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Cited by 102Down syndrome and intellectual disability researchGenomic variations and chromosomal abnormalitiesGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of down Syndrome.

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Gribble, Susan M., Wiseman, Frances K., Clayton, Stephen, Prigmore, Elena, Langley, Elizabeth, Yang, Fengtang, Maguire, Sean, Fu, Beiyuan +14 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0060482PMC PMC3626651
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Abstract

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype--phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.

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  • The Tc1 model had roughly 50 non-functional protein coding genes on HSA21 and was subject to loss of the human chromosome over development, creating mosaic mice difficult to study.

    “However, due to its manner of creation, roughly 50 of the protein coding genes on HSA21 were non-functional and this model was found to be subject to loss of the human chromosome over development creating mosaic mice that were difficult to study (O’Doherty et al., 2005; Gribble et al., 2013).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Gribble et al., 2013

    The Discussion (Gene Expression and Copy Number; page unavailable) says 50 genes on Tc1-Hsa21 are deleted or disrupted and remain functionally disomic. The Introduction (page unavailable) says not all Tc1 cells carry the human transchromosome, supporting mosaicism. It does not establish that the chromosome is lost over development or that mosaicism makes the mice difficult to study; it also does not specify that all 50 genes are protein-coding. (LLM, conf=0.86)

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Authors
Gribble, S. M., Wiseman, F. K., Clayton, S., Prigmore, E., Langley, E., Yang, F., Maguire, S., Fu, B., Rajan, D., Sheppard, O., Scott, C., Hauser, H., Stephens, P. J., Stebbings, L. A., Ng, B. L., Fitzgerald, T., Quail, M. A., Banerjee, R., Rothkamm, K., Tybulewicz, V. L. J., Fisher, E. M. C., & Carter, N. P.
Affiliations
  • Wellcome Sanger Institute (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Health Protection Agency (GB)
  • National Institute for Medical Research (GB)
Corresponding author
Gribble, Susan M.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-04-15
Volume
8
Issue
4
Pages
e60482
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0060482
PMC
PMC3626651
OpenAlex
W2045046980
Cited by
102
References
1
Citations by year
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FWCI
11.25
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (U117527252, WT080174MA, 080174MA, WT 098051, 098327/Z/12/Z, 098051)
  • Medical Research Council (WT098051, U117527252)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
Down syndrome, chromosome 21, trisomy, gene dosage, structural rearrangement, de novo rearrangement, microcell-mediated chromosome transfer, gamma irradiation, radiation-induced DNA damage, genotype-phenotype correlation
MeSH terms
Animals, Chromosomes, Human, Chromosomes, Human, Pair 21, Disease Models, Animal, Down Syndrome, Gamma Rays, Humans, Male, Recombination, Genetic, Trisomy, In Situ Hybridization, Fluorescence, Gene Dosage, Oligonucleotide Array Sequence Analysis, Mice, Comparative Genomic Hybridization, High-Throughput Nucleotide Sequencing

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