L) was observed, and this population sometimes varied over time. To assess the significance of this finding on hematopoietic function, we evaluated the MMC sensitivity of bone marrow mononuclear cells (BMMC) and DEB sensitivity of PHA-L and cultured lymphoblastoid cell lines (LCL) in 42 consecutive FA patients referred to the University of Minnesota. In cases where LCL were DEB-resistant, cultured fibroblasts were also studied. BMMC were cultured in the presence of increasing concentrations of MMC. PHA-L and LCL were cultured in DEB at 0.1 mcg/ml. Wild type BM progenitors (N = 17 subjects) proliferated regardless of increasing MMC concentrations (albeit at decreased efficiency at the highest concentrations) as follows: 0 MMC (normalized to 100%), 5 nM MMC (99% [standard deviation, SD, 16%]), 10 nM MMC (90% [SD 22%]), 25 nM MMC (77% [SD21%]), and 50 nM MMC (44% [SD 30%]). Of the 42 FA patients, BMMC failed to proliferate at 0 nM MMC in 10 patients and at 5 nM MMC in 20 patients. Twelve FA patients had MMC resistant BMMC: cells cultured in 5, 10, 25 and 50 nM MMC grew 44% (SD 28%), 35% (SD 24%), 24% (SD 30%) and 17% (SD 32%) of colony numbers in MMC free culture, respectively. Six of these 12 subjects were PHA-L mosaics as determined by DEB sensitivity testing. Four patients with no growth of BMMC at 0 or 5 nM MMC were also somatic mosaics in their PHA-L and LCL. Thus there was no clear correlation between somatic mosaicism as demonstrated by DEB testing in peripheral blood and sensitivity of BMMC to growth in MMC. Clinically, two patients with hematopoietic somatic mosaicism developed severe marrow aplasia, one of which received hematopoietic stem cell transplantation. Four of the mosaic patients had normal or near normal peripheral blood counts with one patient having clonal hematopoiesis by HUMARA assay and only low levels of metaphases with multiple breaks in multiple DEB studies. While patients with hematopoietic somatic mosaicism had mixed populations of DEB sensitive cells in their peripheral blood, all their fibroblast cultures were DEB sensitive. In summary, these data show that the presence of somatic mosaicism per se does not necessarily prevent bone marrow failure. Moreover, the data suggest that patients with stigmata of FA may have chromosomal breakage studies showing few cells (or no cells) with the characteristic changes of FA; in these cases, skin fibroblasts should be tested as well.

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Priest, James Rush, Charles Gawad, Kristopher M. Kahlig, Joseph K. Yu, Thomas O’Hara, Patrick M. Boyle, Sridharan Rajamani, et al. "Early somatic mosaicism is a rare cause of long-QT syndrome." Proceedings of the National Academy of Sciences 113, no. 41 (September 28, 2016): 11555–60. http://dx.doi.org/10.1073/pnas.1607187113.

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Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

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Zaina, Silvio, Manel Esteller, Isabel Gonçalves, and Gertrud Lund. "Dynamic epigenetic age mosaicism in the human atherosclerotic artery." PLOS ONE 17, no. 6 (June 3, 2022): e0269501. http://dx.doi.org/10.1371/journal.pone.0269501.

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Accelerated epigenetic ageing, a promising marker of disease risk, has been detected in peripheral blood cells of atherosclerotic patients, but evidence in the vascular wall is lacking. Understanding the trends of epigenetic ageing in the atheroma may provide insights into mechanisms of atherogenesis or identify targets for molecular therapy. We surveyed DNA methylation age in two human artery samples: a set of donor-matched, paired atherosclerotic and healthy aortic portions, and a set of carotid artery atheromas. The well-characterized pan-tissue Horvath epigenetic clock was used, together with the Weidner whole-blood-specific clock as validation. For the first time, we document dynamic DNA methylation age mosaicism of the vascular wall that is atherosclerosis-related, switches from acceleration to deceleration with chronological ageing, and is consistent in human aorta and carotid atheroma. At CpG level, the Horvath epigenetic clock showed modest differential methylation between atherosclerotic and healthy aortic portions, weak association with atheroma histological grade and no clear evidence for participation in atherosclerosis-related cellular pathways. Our data suggest caution when assigning a unidirectional DNA methylation age change to the atherosclerotic arterial wall. Also, the results support previous conclusions that epigenetic ageing reflects non-disease-specific cellular alterations.

