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Somatic Mosaicism for Chromosome X and Y Aneuploidies in Monozygotic Twins Heterozygous for Sickle Cell Disease Mutation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2010 (English)In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 152A, no 10, 2595-2598 p.Article in journal (Refereed) Published
Abstract [en]

Somatic genetic variation in health and disease is poorly explored. Monozygotic (MZ) twins are a suitable model for studies of somatic mosaicism since genetic differences in twins derived from the same zygote represent an irrefutable example of somatic variation. We report the analysis of a pair of generally healthy female MZ twins, discordant for somatic mosaicism for aneuploidy of chromosomes X and Y. Both twins are heterozygous carriers of sickle cell disease mutation. Genotyping of blood DNA from both twins using Illumina Human 610 SNP array revealed a copy number imbalance for chromosome X in a proportion of cells in one twin. Fluorescent in situ hybridization (FISH) analysis confirmed monosomy X (45,X) in 7% of proband nucleated blood cells. Unexpectedly, FISH analysis of cells from the other twin revealed 45,X and 46,XY lineages, both present in 1% of cells. The mechanism behind formation of these aneuploidies suggests several aberrant chromosome segregation events in meiosis and mitoses following conception. Our report contributes to the delineation of the frequency of somatic structural genomic variation in normal MZ twins. These results also illustrate the plasticity of the human genome for tolerating large copy number changes in healthy subjects and show the sensitivity of the Illumina platform for detection of aberrations that are present in a minority of the studied cells.

Place, publisher, year, edition, pages
2010. Vol. 152A, no 10, 2595-2598 p.
Keyword [en]
somatic mosaicism, genetic variation, copy number variation, monozygotic twins, chromosome X, chromosome Y, Ullrich-Turner syndrome, aneuploidy, sickle cell trait
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-133838DOI: 10.1002/ajmg.a.33604ISI: 000283103700023OAI: oai:DiVA.org:uu-133838DiVA: diva2:370991
Available from: 2010-11-18 Created: 2010-11-16 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Post-zygotic Genetic Variation in Health and Disease
Open this publication in new window or tab >>Post-zygotic Genetic Variation in Health and Disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Post-zygotic genetic variation has previously been shown in healthy individuals and linked to various disorders. The definition of post-zygotic or somatic variation is the existence of genetically distinct populations of cells in a subject derived from a single zygote. Structural changes in the human genome are a major type of inter-individual genetic variation and copy number variation (CNV), involving changes in the copy number of genes, are one of the best studied category of structural genetic changes. In paper I we reported a pair of healthy female monozygotic (MZ) twins discordant for aneuploidy of chromosomes X and Y, contributing to the delineation of the frequency of somatic variation in MZ twins. It also illustrates the plasticity of the genome for tolerating large aberrations in healthy subjects. In paper II we showed age-related accumulation of copy number variation in the nuclear genomes in vivo for both megabase- and kilobase-range variants. Using age-stratified MZ twins and single-born subjects, we detected megabase-range aberrations in 3.4% of people ≥60 years old but not in individuals younger than 55 years. Moreover, the longitudinal analysis of subjects with aberrations suggests that the aberrant cell clones are not immortalized and disappear from circulation. We also showed that sorted blood cells display different genomic profiles.  The detected recurrent rearrangements are candidates for common age-related defects in blood cells. This work might help to describe the cause of an age-related decline in the number of cell clones in the blood, which is one of the hallmarks of immunosenescence. In paper III we described a variable number tandem repeat (VNTR) ~4 kb upstream of the IFNAR1 gene, which was somatically variable.  We detected 14 alleles displaying inter- and intra-individual variation. Further analyses indicated strong clustering of transcription factor binding sites within this region, suggesting an enhancer. This putative VNTR-based enhancer might influence the transcriptional regulation of neighboring cytokine receptor genes and the pathways they are involved in.

These three studies stress the importance of research on post-zygotic variation in genetics. Furthermore, they emphasize that biobanks should consider sampling of multiple tissues to better address this issue in the genetic studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 873
Keyword
Post-zygotic genetic variation, monozygotic twins, copy number variation, single nucleotide polymorphism, variable number tandem repeat
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-196217 (URN)978-91-554-8614-3 (ISBN)
Public defence
2013-04-23, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2013-04-02 Created: 2013-03-05 Last updated: 2013-12-05Bibliographically approved

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