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D’Gama, Alissa M. "Somatic Mosaicism and Autism Spectrum Disorder." Genes 12, no. 11 (October 26, 2021): 1699. http://dx.doi.org/10.3390/genes12111699.

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Autism spectrum disorder (ASD) is a genetically heterogenous neurodevelopmental disorder. In the early years of next-generation sequencing, de novo germline variants were shown to contribute to ASD risk. These germline mutations are present in all of the cells of an affected individual and can be detected in any tissue, including clinically accessible DNA sources such as blood or saliva. In recent years, studies have also implicated de novo somatic variants in ASD risk. These somatic mutations arise postzygotically and are present in only a subset of the cells of an affected individual. Depending on the developmental time and progenitor cell in which a somatic mutation occurs, it may be detectable in some tissues and not in others. Somatic mutations detectable at relatively low sequencing coverage in clinically accessible tissues are suggested to contribute to 3–5% of simplex ASD diagnoses, and “brain limited” somatic mutations have been identified in postmortem ASD brain tissue. Somatic mutations likely represent the genetic diagnosis in a proportion of otherwise unexplained individuals with ASD, and brain limited somatic mutations can be used as markers to discover risk genes, cell types, brain regions, and cellular pathways important for ASD pathogenesis and to potentially target for therapeutics.

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CASE, MICHAEL A., and HUGH R. MACMILLAN. "ON SIMULATING THE GENERATION OF MOSAICISM DURING MAMMALIAN CEREBRAL CORTICAL DEVELOPMENT." Journal of Biological Systems 17, no. 01 (March 2009): 27–62. http://dx.doi.org/10.1142/s0218339009002740.

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Renewed calls for a systems biology reflect the hope hat enduring biological questions at single-cell and cell-population scales will be resolved as modern molecular biology, with its reductionist program, approaches a nearly-complete characterization of the molecular mechanisms of specific cellular processes. Due to the confounding complexity of biological organization across these scales, computational science is sought to complement the intuition of experimentalists. However, with respect to the molecular basis of cellular processes during development and disease, a gulf between feasible simulations and realistic biology persists. Formidable are the mathematical and computational challenges to conducting and validating cell population-scale simulations, drawn from single-cell level and molecular level details. Nonetheless, in some biological contexts, a focus on core processes crafted by evolution can yield coarse-grained mathematical models that retain explanatory potential despite drastic simplification of known biochemical kinetics. In this article, we bring this modeling philosophy to bear on the nature of neural progenitor cell decision making during mammalian cerebral cortical development. Specifically, we present the computational component to a research program addressing developmental links between (i) the cellular response to endogenous DNA damage, (ii) primary mechanisms of neuronal genetic heterogeneity, or mosaicism, and (iii) the cell fate decision making that defines the population kinetics of neurogenesis.

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Rohrback, Suzanne, Benjamin Siddoway, Christine S. Liu, and Jerold Chun. "Genomic mosaicism in the developing and adult brain." Developmental Neurobiology 78, no. 11 (August 1, 2018): 1026–48. http://dx.doi.org/10.1002/dneu.22626.

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McGowan, R., R. Campbell, A. Peterson, and C. Sapienza. "Cellular mosaicism in the methylation and expression of hemizygous loci in the mouse." Genes & Development 3, no. 11 (November 1, 1989): 1669–76. http://dx.doi.org/10.1101/gad.3.11.1669.

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Vázquez-Diez, Cayetana, and Greg FitzHarris. "Causes and consequences of chromosome segregation error in preimplantation embryos." Reproduction 155, no. 1 (January 2018): R63—R76. http://dx.doi.org/10.1530/rep-17-0569.

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Errors in chromosome segregation are common during the mitotic divisions of preimplantation development in mammalian embryos, giving rise to so-called ‘mosaic’ embryos possessing a mixture of euploid and aneuploid cells. Mosaicism is widely considered to be detrimental to embryo quality and is frequently used as criteria to select embryos for transfer in human fertility clinics. However, despite the clear clinical importance, the underlying defects in cell division that result in mosaic aneuploidy remain elusive. In this review, we summarise recent findings from clinical and animal model studies that provide new insights into the fundamental mechanisms of chromosome segregation in the highly unusual cellular environment of early preimplantation development and consider recent clues as to why errors should commonly occur in this setting. We furthermore discuss recent evidence suggesting that mosaicism is not an irrevocable barrier to a healthy pregnancy. Understanding the causes and biological impacts of mosaic aneuploidy will be pivotal in the development and fine-tuning of clinical embryo selection methods.

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O’Neill, Audrey K., Abigail A. Kindberg, Terren K. Niethamer, Andrew R. Larson, Hsin-Yi Henry Ho, Michael E. Greenberg, and Jeffrey O. Bush. "Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation." Journal of Cell Biology 215, no. 2 (October 17, 2016): 217–29. http://dx.doi.org/10.1083/jcb.201604097.

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Cell segregation is the process by which cells self-organize to establish developmental boundaries, an essential step in tissue formation. Cell segregation is a common outcome of Eph/ephrin signaling, but the mechanisms remain unclear. In craniofrontonasal syndrome, X-linked mosaicism for ephrin-B1 expression has been hypothesized to lead to aberrant Eph/ephrin-mediated cell segregation. Here, we use mouse genetics to exploit mosaicism to study cell segregation in the mammalian embryo and integrate live-cell imaging to examine the underlying cellular and molecular mechanisms. Our data demonstrate that dramatic ephrin-B1–mediated cell segregation occurs in the early neuroepithelium. In contrast to the paradigm that repulsive bidirectional signaling drives cell segregation, unidirectional EphB kinase signaling leads to cell sorting by the Rho kinase–dependent generation of a cortical actin differential between ephrin-B1– and EphB-expressing cells. These results define mechanisms of Eph/ephrin-mediated cell segregation, implicating unidirectional regulation of cortical actomyosin contractility as a key effector of this fundamental process.

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Pyo Park, Sung, In Hwan Hong, Stephen H. Tsang, and Stanley Chang. "Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene." European Journal of Human Genetics 21, no. 11 (February 27, 2013): 1240–48. http://dx.doi.org/10.1038/ejhg.2013.21.

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Koetsier, Paul A., Laurence Mangel, Birgit Schmitz, and Walter Doerfler. "Stability of transgene methylation patterns in mice: Position effects, strain specificity and cellular mosaicism." Transgenic Research 5, no. 4 (July 1996): 235–44. http://dx.doi.org/10.1007/bf01972877.

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Youness, Ali, Charles-Henry Miquel, and Jean-Charles Guéry. "Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases." International Journal of Molecular Sciences 22, no. 3 (January 23, 2021): 1114. http://dx.doi.org/10.3390/ijms22031114.

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Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

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KATOH, KAZUTO, MINESUKE YOKOYAMA, SHIARI KIMURA, YUKIO HIRAMOTO, and HISATO KONDOH. "Analysis of Cellular Mosaicism in a Transgenic Mouse by Histological In Situ Hybridization. (Transgenic mice/mosaics/cell lineage/in situ hybridization)." Development, Growth and Differentiation 30, no. 6 (December 1988): 639–49. http://dx.doi.org/10.1111/j.1440-169x.1988.00639.x.

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Stark, D. J., D. W. Gilmore, J. C. Vance, and J. H. Pearn. "A corneal abnormality associated with trisomy 8 mosaicism syndrome." British Journal of Ophthalmology 71, no. 1 (January 1, 1987): 29–31. http://dx.doi.org/10.1136/bjo.71.1.29.

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Joseph, J. T., M. Upton, C. S. Richards, and D. C. Anthony. "CONGENITAL MYOTONIC DYSTROPHY PATHOLOGY AND SOMATIC MOSAICISM." Journal of Neuropathology and Experimental Neurology 55, no. 5 (May 1996): 668. http://dx.doi.org/10.1097/00005072-199605000-00259.

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Prasad-Sinha, Jayashree, and A. S. Mukherjee. "Cellular autonomy of hyperactivity in segmental X chromosomal aneuploids of Drosophila and dosage compensation." Genetical Research 46, no. 1 (August 1985): 19–29. http://dx.doi.org/10.1017/s0016672300022424.

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SUMMARYTranscription in 9A–11A aneuploid mosaic female larvae of Drosophila melanogaster has been assessed autoradiographically. Eleven larvae were found to exhibit mosaicism out of sixty-six larvae scanned and the percentage of XO and XX nuclei varied from approximately 9 to 100. Irrespective of the number of XX nuclei present the XO nuclei (duplicated for 9A–11A) invariably showed hyperactivity for both the segments. The XX nucleus exhibited a dosage effect for all the three segments of 9A–11A. Results support the transcriptional constancy of the entire X chromosome, as proposed by Maroni and Lucchesi. Cellular autonomy of hyperactivity of the single X chromosome even at the level of segments of the X is thus evident from the present results.

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Tesi, Bianca, Josef Davidsson, Matthias Voss, Timothy Holmes, Tim Ripperger, Samuel Chiang, Lars Nilsson, et al. "Cytopenia, Predisposition to Myelodysplastic Syndrome, Immunodeficiency, and Neurological Disease Caused By Gain-of-Function SAMD9L Mutations Is Frequently Ameliorated By Hematopoietic Revertant Mosaicism." Blood 128, no. 22 (December 2, 2016): 4299. http://dx.doi.org/10.1182/blood.v128.22.4299.4299.

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Abstract Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic diseases characterized by impaired hematopoiesis and progression to acute myeloid leukemia (AML). Although rare, several monogenic causes of familial MDS/AML have recently been molecularly defined. We studied two families with variable manifestation of cytopenia, MDS with cytogenetic aberrations involving chromosome 7, immunodeficiency, and neurologic disease consistent with ataxia-pancytopenia syndrome. Genetic studies uncovered heterozygous missense variants (p.Arg986Cys and p.Ile891Thr) in SAMD9L, a tumor suppressor gene located on chromosome 7. Consistent with a gain-of-function effect, transfection and over-expression of both SAMD9L variants decreased cell proliferation relative to wild-type protein. In the two families, a total of 10 individuals heterozygous for either SAMD9L mutation were identified. Three individuals developed MDS, with monosomy 7 or der(1;7)(q10;p10) as cytogenetic aberrations that encompassed the mutant SAMD9L locus. In an additional five individuals, three of which experienced a spontaneously resolved cytopenic episodes in infancy, we detected mosaic copy-neutral loss of heterozygosity of 7q by uniparental disomy, with loss of the mutated allele, or mosaic cis SAMD9L mutations. By digital PCR, we identified these events in hematopoietic progenitor cell populations, which were further enriched in B and NK cell lineages. Absent in non hematological tissues, these mutations thus represented somatic revertant mosaicism. Clinically, revertant mosaicism was associated with reduced disease severity, although in two individuals neurological manifestations persisted. Of note, two unaffected carriers without revertant mosaicism harbored an additional rare in trans germline SAMD9L p.Thr233Asn missense variant. In cellular assays, the SAMD9L p.Thr233Asn variant increased proliferation, indicating a loss-of-function effect that potentially compensates for the SAMD9L p.Arg986Cys mutation. Together, our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause a disease with cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with chromosome 7 aberrations, where hematopoietic revertant mosaicism is common and ameliorates the clinical presentation. Disclosures Fioretos: Cantargia: Equity Ownership.

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Migeon, Barbara R. "The Role of X Inactivation and Cellular Mosaicism in Women's Health and Sex-Specific Diseases." JAMA 295, no. 12 (March 22, 2006): 1428. http://dx.doi.org/10.1001/jama.295.12.1428.

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Cherfan, Carole G., Thomas P. Link, Dusica Babovic-Vuksanovic, Jay W. Ellison, and Michael C. Brodsky. "Retinal mosaicism in a girl with an X–Y translocation." British Journal of Ophthalmology 97, no. 2 (November 2, 2012): 243. http://dx.doi.org/10.1136/bjophthalmol-2012-301738.

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Bouba, Ioanna, Elissavet Hatzi, Paris Ladias, Prodromos Sakaloglou, Charilaos Kostoulas, and Ioannis Georgiou. "Biological and Clinical Significance of Mosaicism in Human Preimplantation Embryos." Journal of Developmental Biology 9, no. 2 (May 7, 2021): 18. http://dx.doi.org/10.3390/jdb9020018.

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Applications and indications of assisted reproduction technology are expanding, but every new approach is under scrutiny and thorough consideration. Recently, groups of assisted reproduction experts have presented data that support the clinical use of mosaic preimplantation embryos at the blastocyst stage, previously excluded from transfer. In the light of published contemporary studies, with or without clinical outcomes, there is growing evidence that mosaic embryos have the capacity for further in utero development and live birth. Our in-depth discussion will enable readers to better comprehend current developments. This expansion into the spectrum of ART practices requires further evidence and further theoretical documentation, basic research, and ethical support. Therefore, if strict criteria for selecting competent mosaic preimplantation embryos for further transfer, implantation, fetal growth, and healthy birth are applied, fewer embryos will be excluded, and more live births will be achieved. Our review aims to discuss the recent literature on the transfer of mosaic preimplantation embryos. It also highlights controversies as far as the clinical utilization of preimplantation embryos concerns. Finally, it provides the appropriate background to elucidate and highlight cellular and genetic aspects of this novel direction.

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Lareau, Caleb A., Leif S. Ludwig, and Vijay G. Sankaran. "Longitudinal assessment of clonal mosaicism in human hematopoiesis via mitochondrial mutation tracking." Blood Advances 3, no. 24 (December 16, 2019): 4161–65. http://dx.doi.org/10.1182/bloodadvances.2019001196.

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Abstract Our ability to track cellular dynamics in humans over time in vivo has been limited. Here, we demonstrate how somatic mutations in mitochondrial DNA (mtDNA) can be used to longitudinally track the dynamic output of hematopoietic stem and progenitor cells in humans. Over the course of 3 years of blood sampling in a single individual, our analyses reveal somatic mtDNA sequence variation and evolution reminiscent of models of hematopoiesis established by genetic labeling approaches. Furthermore, we observe fluctuations in mutation heteroplasmy, coinciding with specific clinical events, such as infections, and further identify lineage-specific somatic mtDNA mutations in longitudinally sampled circulating blood cell subsets in individuals with leukemia. Collectively, these observations indicate the significant potential of using tracking of somatic mtDNA sequence variation as a broadly applicable approach to systematically assess hematopoietic clonal dynamics in human health and disease.

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Carrette, Lieselot L. G., Roy Blum, Weiyuan Ma, Raymond J. Kelleher, and Jeannie T. Lee. "Tsix–Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function." Proceedings of the National Academy of Sciences 115, no. 32 (July 23, 2018): 8185–90. http://dx.doi.org/10.1073/pnas.1800931115.

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Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2+/− heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix–Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix–Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5–10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.

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Ciosi, Marc, Sarah A. Cumming, Afroditi Chatzi, Eloise Larson, William Tottey, Vilija Lomeikaite, Graham Hamilton, et al. "Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation." Journal of Huntington's Disease 10, no. 1 (February 9, 2021): 53–74. http://dx.doi.org/10.3233/jhd-200433.

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Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.

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Reddy, A. Lakshma, and Philip J. Fialkow. "Influence of dose of initiator on two-stage skin carcinogenesis in BALB/c mice with cellular mosaicism." Carcinogenesis 9, no. 5 (1988): 751–54. http://dx.doi.org/10.1093/carcin/9.5.751.

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Hunt, Camille K., Ahmad Al Khleifat, Ella Burchill, Joerg Ederle, Ammar Al-Chalabi, and Jemeen Sreedharan. "Does genetic anticipation occur in familial Alexander disease?" neurogenetics 22, no. 3 (May 28, 2021): 215–19. http://dx.doi.org/10.1007/s10048-021-00642-9.

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AbstractAlexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent–offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.

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Никитина, Т. В., А. А. Кашеварова, М. М. Гридина, А. А. Хабарова, А. Г. Мензоров, Ю. С. Яковлева, С. А. Васильев, et al. "Modeling of dynamic mosaicism on ring chromosomes in human fibroblasts and IPSCS." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 3() (March 30, 2020): 12–13. http://dx.doi.org/10.25557/2073-7998.2020.03.12-13.

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Митотическая нестабильность кольцевых хромосом может приводить к появлению клеточных клонов с различной генетической структурой. В качестве модели нестабильности кольцевых хромосом в митозе мы использовали фибробласты от пациентов с r(8), r(13), r(18) и r(22) и полученные из них индуцированные плюрипотентные стволовые клетки (ИПСК). Линии ИПСК с r(22) имели относительно стабильный кариотип на протяжении десятков (до 60) пассажей и сохраняли неизменную структуру кольцевой хромосомы. Кариотип линий ИПСК с r(8) и r(18) на ранних пассажах стабильный, планируется его изучение на поздних пассажах. Наибольшее разнообразие кариотипа выявлено в линиях ИПСК с r(13), в которых наблюдали различные перестройки и выраженную клеточную гетерогенность. Определение факторов, влияющих на митотическую стабильность кольцевых хромосом, может иметь значение для консультирования пациентов. Mitotic instability of ring chromosomes can lead to the appearance of cell clones with different genetic structure. IPSCs from fibroblasts of patients with r(8), r(13), r(18), and r(22) were used as a model of ring chromosomes mitotic behavior. Karyotypes of iPSC lines with r(8) and r(18) have so far been evaluated only in the early passages, lines with r(22) have maintained a relatively stable karyotype up to 60 passages. The occurrence of rearrangements and cellular heterogeneity was found characteristic for r(13) iPSCs. The determination of factors affecting the ring chromosomes mitotic stability would be beneficial for the patient’s prognosis.

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Prior, T. W., A. C. Papp, P. J. Snyder, and J. R. Mendell. "Case of the month: Germline mosaicism in carriers of duchenne muscular dystrophy." Muscle & Nerve 15, no. 8 (August 1992): 960–63. http://dx.doi.org/10.1002/mus.880150815.

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Arin, Meral J., Mary Ann Longley, Xiao-Jing Wang, and Dennis R. Roop. "Focal Activation of a Mutant Allele Defines the Role of Stem Cells in Mosaic Skin Disorders." Journal of Cell Biology 152, no. 3 (February 5, 2001): 645–50. http://dx.doi.org/10.1083/jcb.152.3.645.

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Stem cells are crucial for the formation and maintenance of tissues and organs. The role of stem cells in the pathogenesis of mosaic skin disorders remains unclear. To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase. Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

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Kuijk, Ewart, Francis Blokzijl, Myrthe Jager, Nicolle Besselink, Sander Boymans, Susana M. Chuva de Sousa Lopes, Ruben van Boxtel, and Edwin Cuppen. "Early divergence of mutational processes in human fetal tissues." Science Advances 5, no. 5 (May 2019): eaaw1271. http://dx.doi.org/10.1126/sciadv.aaw1271.

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A developing human fetus needs to balance rapid cellular expansion with maintaining genomic stability. Here, we accurately quantified and characterized somatic mutation accumulation in fetal tissues by analyzing individual stem cells from human fetal liver and intestine. Fetal mutation rates were about fivefold higher than in tissue-matched adult stem cells. The mutational landscape of fetal intestinal stem cells resembled that of adult intestinal stem cells, while the mutation spectrum of fetal liver stem cells is distinct from stem cells of the fetal intestine and the adult liver. Our analyses indicate that variation in mutational mechanisms, including oxidative stress and spontaneous deamination of methylated cytosines, contributes to the observed divergence in mutation accumulation patterns and drives genetic mosaicism in humans.

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Abkowitz, J. L., R. L. Ott, J. M. Nakamura, L. Steinmann, P. J. Fialkow, and J. W. Adamson. "Feline glucose-6-phosphate dehydrogenase cellular mosaicism. Application to the study of retrovirus-induced pure red cell aplasia." Journal of Clinical Investigation 75, no. 1 (January 1, 1985): 133–40. http://dx.doi.org/10.1172/jci111665.

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Ribeiro, Mayara C., and Jessica L. MacDonald. "Sex differences in Mecp2-mutant Rett syndrome model mice and the impact of cellular mosaicism in phenotype development." Brain Research 1729 (February 2020): 146644. http://dx.doi.org/10.1016/j.brainres.2019.146644.

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Chandra, Rachna, Stephanie Federici, Zoltán H. Németh, Balázs Csóka, James A. Thomas, Robert Donnelly, and Zoltán Spolarics. "Cellular mosaicism for X-linked polymorphisms and IRAK1 expression presents a distinct phenotype and improves survival following sepsis." Journal of Leukocyte Biology 95, no. 3 (November 5, 2013): 497–507. http://dx.doi.org/10.1189/jlb.0713397.

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Bonifazi, Emanuela, Francesca Gullotta, Laura Vallo, Raniero Iraci, Anna Maria Nardone, Ercole Brunetti, Annalisa Botta, and Giuseppe Novelli. "Use of RNA Fluorescence In Situ Hybridization in the Prenatal Molecular Diagnosis of Myotonic Dystrophy Type I." Clinical Chemistry 52, no. 2 (February 1, 2006): 319–22. http://dx.doi.org/10.1373/clinchem.2005.056283.

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Abstract Background: Myotonic dystrophy type 1 (DM1; OMIM #160900) is an autosomal-dominant genetic disorder with multisystemic clinical features associated with a CTG expansion in the 3′ untranslated region of the DMPK gene on chromosome 19q13.3. A long-PCR protocol to detect the DM1 expansion is rapid, sensitive, and accurate, but interpretative limitations can occur when the expansion size exceeds the PCR amplification range and in cases of somatic mosaicism. Methods: To overcome these problems, we used RNA fluorescence in situ hybridization (RNA-FISH) to study cultured cells derived from chorionic villus samples (CVS) with the DM1 mutation. The RNA-FISH method is designed to detect the distinctive DM1 cellular phenotype, characterized by the presence of nuclei with focal ribonuclear inclusions (foci) containing the DMPK expanded transcripts. We analyzed 6 CVS from DM1-predicted pregnancies and 6 CVS from DM1-negative pregnancies. Results: In 4 DM1-predicted fetuses with a CTG expansion >200 CTG, varying numbers of ribonuclear inclusions were clearly visible in all cells. One case with a somatic mosaicism for the DMPK mutation showed 15% of cells with no nuclear foci. No nuclear signals were detected in all controls examined (n = 6) and in 1 DM1-positive sample with a CTG expansion <100 copies. Conclusion: Nuclear foci, and therefore the DM1 mutation they are caused by, can be detected efficiently on interphase nuclei of trophoblast cells with RNA-FISH when the CTG expansion is >200 copies.

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Tadros, Saber, Aleksei Kondrashov, Sriya Namagiri, Ashis Chowdhury, Yeshavanth Kumar Banasavadi-Siddegowda, and Abhik Ray-Chaudhury. "Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review." Neurosurgery 89, no. 3 (March 8, 2021): 343–63. http://dx.doi.org/10.1093/neuros/nyab019.

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Abstract Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.

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Sapienza, Carmen. "Sex-linked dosage-sensitive modifiers as imprinting genes." Development 108, Supplement (April 1, 1990): 107–13. http://dx.doi.org/10.1242/dev.108.supplement.107.

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It is proposed that differential genome imprinting is the result of dosage-sensitive modifier genes located on the sex chromosomes. Parallels between variegating position-effects in Drosophila, the phenotype elicited by transgenes in the mouse and data from several pediatric tumors indicate that the net result of the activity of such modifier genes is often cellular mosaicism in the expression of affected alleles. The mechanism by which inactivation of affected alleles is achieved is proposed to be through the formation of heterochromatic domains. Because the relevant sex-linked modifying loci are dosage sensitive in their activity, differential imprinting will occur even within homogeneous genetic backgrounds. The presence of allelic variants at these loci in non-inbred populations will give rise to variation in the observed expressivity and mode of inheritance of affected traits.

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Terzic, Barbara, Yue Cui, Andrew C. Edmondson, Sheng Tang, Nicolas Sarmiento, Daria Zaitseva, Eric D. Marsh, Douglas A. Coulter, and Zhaolan Zhou. "X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder." Neurobiology of Disease 148 (January 2021): 105176. http://dx.doi.org/10.1016/j.nbd.2020.105176.

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Haginoya, K., S. Miyabayashi, K. Iinuma, and K. Tada. "Mosaicism of mitochondria in mitochondrial myopathy: an electronmicroscopic analysis of cytochrome c oxidase." Acta Neuropathologica 80, no. 6 (October 1990): 642–48. http://dx.doi.org/10.1007/bf00307633.

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Oostra, Anneke B., Aggie W. M. Nieuwint, Hans Joenje, and Johan P. de Winter. "Diagnosis of Fanconi Anemia: Chromosomal Breakage Analysis." Anemia 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/238731.

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Fanconi anemia (FA) is a rare inherited syndrome with diverse clinical symptoms including developmental defects, short stature, bone marrow failure, and a high risk of malignancies. Fifteen genetic subtypes have been distinguished so far. The mode of inheritance for all subtypes is autosomal recessive, except for FA-B, which is X-linked. Cells derived from FA patients are—by definition—hypersensitive to DNA cross-linking agents, such as mitomycin C, diepoxybutane, or cisplatinum, which becomes manifest as excessive growth inhibition, cell cycle arrest, and chromosomal breakage upon cellular exposure to these drugs. Here we provide a detailed laboratory protocol for the accurate assessment of the FA diagnosis as based on mitomycin C-induced chromosomal breakage analysis in whole-blood cultures. The method also enables a quantitative estimate of the degree of mosaicism in the lymphocyte compartment of the patient.

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Journal articles on the topic 'Cellular mosaicism'

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